bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dual Action of Zinc in Bone and Vascular Calcification
Authors: Kwun In‐Sook , Shin Mee‐Young 
Published: November 2023

Osteogenic calcification is a normal physiological process in bone tissue, anywhere else like the blood vessel, it is a pathological process which is so‐called calcification paradox. The retarded skeletal growth in animals and man is the major sign of zinc inadequacy, which implies the involvement of zinc in osteogenic calcification.Our previous studies showed that inadequate zinc level in osteoblasts decreased osteogenic activities by decreasing extracellular matrix calcification, mainly through the inhibition of alkaline phosphatase (ALP) expression and activity, and by down‐regulation of osteoblast differentiation marker genes (osteopontin, osteocalcin and collagen type I), which is regulated through the reduced and delayed expression of bone‐specific transcription factor Runx2. Therefore, it seems zinc can be a stimulator in bone formation which includes osteogenic bone matrix calcification.Meanwhile, there is emerging evidence that zinc can protect against vascular damage and therefore may decrease the incidence of atherosclerotic plaque calcification. Our recent study using rat aortic smooth muscle cell line (A7r5) and rat primary vascular smooth muscle cells (pVSMC) showed that inadequate zinc level in VSMCs increased VSMC calcification and this calcification is paralleled with VSMC apoptotic pattern, rather than osteogenic calcification mode. In mice study using atherosclerotic model (ApoE null mouse), zinc deficiency promotes aorta Ca and P deposition (vascular calcification), while it decreases Ca and P contents in femur (bone calcification). The findings from our in vitro (osteoblasts and VSMCs) and in vivo (atherosclerotic ApoE null mouse) studies suggest that zinc may have a reciprocal role for calcification in bone (hard tissue) and blood vessel (soft tissue). It can be suggested that zinc may have a potential for therapeutic strategy for atherosclerosis as well as osteopoprosis, both of which involve the process of calcification.Support or Funding Information(Supported by the National Research Foundation of Korea, NRF‐2011‐0014535)
Virtual Surgical Planning and Applications in Plastic and Craniomaxillofacial Surgery
Authors: Basel Sharaf , Matsumoto Jane , Lachman Nirusha , Bite Uldis 
Published: November 2023

Advanced plastic and craniomaxillofacial reconstruction is a multidisciplinary field, requiring communication and accurate planning among various specialists including oncologic surgeons, plastic surgeons, and radiologists. Complex defects may present in pediatric congenital deformities, after trauma or oncologic surgery. Restoration of form and function require precise planning among the various specialists involved and accurate execution of the surgical plan. Often, considerations for bony and soft tissue requirements make the reconstruction more challenging. Virtual surgical planning using computed tomographic imaging, 3D surface imaging technology and computer‐aided design allow the surgeons to perform virtual surgery and generate templates and cutting guides that allow for the precise and expedient recreation of the plan in the operating room. The author presents cases highlighting various reconstructive requirements where virtual planning was used for advanced plastic and craniomaxillofacial reconstruction to achieve precise reconstruction.Support or Funding InformationNone
Inter‐competetion and conversion among TNF‐α‐induced signaling complexes determine the outcomes of TNF‐α signaling
Authors: Yang Zhang‐Hua , Wu Xiao‐Nan , Wang Xuekun , He Peng , Hong Mao , Han Jiahuai 
Published: November 2023

