Publications by authors named "Sung Hoon Lee"

181 Publications

Advances in Microsensors and Wearable Bioelectronics for Digital Stethoscopes in Health Monitoring and Disease Diagnosis.

Adv Healthc Mater 2021 Sep 5:e2101400. Epub 2021 Sep 5.

George W. Woodruff School of Mechanical Engineering and Center for Human-Centric Interfaces and Engineering, Georgia Institute of Technology, Atlanta, GA, 30332, USA.

Acoustic stethoscopes have demonstrated beneficial factors aiding diagnosis from the doctors with accurate body sounds. Still, the conventional acoustic stethoscopes require a substantial amount of clinical experience and hearing skills for the physicians to accurately diagnose symptoms from abnormal sounds. Especially for cardiopulmonary systems, it is crucial to collect sounds with precision since they contain valuable information in specific frequency ranges for various sounds. This review paper summarizes recent advances and technical developments in microsensors, circuits, chips, and integrated electronics for fabricating different digital stethoscopes that offer portable detection of body sounds. They solve the limitations of conventional stethoscopes, aiming for wireless auscultation in digitized medicine. Overall, this comprehensive review will help researchers design and develop new wearable electronics and digital stethoscopes for advancing human healthcare, continuous monitoring, and better diagnosis.
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http://dx.doi.org/10.1002/adhm.202101400DOI Listing
September 2021

Anticancer Effects of Propionic Acid Inducing Cell Death in Cervical Cancer Cells.

Molecules 2021 Aug 16;26(16). Epub 2021 Aug 16.

Biometrology Group, Korea Research Institute of Standards and Science, Daejeon 34113, Korea.

Recent studies found that short-chain fatty acids (SCFAs), which are produced through bacterial fermentation in the gastrointestinal tract, have oncoprotective effects against cervical cancer. The most common SCFAs that are well known include acetic acid, butyric acid, and propionic acid, among which propionic acid (PA) has been reported to induce apoptosis in HeLa cells. However, the mechanism in which SCFAs suppress HeLa cell viability remain poorly understood. Our study aims to provide a more detailed look into the mechanism of PA in HeLa cells. Flow cytometry analysis revealed that PA induces reactive oxygen species (ROS), leading to the dysfunction of the mitochondrial membrane. Moreover, PA inhibits NF-κB and AKT/mTOR signaling pathways and induces LC3B protein levels, resulting in autophagy. PA also increased the sub-G1 cell population that is characteristic of cell death. Therefore, the results of this study propose that PA inhibits HeLa cell viability through a mechanism mediated by the induction of autophagy. The study also suggests a new approach for cervical cancer therapeutics.
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http://dx.doi.org/10.3390/molecules26164951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399869PMC
August 2021

Selenium Nanoparticles as Candidates for Antibacterial Substitutes and Supplements against Multidrug-Resistant Bacteria.

Biomolecules 2021 07 14;11(7). Epub 2021 Jul 14.

Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan 31116, Korea.

