Selenium effectively inhibits ROS-mediated apoptotic neural precursor cell death in vitro and in vivo in traumatic brain injury

AbstractThis study was designed to investigate possible prevention of apoptotic cell death by selenium, an antioxidant, using cultured brain-derived neural progenitor cells (NPCs) and an experimental mouse brain trauma (BT) model. We tested some of the neuroprotective effects of sodium selenite in NPC cells by monitoring thioredoxin reductase (TR) expression, optimum H2O2 removal, and consequent inhibition of pro-apoptotic events including cytochrome c release and caspase 3 and 9 activation. Analysis of key apoptotic regulators during H2O2-induced apoptosis of NPCs showed that selenite blocks the activation of c-jun N-terminal protein kinase (JNK)/P38 mitogen-activated protein kinase (MAPK), and Akt survival protein. Moreover, selenite activates p44/42 MAPK and inhibits the downregulation of Bcl2 in selenite-treated NPC cells. For in vivo experiments, the effects of selenite on H2O2 neurotoxicity were tested using several biochemical and morphologic markers. Here we show that selenite potentially inhibits H2O2-induced apoptosis of NPCs and in traumatic brain injury. This in vivo protective function was also associated with inhibition of H2O2-induced reactive oxygen species (ROS) generation, cytochrome c release and caspase 3 and 9 activation. Our data show that the protective function of selenite through attenuation of secondary pathological events most likely results from its comprehensive effects that block apoptotic cell death, resulting in the maintenance of functional neurons and in inhibition of astrogliosis. The finding that selenite administration prevents secondary pathological events in an animal model of traumatic brain injury, as well as its efficacy, may provide novel drug targets for treating brain trauma

Trends in Tissue Engineering for Blood Vessels

Over the years, cardiovascular diseases continue to increase and affect not only human health but also the economic stability worldwide. The advancement in tissue engineering is contributing a lot in dealing with this immediate need of alleviating human health. Blood vessel diseases are considered as major cardiovascular health problems. Although blood vessel transplantation is the most convenient treatment, it has been delimited due to scarcity of donors and the patient’s conditions. However, tissue-engineered blood vessels are promising alternatives as mode of treatment for blood vessel defects. The purpose of this paper is to show the importance of the advancement on biofabrication technology for treatment of soft tissue defects particularly for vascular tissues. This will also provide an overview and update on the current status of tissue reconstruction especially from autologous stem cells, scaffolds, and scaffold-free cellular transplantable constructs. The discussion of this paper will be focused on the historical view of cardiovascular tissue engineering and stem cell biology. The representative studies featured in this paper are limited within the last decade in order to trace the trend and evolution of techniques for blood vessel tissue engineering

Peroxiredoxin 3 deficiency induces cardiac hypertrophy and dysfunction by impaired mitochondrial quality control

Mitochondrial quality control (MQC) consists of multiple processes: the prevention of mitochondrial oxidative damage, the elimination of damaged mitochondria via mitophagy and mitochondrial fusion and fission. Several studies proved that MQC impairment causes a plethora of pathological conditions including cardiovascular diseases. However, the precise molecular mechanism by which MQC reverses mitochondrial dysfunction, especially in the heart, is unclear. The mitochondria-specific peroxidase Peroxiredoxin 3 (Prdx3) plays a protective role against mitochondrial dysfunction by removing mitochondrial reactive oxygen species. Therefore, we investigated whether Prdx3-deficiency directly leads to heart failure via mitochondrial dysfunction. Fifty-two-week-old Prdx3-deficient mice exhibited cardiac hypertrophy and dysfunction with giant and damaged mitochondria. Mitophagy was markedly suppressed in the hearts of Prdx3-deficient mice compared to the findings in wild-type and Pink1-deficient mice despite the increased mitochondrial damage induced by Prdx3 deficiency. Under conditions inducing mitophagy, we identified that the damaged mitochondrial accumulation of PINK1 was completely inhibited by the ablation of Prdx3. We propose that Prdx3 interacts with the N-terminus of PINK1, thereby protecting PINK1 from proteolytic cleavage in damaged mitochondria undergoing mitophagy. Our results provide evidence of a direct association between MQC dysfunction and cardiac function. The dual function of Prdx3 in mitophagy regulation and mitochondrial oxidative stress elimination further clarifies the mechanism of MQC in vivo and thereby provides new insights into developing a therapeutic strategy for mitochondria-related cardiovascular diseases such as heart failure. © 20221

Cytoplasmic Extracts from Adipose Tissue Stromal Cells Alleviates Secondary Damage by Modulating Apoptosis and Promotes Functional Recovery Following Spinal Cord Injury

