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Metalloallostery and Transition Metal Signaling: Bioinorganic Copper Chemistry Beyond Active Sites.
Pham, VN, Chang, CJ
Angewandte Chemie (International ed. in English). 2023;(11):e202213644
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Abstract
Transition metal chemistry is essential to life, where metal binding to DNA, RNA, and proteins underpins all facets of the central dogma of biology. In this context, metals in proteins are typically studied as static active site cofactors. However, the emergence of transition metal signaling, where mobile metal pools can transiently bind to biological targets beyond active sites, is expanding this conventional view of bioinorganic chemistry. This Minireview focuses on the concept of metalloallostery, using copper as a canonical example of how metals can regulate protein function by binding to remote allosteric sites (e.g., exosites). We summarize advances in and prospects for the field, including imaging dynamic transition metal signaling pools, allosteric inhibition or activation of protein targets by metal binding, and metal-dependent signaling pathways that underlie nutrient vulnerabilities in diseases spanning obesity, fatty liver disease, cancer, and neurodegeneration.
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A Computational Pitting Corrosion Model of Magnesium Alloys.
Chang, CJ, Chang, CH, Hung, TK
Frontiers in bioengineering and biotechnology. 2022;:887444
Abstract
Controlling the corrosion rate of implants to maintain mechanical properties during tissue healing is significant in developing magnesium alloy implants. In addition to surface treatment and material properties, the study of geometric alteration and mechanical strength are also vital for implant development. In this study, we developed a three-dimensional model for semi-autonomous computational pitting corrosion. It is based on the Monte Carlo method, modeling magnesium alloy implants toward clinical application. The corrosion probability is based on the number of exposed surfaces to saline and the oxidation characteristics of the elements. The computational results are well compared with the experimental measurement using micro-computed tomography (micro-CT) in 500 h. Subsequently, the computational analysis is extended to 3,000 h of corrosion analysis. The 3D model appears promising to assist the development of biodegradable implants.
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Hydrostatic pressure facilitates calcium deposition and osteogenic gene expression in the osteoblastic differentiation of placenta-derived multipotent cells.
Cheng, CC, Chung, CA, Chang, CJ, Cheng, YC, Huang, CJ, Chien, CC, Lin, HT
Taiwanese journal of obstetrics & gynecology. 2022;(2):270-276
Abstract
OBJECTIVE We tested the osteoblastic differentiation effects caused by physical stimulation such as hydrostatic pressure using placenta-derived multipotent cells. MATERIALS AND METHODS The placenta-derived multipotent cells (PDMCs) were treated with osteogenic medium to induce PDMCs differentiation into osteoblast-like cells. The induced PDMCs were stimulated using hydrostatic pressure at a magnitude of 30 kPa for 1 h/day for up to 12 days. The calcium deposition monitored by Alizarin Red staining and the calcium content of each experimental group were quantified. RESULTS The results demonstrated both the calcium deposition and concentration were elevated through hydrostatic pressure stimulation. Moreover, in order to indicate of PDMC osteodifferentiation, RT-qPCR analysis were performed and mRNA expression of osteoblast differentiation markers (type I collagen, alkaline phosphatase, RUNX2, and BGLAP), the bone morphogenetic protein family (BMP1-7) and BMP receptors (BMPR1A, BMPR1B, and BMPR2) were examined. Among them, the mRNA levels of RUNX2, COL1A1, BMP1, BMP3, and BMPR1A increased significantly in the hydrostatic-pressure-stimulated groups, whereas BGLAP, ALP, BMP2, BMP6, BMPR1B, and BMPR2 exhibited a slight upregulation between the control and experimental groups, indicating the specific signal route induced by hydrostatic pressure on PDMCs. CONCLUSION Our results revealed the beneficial effects of stem cells stimulated using hydrostatic pressure, which could enhance calcium deposition considerably and facilitate osteodifferentiation, and the results may be applied to tissue regeneration in the near future.
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Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo.
Murphy, MP, Bayir, H, Belousov, V, Chang, CJ, Davies, KJA, Davies, MJ, Dick, TP, Finkel, T, Forman, HJ, Janssen-Heininger, Y, et al
Nature metabolism. 2022;(6):651-662
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Abstract
Multiple roles of reactive oxygen species (ROS) and their consequences for health and disease are emerging throughout biological sciences. This development has led researchers unfamiliar with the complexities of ROS and their reactions to employ commercial kits and probes to measure ROS and oxidative damage inappropriately, treating ROS (a generic abbreviation) as if it were a discrete molecular entity. Unfortunately, the application and interpretation of these measurements are fraught with challenges and limitations. This can lead to misleading claims entering the literature and impeding progress, despite a well-established body of knowledge on how best to assess individual ROS, their reactions, role as signalling molecules and the oxidative damage that they can cause. In this consensus statement we illuminate problems that can arise with many commonly used approaches for measurement of ROS and oxidative damage, and propose guidelines for best practice. We hope that these strategies will be useful to those who find their research requiring assessment of ROS, oxidative damage and redox signalling in cells and in vivo.