In recent years, multidrug-resistant (MDR) bacteria have increased rapidly, representing a major threat to human health. This problem has created an urgent need to identify alternatives for the treatment of MDR bacteria. The aim of this study was to identify the antibacterial activity of selenium nanoparticles (SeNPs) and selenium nanowires (SeNWs) against MDR bacteria and assess the potential synergistic effects when combined with a conventional antibiotic (linezolid). SeNPs and SeNWs were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), zeta potential, and UV-visible analysis. The antibacterial effects of SeNPs and SeNWs were confirmed by the macro-dilution minimum inhibitory concentration (MIC) test. SeNPs showed MIC values against methicillin-sensitive (MSSA), methicillin-resistant (MRSA), vancomycin-resistant (VRSA), and vancomycin-resistant enterococci (VRE) at concentrations of 20, 80, 320, and >320 μg/mL, respectively. On the other hand, SeNWs showed a MIC value of >320 μg/mL against all tested bacteria. Therefore, MSSA, MRSA, and VRSA were selected for the bacteria to be tested, and SeNPs were selected as the antimicrobial agent for the following experiments. In the time-kill assay, SeNPs at a concentration of 4X MIC (80 and 320 μg/mL) showed bactericidal effects against MSSA and MRSA, respectively. At a concentration of 2X MIC (40 and 160 μg/mL), SeNPs showed bacteriostatic effects against MSSA and bactericidal effects against MRSA, respectively. In the synergy test, SeNPs showed a synergistic effect with linezolid (LZD) through protein degradation against MSSA and MRSA. In conclusion, these results suggest that SeNPs can be candidates for antibacterial substitutes and supplements against MDR bacteria for topical use, such as dressings. However, for use in clinical situations, additional experiments such as toxicity and synergistic mechanism tests of SeNPs are needed.
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http://dx.doi.org/10.3390/biom11071028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8301847PMC
July 2021

Review on Interfacial Bonding Mechanism of Functional Polymer Coating on Glass in Atomistic Modeling Perspective.

Polymers (Basel) 2021 Jul 8;13(14). Epub 2021 Jul 8.

Corning Technology Center Korea, Corning Precision Materials Co., Ltd., 212 Tangjeong-ro, Asan 31454, Chungcheongnam-do, Korea.

Atomistic modeling methods are successfully applied to understand interfacial interaction in nanoscale size and analyze adhesion mechanism in the organic-inorganic interface. In this paper, we review recent representative atomistic simulation works, focusing on the interfacial bonding, adhesion strength, and failure behavior between polymer film and silicate glass. The simulation works are described under two categories, namely non-bonded and bonded interaction. In the works for non-bonded interaction, three main interactions, namely van der Waals interaction, polar interaction, and hydrogen bonds, are investigated, and the contributions to interfacial adhesion energy are analyzed. It is revealed that the most dominant interaction for adhesion is hydrogen bonding, but flexibility of the polymer film and modes of adhesion measurement test do affect adhesion and failure behavior. In the case of bonded interactions, the mechanism of covalent silane bond formation through condensation and hydrolysis process is reviewed, and surface reactivity, molecular density, and adhesion properties are calculated with an example of silane functionalized polymer. Besides interfacial interactions, effects of external conditions, such as surface morphology of the glass substrate and relative humidity on the adhesion and failure behavior, are presented, and modeling techniques developed for building interfacial system and calculating adhesion strengths are briefly introduced.
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http://dx.doi.org/10.3390/polym13142244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309365PMC
July 2021

Anti-inflammatory effect of Ailanthus altissima (Mill.) Swingle leaves in lipopolysaccharide-stimulated astrocytes.

J Ethnopharmacol 2021 Jul 13:114258. Epub 2021 Jul 13.

Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea. Electronic address:

Ethnopharmacological Relevance: Activated astrocytes are involved in the progression of neurodegenerative diseases. Traditionally, Ailanthus altissima (Mill.) Swingle, widely distributed in East Asia, has been used as a medicine for the treatment of fever, gastric diseases, and inflammation. Although A. altissima has been reported to play an anti-inflammatory role in peripheral tissues or cells, its role in the central nervous system (CNS) remains unclear.

Aim Of The Study: In the present study, we investigated the anti-inflammatory effects and mechanism of action of A. altissima in primary astrocytes stimulated by lipopolysaccharide (LPS).

Materials And Methods: A nitrite assay was used to measure nitric oxide (NO) production, and the tetrazolium salt 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was performed to determine cytotoxicity. The expression levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and mitogen-activated protein kinase (MAPK) were determined with western blotting. Reverse-transcription PCR was used to assess the expression of inflammatory cytokines. The levels of reactive oxygen species were measured using 2,7-dichlorodihydrofluorescein diacetate. Luciferase assay and immunocytochemistry were used for assessing nuclear factor-kappa B (NF-κB) transcription and p65 localization, respectively. Memory and social interaction were analyzed using the Y-maze and three-chamber tests, respectively.