Inflammatory gene induction, apoptosis and necroptosis are major cellular responses of the cells exposed to tumor necrosis factor (TNF)‐α. Here we systematically investigated inter‐relationships among the key signaling molecules that control these cellular processes to uncover the molecular mechanism underlying the inter‐competetion and conversion among TNF‐α induced signaling complexes that elicit multiple alternative outcomes of TNF‐α in a murine system. By taking advantage of quantitative mass spectrometry, we found that the amount of Receptor interacting protein 1 (Rip1) and Tradd recruited to the TNF receptor 1 (TNFR1) complex is the initial determinant factor that governs the cell's decision to undergo cell death or not. Rip1 in complex I downstream of TNFR1 engagement not only initiates the signaling for inflammatory gene expression but also inhibits Tradd‐dependent recruitment of Fadd and caspase‐8 that can lead to rapid apoptosis. When there is no Rip3 or Mlkl in cells, elimination of the ubiquitination of Rip1 leads to formation of complex II, which triggers slower apoptosis than occurs in the absence of Rip1. Complex II can be converted to the necrosome when there are sufficient Rip3 and Mlkl. Both caspase‐8 and Flip can function in the necrosome to suppress necroptosis. Recruitment of Rsk1 to the necrosome is another layer of security to process necroptosis because Rsk1 inactivates caspase‐8 by phosphorylation. Thus, Rip1 is the central controller for cells to have induction of inflammatory genes and/or cell death; the interplay among Rip3, caspase‐8, Flip and Rsk1 determines whether the cells undergo apoptosis or necroptosis.Support or Funding InformationThis work was supported by the National Basic Research Program of China (973 Program; 2015CB553800), the National Scientific and Technological Major Project (2013ZX10002‐002), the National Natural Science Foundation of China (91429301, 31420103910, 31330047 and 31221065), the Hi‐Tech Research and Development Program of China (863 program; 2012AA02A201), the 111 Project (B12001), the Science and Technology Foundation of Xiamen (No. 3502Z20130027), the National Science Foundation of China for Fostering Talents in Basic Research (Grant No.J1310027) and the Open Research Fund of State Key Laboratory of Cellular Stress Biology, Xiamen University.
Cathepsin Localization and Activity on the Intestinal Epithelial Barrier of Rats following Hemorrhagic Shock and Reperfusion
Authors: Courelli Asimina S. , DeLano Frank , Schmid‐Schonbein Geert W. 
Published: November 2023

Damage to the intestinal epithelial barrier during hemorrhagic shock results in tissue destruction and increased permeability. Although the downstream effects of damage to the intestinal epithelial barrier have been investigated, the mechanism behind the increase in permeability has not been elucidated. Previous studies have suggested a proteolytic source for the degradation, but the spectrum of proteolytic enzymes in the intestinal tissue is very broad. We employed mass‐spectroscopy based proteomic analysis of a jejunal intestinal sample obtained from a young adult male Wistar rat (flushed with PBS to remove luminal contents) and found that the enzymes with the greatest relative abundance among the proteolytic enzymes were cathepsin–B, –C, and –Z. We examined cathepsin localization profiles using rat tissue from normal control (NC) Wistar rats and rats that underwent ischemia (at a blood pressure of 35 mmHg) followed by 2 hours of reperfusion (IR). Immuno‐histochemistry (IHC) was used to determine the cathepsin localization profiles. In the case of NC, comparison of cathepsin–B, –C, and –Z localization profiles of the intestinal epithelial barrier between rats (in our study) and humans (Swedish Human Protein Atlas) revealed a significant degree of similarity. Western Blots and gel zymography were conducted to determine changes in cathepsin concentration and activity respectively. Western blots showed a decrease in cathepsin levels, while gel zymography showed no changes in cathepsin activity between NC and IR groups. However, cathepsin activity per mole of total cathepsin (expressed by the ratio between the gel zymography and western blot bands) was higher in the case of IR, supporting the potential role cathepsins play in causing damage to intestinal tissue during hemorrhagic shock, leading to increased intestinal permeability.Support or Funding InformationSupported by HL 10881.
Cellular stress response 1 regulates RNA splicing of epidermal growth factor receptor and platelet‐derived growth factor receptor through inactivation of splicing factor 3A3
Authors: Luo Jianhua , Zuo Ze‐Hua , Yu Yan P 
Published: November 2023

Cellular stress response 1 (CSR1) is a tumor suppressor gene that plays an important role in regulating cell death. In this report, we showed that the N‐terminus of CSR1 interacts with splicing factor 3A, subunit 3 (SF3A3). The SF3A3 binding motif was identified in the region of amino acids 62–91 of CSR1 through cell‐free binding analyses. The interaction between CSR1 and SF3A3 led to migration of SF3A3 from nucleus to cytoplasm. The cytoplasmic redistribution of SF3A3 significantly reduced the splicing efficiency of epidermal growth factor receptor and platelet‐derived growth factor receptor. Induction of CSR1 or down‐regulation of SF3A3 also significantly reduced the splicing activity of oxytocin reporter gene both in vivo and in vitro. Mutant CSR1 that lacks the SF3A3 binding motif contained no RNA splicing regulatory activity, while the peptide corresponding to the SF3A3 binding motif in CSR1 interfered with the wild type CSR1 mediated inhibition of RNA splicing. Interaction of CSR1 and SF3A3 is essential for CSR1 mediated cell death. To our knowledge, this is the first report demonstrating that RNA splicing is negatively regulated by redistribution of a splicing factor.Support or Funding InformationNational Cancer Institute (RO1 CA098249)
Moringa oleifera Whole Methanolic Leaf Extract Attenuates Levels of Angiogenic Factors in the Cervix of Preterm Labor Mice Models
Authors: Fitch Morgan , Ray Savannah , Zwetsloot Kevin A. , Mowa Chishimba 
Published: November 2023