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Connecting copper and cancer: from transition metal signalling to metalloplasia.
Ge, EJ, Bush, AI, Casini, A, Cobine, PA, Cross, JR, DeNicola, GM, Dou, QP, Franz, KJ, Gohil, VM, Gupta, S, et al
Nature reviews. Cancer. 2022;(2):102-113
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Abstract
Copper is an essential nutrient whose redox properties make it both beneficial and toxic to the cell. Recent progress in studying transition metal signalling has forged new links between researchers of different disciplines that can help translate basic research in the chemistry and biology of copper into clinical therapies and diagnostics to exploit copper-dependent disease vulnerabilities. This concept is particularly relevant in cancer, as tumour growth and metastasis have a heightened requirement for this metal nutrient. Indeed, the traditional view of copper as solely an active site metabolic cofactor has been challenged by emerging evidence that copper is also a dynamic signalling metal and metalloallosteric regulator, such as for copper-dependent phosphodiesterase 3B (PDE3B) in lipolysis, mitogen-activated protein kinase kinase 1 (MEK1) and MEK2 in cell growth and proliferation and the kinases ULK1 and ULK2 in autophagy. In this Perspective, we summarize our current understanding of the connection between copper and cancer and explore how challenges in the field could be addressed by using the framework of cuproplasia, which is defined as regulated copper-dependent cell proliferation and is a representative example of a broad range of metalloplasias. Cuproplasia is linked to a diverse array of cellular processes, including mitochondrial respiration, antioxidant defence, redox signalling, kinase signalling, autophagy and protein quality control. Identifying and characterizing new modes of copper-dependent signalling offers translational opportunities that leverage disease vulnerabilities to this metal nutrient.
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Probiotic Lactobacillus casei: Effective for Managing Childhood Diarrhea by Altering Gut Microbiota and Attenuating Fecal Inflammatory Markers.
Lai, HH, Chiu, CH, Kong, MS, Chang, CJ, Chen, CC
Nutrients. 2019;11(5)
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Plain language summary
Acute diarrhoea caused by pathogens may induce gastroenteritis (inflammation of the stomach and intestines), bloody stool, or severe intra-abdominal infections that establish disease and increase the economic burden, especially among infantile and childhood populations. The aim of the study was to determine whether probiotics (Lactobacilluscasei) inhibited gastrointestinal infection and reduced the associated inflammatory response. The study is a prospective, randomized, case-controlled study which enrolled 81 children aged between 6 months and 6 years. The participants were divided into 2 groups (Lactobacilluscasei variety rhamnosus treatment and a no probiotic control). Study results indicate that probiotics can reduce the severity and duration of diarrhoea. Furthermore, probiotic colonisation improved bowel habits and reduced abdominal pain or colic and bloating. Authors conclude that the efficacy of probiotic preparations for the treatment of acute childhood diarrhoea is related to individual bacteria strains. Thus, the population and modulation of intestinal gut/probiotic bacteria can be restored through the reduction of intestinal inflammatory reactions.
Abstract
BACKGROUND Acute diarrhea is a major cause of childhood morbidity and an economic burden for families. The aim of this study is to explore the effect of probiotics on clinical symptoms, intestinal microbiota, and inflammatory markers during childhood diarrhea. METHODS Children (n = 81) aged six months to six years (mean age 2.31 years) hospitalized for acute diarrhea were randomized to receive probiotics (Lactobacillus casei variety rhamnosus; n = 42) or no probiotics (n = 39) orally twice daily for seven days. Feces samples were also collected to evaluate microbial content using a traditional agar plate and next-generation sequencing. Immunoglobulin A (IgA), lactoferrin, and calprotectin were determined by enzyme-linked immunosorbent assay (ELISA) and compared in different groups. Other clinical symptoms or signs, including fever, vomiting, diarrhea, abdominal pain, bloated abdomen, daily intake, appetite, and body weight were also assessed. RESULTS Data were collected from 81 individuals across three different time points. Total fecal IgA levels in fecal extracts of the probiotics group were higher than those in the control group, reaching statistical significance (p < 0.05). Concentrations of fecal lactoferrin and calprotectin were significantly downregulated in patients with probiotic Lactobacillus casei variety rhamnosus (Lc) consumption compared to those of the control (p < 0.05). Probiotic Lc administration may be beneficial for gut-microbiota modulation, as shown by the data collected at one week after enrollment. Counts of Bifidobacteria and Lactobacillus species were elevated in stool culture of the probiotic group. Appetite and oral intake, body-weight gain, abdominal pain, bloating, as well as bowel habits (diarrhea) were much better in children receiving probiotics compared with those in the control group. CONCLUSION Fecal IgA increased during acute diarrhea under Lc treatment; in contrast, fecal lactoferrin and calprotectin were downregulated during acute diarrhea under Lc treatment. Probiotic Lc may be a useful supplement for application in children during acute diarrhea to reduce clinical severity and intestinal inflammatory reaction.
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Probiotics, prebiotics and amelioration of diseases.