Results: The ethanol extract of A. altissima leaves (AAE) inhibited iNOS and COX-2 expression in LPS-stimulated astrocytes. Moreover, AAE reduced the transcription of various proinflammatory mediators, hindered NF-κB activation, and suppressed extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activation without p38 activation. Ultra-high performance liquid chromatography with mass spectrometry analysis revealed that AAE comprised ethyl gallate, quercetin, and kaempferol, along with luteolin, which has anti-inflammatory properties, and repressed LPS-induced nitrite levels and the nuclear translocation of p65. Finally, oral administration of AAE attenuated LPS-induced memory and social impairment in mice and repressed LPS-induced ERK and JNK activation in the cortices of mice.

Conclusion: AAE could have therapeutic uses in the treatment of neuroinflammatory diseases via suppression of astrocyte activation.
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http://dx.doi.org/10.1016/j.jep.2021.114258DOI Listing
July 2021

Risk of fracture in antidepressant users with concurrent use of benzodiazepines: A self-controlled case-series analysis.

Bone 2021 Dec 10;153:116109. Epub 2021 Jul 10.

College of Pharmacy, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea. Electronic address:

Objective: Despite the fracture risk associated with both antidepressant (AD) medication and benzodiazepines (BDZs), they are commonly prescribed simultaneously. However, studies elucidating the effects of concurrent use of BDZs and ADs on the risk fracture are scant. The objective of this study was to evaluate the risk of fracture associated with concurrent use of BDZs in AD users, using a self-controlled case-series analysis.

Methods: A self-controlled case-series analysis, in which the participants act as their own control, was conducted using the Korean National Health Insurance Service-National Sample Cohort database (2002-2015). We studied AD users who were prescribed BDZs and diagnosed with a fracture. The risk periods were subdivided into consecutive periods (1-30, 31-60, and > 60 days) after receiving a BDZ. A 2-week pre-exposure period and a 2-week post-exposure period were also included. The incidence rate ratio (IRR) was estimated after adjusting for age and use of co-medications.

Results: A total of 3020 patients were identified during the study period. There was an increased fracture risk in the first 30 days following BDZ use (IRR: 1.88, 95% confidence interval [CI] 1.66-2.12), in the 31-60-day period (1.73, 95% CI 1.48-2.02), and beyond the 60-day period (IRR: 1.68, 95% CI 1.47-1.91). The risks of fracture were greater in men and older patients.

Conclusion: The concomitant use of BDZs and ADs was related to a significant increase in fracture risk. AD users should be aware of the fracture risk with concomitant BDZ use, especially for first-time BDZ users and for elderly patients.
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http://dx.doi.org/10.1016/j.bone.2021.116109DOI Listing
December 2021

Molecule-Resolved Visualization of Particulate Matter on Human Skin Using Multimodal Nonlinear Optical Imaging.

Int J Mol Sci 2021 May 14;22(10). Epub 2021 May 14.

Safety Measurement Institute, Korea Research Institute of Standards and Science, Daejeon 34113, Korea.

Precise measurement of particulate matter (PM) on skin is important for managing and preventing PM-related skin diseases. This study aims to directly visualize the deposition and penetration of PM into human skin using a multimodal nonlinear optical (MNLO) imaging system. We successfully obtained PM particle signals by merging two different sources, C-C vibrational frequency and autofluorescence, while simultaneously visualizing the anatomical features of the skin via keratin, collagen, and elastin. As a result, we found morphologically dependent PM deposition, as well as increased deposition following disruption of the skin barrier via tape-stripping. Furthermore, PM penetrated more and deeper into the skin with an increase in the number of tape-strippings, causing a significant increase in the secretion of pro-inflammatory cytokines. Our results suggest that MNLO imaging could be a useful technique for visualizing and quantifying the spatial distribution of PM in ex vivo human skin tissues.
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http://dx.doi.org/10.3390/ijms22105199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156198PMC
May 2021

The Protective Effect of Extract in Ultraviolet B-Induced Human Dermal Fibroblasts and Skin Equivalent Models.