On average, 1 in 10 births in the United States are born premature, and the leading cause is microbial infection and inflammation. Current treatments have serious side effects and are undermined by the growing multi resistance to anti‐microbial agents. We recently demonstrated a positive feed forward relationship between expression of vascular endothelial growth factor (VEGF), a key angiogenic factor, in mice cervix and inflammation. We also revealed that Moringa oleifera, an ancient medicinal plant, exhibit potent anti‐bacterial (E. coli) and ‐inflammatory activities in vitro and in cervix of the same mice models, respectively. Here, we test whether Moringa oleifera can also modulate expression of VEGF and other angiogenic factors in the cervix of preterm labor mice models. Cervical tissues of pregnant mice were harvested and analyzed using real‐time PCR (qPCR) and Western blot after specific treatments [2 hour pretreatment with Moringa oleifera (4.8 μg/50 μL methanol, oral) followed by 2 hour treatment with lipopolysaccharide (LPS) (100 μg/50 μL 1X PBS, i.p.)]. Other angiogenic factors examined include VEGF receptor 1 (Flt‐1), VEGF receptor 2 (KDR), and endothelin‐1 (End‐1). The results show that Moringa oleifera whole leaf methanolic extract overall down regulates expression of VEGF, KDR, and End‐1 mRNAs, while it had no significant effect on the expression of Flt‐1. Based on these data, we conclude that Moringa oleifera may be used to intercept the positive feed forward loop between angiogenic and inflammatory factors, and thus potentially tone down inflammation and subsequently preterm labor.Support or Funding InformationAppalachian State University, Office of Student Research.
Reacquisition of E‐cadherin Expression in Metastatic Signet Ring Cell Carcinoma: A Potential Anchor for Metastatic Deposition
Authors: Ma Yihong , Siegal Gene P , Wei Shi 
Published: November 2023

E‐cadherin is a cell‐cell adhesion molecule with pivotal roles in epithelial cell behavior. Loss of E‐cadherin leads to disappearance of epithelial characteristics and down‐regulation of migratory and invasive properties of cells, a process known as epithelial–mesenchymal transition (EMT), fundamental to the initiation of metastasis during cancer progression. Signet ring cell carcinoma (SRCC) is an aggressive histologic subtype of adenocarcinoma with a diffuse infiltrative nature. We have previously demonstrated that reduced expression of E‐cadherin is a frequent event in SRCCs of various organ systems. The aim of this study was to examine the expression of E‐cadherin in paired primary and metastatic SRCCs to further explore the potential role of this molecule in metastatic dissemination of this unique tumor type.MethodsThirty‐four consecutive cases of SRCC from various organ systems with both primary and metastatic tumoral tissue available were retrieved from the authors’ institution between 2004 and 2014. The intensity of membranous E‐cadherin expression was scored as 3+ (strong; equivalent to adjacent normal epithelium), 2+ (moderate), or 1+ (weak), while no staining was assigned a score of 0. A score of 2+ or less was regarded as reduced expression. Chi‐square or paired t‐test was used for statistical analysis, when appropriate.ResultsLoss or reduction of E‐cadherin expression was a distinguishing feature of primary SRCCs and was observed in 27 (79%) of primary tumor specimens. Interestingly, lost or reduced E‐cadherin expression was less frequently seen in metastatic SRCCs when compared to their primary counterparts, and was only found in 18 tumors (53%) at distant relapse (Odds ratio 3.4; p=0.04). The mean score of E‐cadherin expression of primary SRCCs was significantly lower than that of their metastatic counterparts (2.3 vs. 1.8; p=0.001).ConclusionsWhile the reduced E‐cadherin in primary SRCCs supports its role during EMT in tumor progression/metastatic dissemination, the re‐expression of E‐cadherin in SRCC cells at distant relapse sites implies a reversal to their epithelial phenotype (mesenchymal‐epithelial transition; MET) which, in turn, helps tumor cells to anchor and form cohesive metastatic deposits. Thus, opportunistic tumor cells may modulate this process to their advantage to go through EMT‐MET for successful metastasis, a phenomenon potentially regulated by epigenetic mechanisms rather than the accumulation of mutations and other genetic changes which are, by default, irreversible. Further elucidation of this process will help in the development of novel targets for antimetastatic therapies.Support or Funding InformationNone
Upregulation of Matrix Degrading Enzymes and Lubricin in the Pathogenesis of Joint Disease Requiring Arthroplasty
Authors: Wanderling Chris , Emanuele Nicholas , Carlsgaard Peter , Lilles Jeff , Schnettler Tim , Syed Daneyal , Guler Nil , Hopkinson William , Hoppensteadt Debra , Fareed Jawed 
Published: November 2023