Spinal cord injury (SCI) typically results from sustained trauma to the spinal cord, resulting in loss of neurologic function at the level of the injury. However, activation of various physiological mechanisms secondary to the initial trauma including edema, inflammation, excito-toxicity, excessive cytokine release and apoptosis may exacerbate the injury and/or retard natural repair mechanisms. Herein, we demonstrate that cytoplasmic extracts prepared from adipose tissue stromal cells (ATSCs) inhibits H2O2-mediated apoptosis of cultured spinal cord-derived neural progenitor cells (NPCs) resulting in increased cell survival. The ATSC extracts mediated this effect by decreasing caspase-3 and c-Jun–NH2-terminal kinase (SAPK/JNK) activity, inhibiting cytochrome c release from mitochondria and reducing Bax expression levels in cells. Direct injection of ATSC extracts mixed with Matrigel into the spinal cord immediately after SCI also resulted in reduced apoptotic cell death, astrogliosis and hypo-myelination but did not reduce the extent of microglia infiltration. Moreover, animals injected with the ATSC extract showed significant functional improvement of hind limbs as measured by the BBB (Basso, Beattie and Bresnahan) scale. Collectively, these studies show a prominent therapeutic effect of ATSC cytoplasmic extracts on SCI principally caused by an inhibition of apoptosis-mediated cell death, which spares white matter, oligodendrocytes and neurons at the site of injury. The ability of ATSC extracts to prevent secondary pathological events and improve neurologic function after SCI suggests that extracts prepared from autologous cells harvested from SCI patients may have clinical utility.This work was supported by the 21st Century Frontier/Stem Cell Research Committee (SC3130)

Public Interest in Cognitive Impairment: An Analysis of the Top 50 Articles on Cognitive Impairment on Altmetric

Background. As the average life expectancy continues to increase, interest in cognitive impairment is increasing. Nowadays, as social media expands its reach, academic research is spreading through social media, changing the way and speed by which research is propagated and also who consumes this content. Therefore, using Altmetric, a new web-based set of metrics that analyzes the impact of content on social media platforms, we investigated the characteristics of influential research articles on the topic of cognitive impairment in social media. Methods. An Altmetric Explorer search was performed on May 25, 2018, to extract the following information: (i) journal name, (ii) journal impact factor (IF), (iii) year of publication, (iv) article topic, (v) article type, and (vi) cognitive impairment subtype. Results. The journal “Neurology” was the most cited journal for cognitive impairment articles shared on social media. Among the various types of cognitive impairment, most articles were related to dementia (all subtypes), Alzheimer’s disease, and aging. The most common article type was original scientific paper, especially cohort study. The most popular topic was the identification of protective or risk factors for cognitive impairment. Conclusion. The characteristics of articles with a high Altmetric Attention Score were somewhat different from those of articles with a high number of traditional citations. Social media had the disadvantage that it was difficult to verify the authenticity of the primary source in question, but the advantage was that it could immediately determine the trends regarding how information about that source was being shared and consumed. Therefore, it may be advisable to use Altmetric analysis in combination with traditional methods of evaluating the research articles to understand the dissemination of scientific research and to direct future research

Anti-inflammatory effect of platelet-rich plasma on nucleus pulposus cells with response of TNF-α and IL-1.

The purpose of this study was to investigate the anti-inflammatory effect of platelet-rich plasma (PRP) with collagen matrix on human nucleus pulposus (NP) cell in response to pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 (IL-1). NP cells from human disks were cultured in a monolayer and maintained in the collagen matrix prior to the addition of recombinant human IL-1 and TNF-α. After applying IL-1 and TNF-α, PRP prepared by using a commercially available platelet concentration system was added. The response was investigated using real-time PCR for mRNA expression of type II collagen, aggrecan, matrix metalloproteinase-3 (MMP-3), and cyclooxygenase-2 (COX-2). The combination of IL-1β and TNF-α led to decrease of matrix synthesis gene expression such as collagen type II and aggrecan and increase of the degradation gene expression of COX-2 and MMP-3, compared to the control. Consecutive PRP exposure significantly recovered the down-regulated gene expression of collagen type II and aggrecan and significantly reduced the increased MMP-3 and COX-2 gene expression, compared to that of control groups with pro-inflammatory cytokines. The administration of PRP with collagen matrix markedly suppressed cytokine-induced pro-inflammatory degrading enzymes and mediators in the NP cell. It also rescued gene expression concerning matrix synthesis, thereby stabilizing NP cell differentiation.OAIID:oai:osos.snu.ac.kr:snu2014-01/102/0000004226/1SEQ:1PERF_CD:SNU2014-01EVAL_ITEM_CD:102USER_ID:0000004226ADJUST_YN:NEMP_ID:A079510DEPT_CD:801CITE_RATE:2.875FILENAME:j orthop res-2014_kim_anti inflammatory effect of platelet rich plasma on nucleus pulposus cells.pdfDEPT_NM:의학과EMAIL:[email protected]_YN:YCONFIRM:

NOLC1 knockdown suppresses prostate cancer progressions by reducing AKT phosphorylation and β-catenin accumulation