Ann Dermatol 2020 Jun 24;32(3):251-254. Epub 2020 Apr 24.

Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Korea.

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http://dx.doi.org/10.5021/ad.2020.32.3.251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992618PMC
June 2020

Neuronal Autophagy: Characteristic Features and Roles in Neuronal Pathophysiology.

Biomol Ther (Seoul) 2021 Apr 20. Epub 2021 Apr 20.

College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.

Autophagy is an important degradative pathway that eliminates misfolded proteins and damaged organelles from cells. Autophagy is crucial for neuronal homeostasis and function. A lack of or deficiency in autophagy leads to the accumulation of protein aggregates, which are associated with several neurodegenerative diseases. Compared with non-neuronal cells, neurons exhibit rapid autophagic flux because damaged organelles or protein aggregates cannot be diluted in post-mitotic cells; because of this, these cells exhibit characteristic features of autophagy, such as compartment-specific autophagy, which depends on polarized structures and rapid autophagy flux. In addition, neurons exhibit compartment-specific autophagy, which depends on polarized structures. Neuronal autophagy may have additional physiological roles other than amino acid recycling. In this review, we focus on the characteristics and regulatory factors of neuronal autophagy. We also describe intracellular selective autophagy in neurons and its association with neurodegenerative diseases.
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http://dx.doi.org/10.4062/biomolther.2021.012DOI Listing
April 2021

Upper Extremity Deep Vein Thrombosis After Botulinum Toxin Injection: A Case Report.

Ann Rehabil Med 2021 Apr 14;45(2):160-164. Epub 2021 Apr 14.

Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.

Botulinum toxin (BoNT) injection is widely used to improve spasticity. However, after the treatment, the patient may experience pain, inflammation, swelling and redness at the injection site. In this case, we addressed deep vein thrombosis (DVT) after BoNT treatment of the upper limb. A male aged 37 years had spasticity and dystonia in his left upper extremity. BoNT-A 100 U was injected into the left biceps brachii and an equal amount into the brachialis to relieve spasticity. After three days, he developed redness and painful swelling in the left upper arm and the next day, through the upper extremity computed tomography venography, DVT was identified in the left cephalic vein. The thrombus resolved after the anticoagulation therapy with rivaroxaban (Xarelto). We hypothesized the role of mainly three mechanisms in the development of DVT in this case: repetitive strenuous activity, relative stasis due to reduced muscle tone, and possible direct mechanical damage to the vessel wall.
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http://dx.doi.org/10.5535/arm.20118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137386PMC
April 2021

Methods of measuring presynaptic function with fluorescence probes.

Appl Microsc 2021 Mar 17;51(1). Epub 2021 Mar 17.

College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.

Synaptic vesicles, which are endogenous to neurotransmitters, are involved in exocytosis by active potentials and release neurotransmitters. Synaptic vesicles used in neurotransmitter release are reused via endocytosis to maintain a pool of synaptic vesicles. Synaptic vesicles show different types of exo- and endocytosis depending on animal species, type of nerve cell, and electrical activity. To accurately understand the dynamics of synaptic vesicles, direct observation of synaptic vesicles is required; however, it was difficult to observe synaptic vesicles of size 40-50 nm in living neurons. The exo-and endocytosis of synaptic vesicles was confirmed by labeling the vesicles with a fluorescent agent and measuring the changes in fluorescence intensity. To date, various methods of labeling synaptic vesicles have been proposed, and each method has its own characteristics, strength, and drawbacks. In this study, we introduce methods that can measure presynaptic activity and describe the characteristics of each technique.
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http://dx.doi.org/10.1186/s42649-021-00051-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969681PMC
March 2021

Clinical brightening efficacy and safety of Melasolv™ (3,4,5-trimethoxy cinnamate thymol ester, TCTE) in Southeast Asian women.