IntroductionThe prevalence of total knee and hip arthroplasty (TKA and THA) has been increasing; it is projected that TKA and THA procedures will increase to over 4 million procedures by 2030. Since TKA and THA are performed on individuals who experience joint degeneration, it is of interest to study the matrix degrading enzymes (MDE) such as elastase, collagenase‐1, and heparanase. Lubricin is a synovial/joint glycoprotein‐detectable in circulation‐ that plays a vital role in joint mobility by reducing friction in the joint and may have matrix‐stabilizing properties. Previous studies have investigated MDEs in TKA and THA patients, particularly involving prosthesis loosening, yet the role of lubricin is unclear. Simultaneous MDE and lubricin measurement may provide insight on the role of lubricin and these MDEs in the pathogenesis of joint diseases.MethodsBlood samples were obtained from patients undergoing THA or TKA procedures as de‐identified samples day one pre‐op and day one post‐op. Patient blood samples were collected in 3.2% sodium citrate to obtain plasma. Patient and control plasma samples were stored at −80°C. Plasma samples were analyzed utilizing commercially available ELISA kits for elastase, collagenase‐1, heparanase, and lubricin.ResultsIn comparison to normal samples, collagenase and elastase levels were significantly higher in the pre‐op samples (p<0.0001). However heparanase levels were not significantly different between the normal and patient group (p<0.748). On post‐op day 1, a further increase in the collagenase and elastase levels were noted again (p<0.0001). No further increase was evident in the heparanase level. Lubricin levels were markedly higher in the patient groups in comparison to the normal (p<0.0001). On post‐op day 1 marked enhancement of circulating lubricin was noted.DiscussionThe increased levels of lubricin suggest that, joint matrix deteriorates during joint degeneration damaging the capsule allows the joint fluid into systemic circulation. This may be the primary cause of the increased level of lubricin in circulation. Since DJD is a systemic disease with multiple pathogenic factors, it may result in the upregulation of collagenase and elastase. The role of heparanase remains unclear and requires further exploration. It is likely that lubricin may regulate the functional behavior of matrix degrading proteins. These studies also suggest that beside matrix degrading proteins, lubricin may also have a prognostic role in DJD.
Extracellular matrix (ECM)‐stiffness regulated cancer cell (A549) migration
Authors: Gweon Bomi , Li Zeyuan , Shin Yujin , Yoo Hongki , Shin Jennifer H. 
Published: November 2023

Extracellular matrix (ECM)‐stiffness is one of the potent regulator of cell physiology such as proliferation, morphology, and migration. From previous studies, it has been known that tumor develops increased collagen deposition at the surrounding tissues. The presence of this dense collagen matrix is shown to promote tissue‐stiffening and, further, metastatic outcomes. However, little is known about how this mechanical stimulation, ECM‐stiffening, are transduced into cells and derive tumor progression. To investigate the relationship, we grew human lung carcinoma cells (A549) on the collagen coated ECM synthesized by polyacrylamide with physiologically relevant range stiffness (0.3 ~ 150 kPa). We chose A549 cells because A549s are reported to be sensitive to ECM‐stiffness. To correlate the ECM‐stiffness to metastatic behavior of cells, we observed migration of cells under microscope for about 24 hours equipped with incubator. In order to track the path of individual cell movement, we kept the cell population in sparse condition during this 24 hours. When we measured the migration speed, cells on soft substrate (0.3 kPa) migrated relatively slower compare to the ones on stiffer substrate (19 kPa and 153 kPa). Cells, also, tend to spread slightly less on soft substrate (0.3 kPa). To determine if these alterations in cell physiological induced by ECM‐stiffness change is related to cytoskeletal contractility, we additionally measured cellular traction.Support or Funding InformationThis work was supported by the National Research Foundation of Korea Grant funded by the Korean Government (NRF‐2014R1A6A3A04059713 and NRF‐2013S1A2A2035518).
Inhibitory Effect of Luteolin on Hepatic Stellate Cell Activation Is STAT3 Dependent
Authors: Wang Xiaofu , Bohanon Fredrick J. , Lopez Omar Nunez , Kandathiparampil Arline J , Zhou Jia , Radhakrishnan Ravi S 
Published: November 2023