Although several studies have focused on cancer diagnosis and therapy, prostate cancer (PC) remains an intractable disease. Androgen deprivation therapy (ADT), which is used to treat early stage PC can lead to the development of castration-resistant prostate cancer (CRPC), which is highly associated with androgen receptor (AR) mutations. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) is a chaperone that shuttles between the nucleus and the cytoplasm. Studies suggest that NOLC1 regulates PC progression; however, the underlying mechanisms remain unclear. Herein, we showed that NOLC1 knockdown suppresses PC cell proliferation by altering the signaling pathways and the expression of various proteins involved in DNA replication, amino acid metabolism, and RNA processing. Mechanistically, NOLC1 knockdown suppressed cell cycle progression by inhibiting AKT phosphorylation and β-catenin accumulation. Finally, we showed that NOLC1 expression is higher in human PC than in human hyperplastic prostate tissues. Altogether, we demonstrated that NOLC1 knockdown suppresses the progression of both AR-positive and AR-negative PC cells by inducing changes in the expression of several genes leading to cell cycle arrest. Thus, NOLC1 might be a novel and promising therapeutic target for PC. © 2022 Elsevier Inc.FALS

Carfilzomib Delivery by Quinic Acid-Conjugated Nanoparticles: Discrepancy Between Tumoral Drug Accumulation and Anticancer Efficacy in a Murine 4T1 Orthotopic Breast Cancer Model

Despite being a major breakthrough in multiple myeloma therapy, carfilzomib (CFZ, a second-generation proteasome inhibitor drug) has been largely ineffective against solid cancer, possibly due to its pharmacokinetic drawbacks including metabolic instability. Recently, quinic acid (QA, a low-affinity ligand of selectins upregulated in peritumoral vasculature) was successfully utilized as a surface modifier for nanoparticles containing paclitaxel. Here, we designed QA-conjugated nanoparticles containing CFZ (CFZ@QANP; the surface of poly(lactic-co-glycolic acid) nanoparticles modified by conjugation with a QA derivative). Compared to the clinically used cyclodextrin-based formulation (CFZ-CD), CFZ@QANP enhanced the metabolic stability and in vivo exposure of CFZ in mice. CFZ@QANP, however, showed little improvement in suppressing tumor growth over CFZ-CD against the murine 4T1 orthotopic breast cancer model. CFZ@QANP yielded no enhancement in proteasomal inhibition in excised tumors despite having a higher level of remaining CFZ than CFZ-CD. These results likely arise from delayed, incomplete CFZ release from CFZ@QANP as observed using biorelevant media in vitro. These results suggest that the applicability of QANP may not be predicted by physicochemical parameters commonly used for formulation design. Our current results highlight the importance of considering drug release kinetics in designing effective CFZ formulations for solid cancer therapy. (C) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.Y

KRAS mutation status and clinical outcome of preoperative chemoradiation with cetuximab in locally advanced rectal cancer: A pooled analysis of 2 phase II trials

Purpose: Cetuximab-containing chemotherapy is known to be effective for KRAS wild-type metastatic colorectal cancer; however, it is not clear whether cetuximab-based preoperative chemoradiation confers an additional benefit compared with chemoradiation without cetuximab in patients with locally advanced rectal cancer. Methods and Materials: We analyzed EGFR, KRAS, BRAF, and PIK3CA mutation status with direct sequencing and epidermal growth factor receptor (EGFR) and Phosphatase and tensin homolog (PTEN) expression status with immunohistochemistry in tumor samples of 82 patients with locally advanced rectal cancer who were enrolled in the IRIX trial (preoperative chemoradiation with irinotecan and capecitabine; n=44) or the ERBIRIX trial (preoperative chemoradiation with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except for the administration of cetuximab; radiation therapy was administered at a dose of 50.4 Gy/28 fractions and irinotecan and capecitabine were given at doses of 40 mg/m(2) weekly and 1650 mg/m(2)/day, respectively, for 5 days per week. In the ERBIRIX trial, cetuximab was additionally given with a loading dose of 400 mg/m(2) on 1 week before radiation, and 250 mg/m(2) weekly thereafter. Results: Baseline characteristics before chemoradiation were similar between the 2 trial cohorts. A KRAS mutation in codon 12, 13, and 61 was noted in 15 (34%) patients in the IRIX cohort and 5 (13%) in the ERBIRIX cohort (P=.028). Among 62 KRAS wild-type cancer patients, major pathologic response rate, disease-free survival and pathologic stage did not differ significantly between the 2 cohorts. No mutations were detected in BRAF exon 11 and 15, PIK3CA exon 9 and 20, or EGFR exon 18-24 in any of the 82 patients, and PTEN and EGFR expression were not predictive of clinical outcome. Conclusions: In patients with KRAS wild-type locally advanced rectal cancer, the addition of cetuximab to the chemoradiation with irinotecan plus capecitabine regimen was not associated with improved clinical outcome compared with chemoradiation without cetuximab. (C) 2013 Elsevier Inc