J Cosmet Dermatol 2021 Sep 9;20(9):2851-2859. Epub 2021 Feb 9.

AMOREPACIFIC Research and Development Center, Gyeonggi-do, Korea.

Background: Skin darkening because of increased and irregular synthesis of melanin causes melasma, solar lentigo, and freckles. Melasolv™, produced in the early 2000s, shows potent depigmenting effect and has low cytotoxicity. It has been used as a brightening agent in cosmetics for decades.

Aims: This study was conducted to investigate whether Melasolv™ is effective for the skin of ASEAN (Southeast Asia) women.

Methods: We recruited ASEAN women in Singapore and divided them into two groups (active group vs. placebo group). Melasolv and placebo formulations were applied twice a day for 12 weeks. The changes in the pigmented spots were visually evaluated by an expert and assessed using a spectrophotometer and Mexameter at 0, 4, 8, and 12 weeks.

Results: The visual evaluation revealed significant improvements, in both size and color intensity, in the active group compared with those in the placebo group at 12 weeks. In the spectrophotometric evaluation, the L* value of the pigmented spots in the active group was significantly higher than that in the placebo group at 12 weeks. Similar results were obtained in the evaluation using the Mexameter. After 12 weeks, the melanin index of the pigmented spots significantly decreased, and it was significantly higher than that in the placebo group. There was no significant change in the erythema index. In the image analysis, there were no significant differences in skin color brightness and evenness in the active group compared with those in the placebo group.

Conclusion: Melasolv can be effective used for skin brightening.
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http://dx.doi.org/10.1111/jocd.13969DOI Listing
September 2021

Characteristics of Treponema denticola lipooligosaccharide in presence of hemin and quorum-sensing molecule.

Arch Oral Biol 2021 Apr 23;124:105062. Epub 2021 Jan 23.

Department of Oral Microbiology and Immunology, College of Dentistry, Dankook University, Cheonan, Republic of Korea. Electronic address:

Objectives: The study aimed to examine the diverse bioactivity of lipooligosaccharide extracted from T. denticola cultured in the presence of hemin and quorum-sensing inhibitor.

Design: T. denticola was cultured in the presence or absence hemin or 2(5 H)-furanone, and lipooligosaccharide from T. denticola cultured in various conditions was extracted using an extraction kit. To investigate bioactivity of the lipooligosaccharide, human gingival fibroblasts (HGFs) were treated with the extracted lipooligosaccharide in the presence or absence of Tannerella forsythia lipopolysaccharide. The induction of cytokine expressions was investigated by real-time RT-PCR and ELISA, and the signaling pathway was examined by immunoblotting. To investigate antagonistic mechanisms of the lipooligosaccharide, HGFs were cotreated with fluorescence-labeled T. forsythia lipopolysaccharide and the extracted lipooligosaccharide. Binding of T. forsythia lipopolysaccharide to the cell was analyzed by a flow cytometer.

Results: Lipooligosaccharide induced a low level of cytokine expression at high concentration of hemin or 2(5 H)-furanone. Lipooligosaccharide extracted from T. denticola cultured in higher concentration of hemin and 2(5 H)-furanone had a greater inhibitory effect on induction of cytokine expression by T. forsythia lipopolysaccharide. Further, lipooligosaccharide inhibited the activation of NF-κB and mitogen-activated protein kinase signaling pathways by T. forsythia lipopolysaccharide. Lipooligosaccharide inhibited the binding of T. forsythia lipopolysaccharide to HGFs in the presence of CD14 and LBP.