IntroductionSTAT3 is activated in a majority of cancer and other fast growing cells, such as activated hepatic stellate cells (HSC), which are the primary effector of liver fibrosis. Tyr705 phosphorylation of STAT3 is a key step for its function, so it has become a widely explored target for new drug development. Luteolin is an important member of the flavonoid family and has anti‐tumorigenic, anti‐oxidant, and anti‐inflammatory properties. Previously, we have reported that luteolin has a significant anti‐fibrogenic effect on activated HSC. However, its molecular mechanisms remain unclear. In this present study, we determined the role of STAT3 on luteolin‐induced HSC inactivation.MethodsThe activated human and rat hepatic stellate cell lines LX‐2 and HSC‐T6 were used for this study. Cellular proteins were analyzed by immunoblotting and immunofluorescence. Cell proliferation following STAT3 inhibitors treatment was assessed with Alamar Blue assay.ResultsLuteolin treatment significantly inhibited pSTAT3 (Tyr705) protein expression (p<0.001) in both a time‐ and dose‐dependent manner by immunoblot assay and confirmed by immunofluorescence staining. Additionally, luteolin suppressed pSTAT3 nuclear translocation (p=0.009) and its transcriptional activity (p=0.03). The downstream effectors of STAT3 pathway, c‐Myc and cyclin D1, were inhibited by luteolin treatment (p<0.0001). Importantly, treatment with STAT3 inhibitors, Stattic and SH‐4‐54, resulted in a marked decrease in LX‐2 cell growth and expression of HSC activation marker α‐smooth muscle actin, which was similar following luteolin treatment.ConclusionLuteolin treatment inhibited STAT3 signaling and its target genes. STAT3 inhibitors attenuate LX‐2 cell growth and activation. Luteolin may affect HSC activation through the STAT3 pathway.Support or Funding InformationNational Institutes of Health: T32‐GM8256
Effect of Opioids on Integrity of White Matter
Authors: Korneeva Nadejda L , Fan Ruping , Schrott Lisa M , Arnold Thomas , Graham Derrel 
Published: November 2023

Oxycodone (6‐deoxy‐7,8‐dehydro‐14‐hydroxy‐3‐O‐methyl‐6‐oxomorphine) is a strong semi‐synthetic opioid. It is prescribed to treat different types of pain especially when other opioids are ineffective. Oxycodone has close structural similarity to morphine and heroin and binds not only m‐ but also k‐opioid receptors. Unfortunately, similar to other opioids, repetitive oxycodone administration has the potential to develop analgesic tolerance, withdrawal, and addiction. Recently, another concern regarding the effect of chronic or over‐dose opioid exposure has emerged: their effect on neuronal degeneration. Leukoencephalopathy or damage of white matter has been described as one of the effects that heroin abusers develop, and was recently documented in a patient after morphine and oxycodone administration. The exact mechanisms underlying the neurotoxic effect of opioids on the Central Nervous System are still not fully understood. To investigate the effect of opioid treatment on rat white matter we used an animal model in which female rats were gavaged with 15 mg/kg oxycodone every 24 hours for 30 days. In our study we observed that chronic oxycodone exposure induces oxidative/nitrosidative stresses in three brain areas in rats: nucleus accumbens, cortex and brain stem. We demonstrated activation of pro‐apoptotic machinery in rat brains after oxycodone treatment. Interestingly, activated caspase 3 was predominantly localized in areas containing white matter suggesting increased axonal damages after chronic oxycodone exposure. The increased level of a‐synuclein aggregates and amyloid precursor protein (APP) in oxycodone‐exposed cerebellum confirmed the axonal injury. We also demonstrated induction of pro‐apoptotic protein Bax by oxycodone, morphine and DAMGO in breast carcinoma cells MCF7, which are known to express the m‐opioid receptor.Support or Funding InformationLMS was supported by Grant No. 2R01GM20818 from the National Institute of General Medical Sciences.