Tsai, YL, Lin, TL, Chang, CJ, Wu, TR, Lai, WF, Lu, CC, Lai, HC
Journal of biomedical science. 2019;(1):3
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Abstract
Dysbiosis of gut microbiota is closely related to occurrence of many important chronic inflammations-related diseases. So far the traditionally prescribed prebiotics and probiotics do not show significant impact on amelioration of these diseases in general. Thus the development of next generation prebiotics and probiotics designed to target specific diseases is urgently needed. In this review, we first make a brief introduction on current understandings of normal gut microbiota, microbiome, and their roles in homeostasis of mucosal immunity and gut integrity. Then, under the situation of microbiota dysbiosis, development of chronic inflammations in the intestine occurs, leading to leaky gut situation and systematic chronic inflammation in the host. These subsequently resulted in development of many important diseases such as obesity, type 2 diabetes mellitus, liver inflammations, and other diseases such as colorectal cancer (CRC), obesity-induced chronic kidney disease (CKD), the compromised lung immunity, and some on brain/neuro disorders. The strategy used to optimally implant the effective prebiotics, probiotics and the derived postbiotics for amelioration of the diseases is presented. While the effectiveness of these agents seems promising, additional studies are needed to establish recommendations for most clinical settings.
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Activity-based sensing fluorescent probes for iron in biological systems.
Aron, AT, Reeves, AG, Chang, CJ
Current opinion in chemical biology. 2018;:113-118
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Abstract
Iron is an essential nutrient for life, and its capacity to cycle between different oxidation states is required for processes spanning oxygen transport and respiration to nucleotide synthesis and epigenetic regulation. However, this same redox ability also makes iron, if not regulated properly, a potentially dangerous toxin that can trigger oxidative stress and damage. New methods that enable monitoring of iron in living biological systems, particularly in labile Fe2+ forms, can help identify its contributions to physiology, aging, and disease. In this review, we summarize recent developments in activity-based sensing (ABS) probes for fluorescence Fe2+ detection.
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Detecting Triple-Vessel Disease with Cadmium Zinc Telluride-Based Single-Photon Emission Computed Tomography Using the Intensity Signal-to-Noise Ratio between Rest and Stress Studies.
Fang, YD, Su, TP, Chang, CJ, Ho, KC, Su, M, Yen, TC
Contrast media & molecular imaging. 2017;:4945680
Abstract
The purpose of this study was to investigate if a novel parameter, the stress-to-rest ratio of the signal-to-noise ratio (RSNR) obtained with a cadmium zinc telluride (CZT) SPECT scanner, could be used to distinguish triple-vessel disease (TVD) patients. Methods. One hundred and two patients with suspected coronary artery disease were retrospectively involved. Each subject underwent a Tl-201 SPECT scan and subsequent coronary angiography. Subjects were separated into TVD (n = 41) and control (n = 61) groups based on coronary angiography results using 50% as the stenosis cutoff. The RSNR was calculated by dividing the stress signal-to-noise ratio (SNR) by the rest SNR. Summed scores were calculated using quantitative perfusion SPECT (QPS) for all subjects. Results. The RSNR in the TVD group was found to be significantly lower than that in the control group (0.83 ± 0.15 and 1.06 ± 0.17, resp.; P < 0.01). Receiver-operating characteristic (ROC) analysis showed that RSNR can detect TVD more accurately than the summed difference score with higher sensitivity (85% versus 68%), higher specificity (90% versus 72%), and higher accuracy (88% versus 71%). Conclusion. The RSNR may serve as a useful index to assist the diagnosis of TVD when a fully automatic quantification method is used in CZT-based SPECT studies.
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Increasing extracellular H2O2 produces a bi-phasic response in intracellular H2O2, with peroxiredoxin hyperoxidation only triggered once the cellular H2O2-buffering capacity is overwhelmed.
Tomalin, LE, Day, AM, Underwood, ZE, Smith, GR, Dalle Pezze, P, Rallis, C, Patel, W, Dickinson, BC, Bähler, J, Brewer, TF, et al
Free radical biology & medicine. 2016;:333-48
Abstract
Reactive oxygen species, such as H2O2, can damage cells but also promote fundamental processes, including growth, differentiation and migration. The mechanisms allowing cells to differentially respond to toxic or signaling H2O2 levels are poorly defined. Here we reveal that increasing external H2O2 produces a bi-phasic response in intracellular H2O2. Peroxiredoxins (Prx) are abundant peroxidases which protect against genome instability, ageing and cancer. We have developed a dynamic model simulating in vivo changes in Prx oxidation. Remarkably, we show that the thioredoxin peroxidase activity of Prx does not provide any significant protection against external rises in H2O2. Instead, our model and experimental data are consistent with low levels of extracellular H2O2 being efficiently buffered by other thioredoxin-dependent activities, including H2O2-reactive cysteines in the thiol-proteome. We show that when extracellular H2O2 levels overwhelm this buffering capacity, the consequent rise in intracellular H2O2 triggers hyperoxidation of Prx to thioredoxin-resistant, peroxidase-inactive form/s. Accordingly, Prx hyperoxidation signals that H2O2 defenses are breached, diverting thioredoxin to repair damage.