Conclusions: The characteristics of T. denticola lipooligosaccharide may be altered by bacterial communication and host factors.
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http://dx.doi.org/10.1016/j.archoralbio.2021.105062DOI Listing
April 2021

1-Methoxylespeflorin G11 Protects HT22 Cells from Glutamate-Induced Cell Death through Inhibition of ROS Production and Apoptosis.

J Microbiol Biotechnol 2021 Feb;31(2):217-225

College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea.

This study aimed to investigate the neuroprotective effects of 1-methoxylespeflorin G11 (MLG), a pterocarpan, against glutamate-induced neurotoxicity in neuronal HT22 hippocampal cells. The protective effects of MLG were evaluated using MTT assay and microscopic analysis. The extent of apoptosis was studied using flow cytometric analysis performed on the damaged cells probed with annexin V/propidium iodide. Moreover, mitochondrial reactive oxygen species (ROS) were assessed using flow cytometry through MitoSOXTM Red staining. To determine mitochondrial membrane potential, staining with tetramethylrhodamine and JC-1 was performed followed by flow cytometry. The results demonstrated that MLG attenuates glutamate-induced apoptosis in HT22 cells by inhibiting intracellular ROS generation and mitochondrial dysfunction. Additionally, MLG prevented glutamate-induced apoptotic pathway in HT22 cells through upregulation of Bcl-2 and downregulation of cleaved PARP-1, AIF, and phosphorylated MAPK cascades. In addition, MLG treatment induced HO-1 expression in HT22 cells. These results suggested that MLG exhibits neuroprotective effects against glutamate-induced neurotoxicity in neuronal HT22 cells by inhibiting oxidative stress and apoptosis.
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http://dx.doi.org/10.4014/jmb.2011.11032DOI Listing
February 2021

Antimicrobial activity and biocompatibility of the mixture of mineral trioxide aggregate and nitric oxide-releasing compound.

J Dent Sci 2021 Jan 18;16(1):29-36. Epub 2020 Aug 18.

Department of Oral Microbiology and Immunology, College of Dentistry, Dankook University, Cheonan, Republic of Korea.

Background/purpose: Antimicrobial activity and biocompatibility of root canal sealer are related to the success of endodontic treatments. This study investigated the efficacy of mixture of mineral trioxide aggregate (MTA) and a NO-releasing compound for the antimicrobial activity, biocompatibility, and physical properties.

Materials And Methods: MTA was mixed with diethylenetriamine-NO (MTA-NO), and the extracts from MTA and the MTA-NO mixture before and after setting was obtained were investigated the antimicrobial activity against and . After setting MTA and MTA-NO, pulp cell was incubated in the presence of MTA and MTA-NO disk using Transwell® cell culture insert, and the proliferation assay and mineralization-stimulated factors of the cells were analyzed by MTT assay and real-time RT-PCR, respectively. The physical properties of MTA and the MTA-NO mixture, such as surface hardness and flowability was also analyzed.

Results: The MTA-NO mixture showed stronger antimicrobial activity against and than that by MTA. Both MTA and MTA-NO mixture increase the ratio of cell proliferation and induced the expression of alkaline phosphatase, collagen type I, osteocalcin, and osteopontin. Moreover, the induction of gene expression by MTA-NO mixture was higher than that by MTA alone. No significant difference was observed for surface hardness and flowability between MTA and MTA-NO mixture.

Conclusion: The addition of a NO-releasing compound to the endodontic treatment using MTA root canal sealer might reduce the risk of bacterial infection and help to regenerate the dental pulp tissue.
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http://dx.doi.org/10.1016/j.jds.2020.07.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770295PMC
January 2021

Assessing Diagnostic and Severity Grading Accuracy of Ultrasound Measurements for Carpal Tunnel Syndrome Compared to Electrodiagnostics.

PM R 2021 Aug 23;13(8):852-861. Epub 2021 Jan 23.

Division of Physical Medicine & Rehabilitation, Department of Orthopaedics, Stanford University, Stanford, CA, USA.

Background: The combined sensory index (CSI) is the most sensitive electrodiagnostic criteria for carpal tunnel syndrome (CTS), and the CSI and Bland criteria have been shown to predict surgical treatment outcomes. The proposed ultrasound measurements have not been assessed against the CSI for diagnostic accuracy and grading of CTS severity.

Objective: To investigate the use of ultrasound evaluations for both diagnosis and assessment of severity grading of CTS in comparison to electrodiagnostic assessment.

Design: All patients underwent an electrodiagnostic evaluation using the CSI and Bland severity grading. Each patient underwent an ultrasound evaluation including cross-sectional area (CSA), the change in CSA from the forearm to the tunnel (∆CSA), and the wrist-forearm ratio (WFR). These measurements were assessed for diagnostic and severity grading accuracy using the CSI as the gold standard.

Setting: Tertiary academic center.

Participants: All patients referred for electrodiagnostic evaluation for CTS were eligible for the study. Only those with idiopathic CTS were included and those with prior CTS treatment were also excluded. Ninety-five patients were included in the study.

Interventions: Not applicable.

Main Outcome Measures: The primary study outcome measure was concordance between CSI diagnosis and severity categories and the ultrasound measurements. Both outcomes were also assessed using Bland criteria.

Results: Optimal cut-points for diagnosis of CTS were found to be CSA ≥12 mm , ∆CSA ≥4 mm , WFR ≥1.4. Using these cut-points, C-statistics comparing diagnosis of CTS using ultrasound measurements versus using the CSI ranged from 0.893-0.966. When looking at CSI severity grading compared to ∆CSA, however, the C-statistics were 0.640-0.661 with substantial overlap between severity groups.

Conclusions: Although ultrasound measurements had high diagnostic accuracy for CTS based on the CSI criteria, ultrasound measurements were unable to adequately distinguish between CSI severity groups among patients with CTS.
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http://dx.doi.org/10.1002/pmrj.12533DOI Listing
August 2021

An adenoviral vector encoded with the GPx-1 gene attenuates memory impairments induced by β-amyloid (1-42) in GPx-1 KO mice via activation of M1 mAChR-mediated signalling.

Free Radic Res 2021 Jan 10;55(1):11-25. Epub 2020 Dec 10.

Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, Republic of Korea.

In the present study, we examined whether glutathione peroxidase-1 (GPx-1), a major HO scavenger in the brain, affects memory deficits induced by Aβ (1-42) in mice. Treatment with 400 pmol/5 μl Aβ (1-42) (i.c.v.) resulted in a reduction of GPx-1 expression in wild-type (WT) mice. An Aβ (1-42)-induced reduction in acetylcholine (ACh) level was observed in the hippocampus. Treatment with Aβ (1-42) consistently resulted in reduced expression and activity of choline acetyltransferase (ChAT) and in an increase in expression and activity of acetylcholinesterase (AChE). Upon examining each of the muscarinic acetylcholine receptors (mAChRs) and nicotinic AChRs, we noted that Aβ (1-42) treatment selectively reduced the levels of M1 mAChR. In addition, Aβ (1-42) induced a significant reduction in phospho-cAMP response element-binding protein (p-CREB) and brain-derived neurotrophic factor (BDNF) expression. The cholinergic impairments induced by Aβ (1-42) were more pronounced in GPx-1 knockout mice than in WT mice. Importantly, an adenoviral vector encoded with the GPx-1 gene (Ad-GPx-1) significantly rescued Aβ (1-42)-induced cholinergic impairments in GPx-1 knockout mice. In addition, M1 mAChR antagonist dicyclomine significantly counteracted Ad-GPx-1-mediated increases in p-CREB and BDNF expression, as well as memory-enhancing effects in GPx-1 knockout mice, thus indicating that M1 mAChR might be a critical mediator for the rescue effects of Ad-GPx-1. Combined, our results suggest that GPx-1 gene protected against Aβ (1-42)-induced memory impairments activation of M1 mAChR-dependent CREB/BDNF signalling.
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http://dx.doi.org/10.1080/10715762.2020.1854455DOI Listing
January 2021

Metasurface-driven OLED displays beyond 10,000 pixels per inch.

Science 2020 Oct;370(6515):459-463

Geballe Laboratory for Advanced Materials, Stanford University, Stanford, CA 94305, USA.

Optical metasurfaces are starting to find their way into integrated devices, where they can enhance and control the emission, modulation, dynamic shaping, and detection of light waves. In this study, we show that the architecture of organic light-emitting diode (OLED) displays can be completely reenvisioned through the introduction of nanopatterned metasurface mirrors. In the resulting meta-OLED displays, different metasurface patterns define red, green, and blue pixels and ensure optimized extraction of these colors from organic, white light emitters. This new architecture facilitates the creation of devices at the ultrahigh pixel densities (>10,000 pixels per inch) required in emerging display applications (for instance, augmented reality) that use scalable nanoimprint lithography. The fabricated pixels also offer twice the luminescence efficiency and superior color purity relative to standard color-filtered white OLEDs.
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http://dx.doi.org/10.1126/science.abc8530DOI Listing
October 2020

Glutathione Peroxidase-1 Knockout Facilitates Memory Impairment Induced by β-Amyloid (1-42) in Mice via Inhibition of PKC βII-Mediated ERK Signaling; Application with Glutathione Peroxidase-1 Gene-Encoded Adenovirus Vector.

Neurochem Res 2020 Dec 16;45(12):2991-3002. Epub 2020 Oct 16.

Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 24341, Republic of Korea.

A growing body evidence suggests that selenium (Se) deficiency is associated with an increased risk of developing Alzheimer's disease (AD). Se-dependent glutathione peroxidase-1 (GPx-1) of a major antioxidant enzyme, and the most abundant isoform of GPx in the brain. In the present study, we investigated whether GPx-1 is protective against memory impairments induced by beta-amyloid (Aβ) (1-42) in mice. As the alteration of protein kinase C (PKC)-mediated ERK activation was recognized in the early stage of AD, we examined whether the GPx-1 gene modulates Aβ (1-42)-induced changes in PKC and ERK levels. We observed that Aβ (1-42) treatment (400 pmol, i.c.v.) significantly decreased PKC βII expression in the hippocampus of mice. Aβ (1-42)-induced neurotoxic changes [i.e., oxidative stress (i.e., reactive oxygen species, 4-hydroxy-2-noneal, and protein carbonyl), reduced PKC βII and phospho-ERK expressions, and memory impairment under Y-maze and passive avoidance test] were more pronounced in GPx-1 knockout than in wild type mice. Importantly, exposure to a GPx-1 gene-encoded adenovirus vector (Adv-GPx-1) significantly increased GPx-1 mRNA and GPx activity in the hippocampus of GPx-1 knockout mice. Adv-GPx-1 exposure also significantly blocked the neurotoxic changes induced by Aβ (1-42) in GPx-1 knockout mice. Treatment with ERK inhibitor U0126 did not significantly change Adv-GPx-1-mediated attenuation in PKC βII expression. In contrast, treatment with PKC inhibitor chelerythrine (CHE) reversed Adv-GPx-1-mediated attenuation in ERK phosphorylation, suggesting that PKC βII-mediated ERK signaling is important for Adv-GPx-1-mediated potentials against Aβ (1-42) insult. Our results suggest that treatment with the antioxidant gene GPx-1 rescues Aβ (1-42)-induced memory impairment via activating PKC βII-mediated ERK signaling.
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http://dx.doi.org/10.1007/s11064-020-03147-3DOI Listing
December 2020

Preparation of Hot-Melt Extruded Dosage Form for Enhancing Drugs Absorption Based on Computational Simulation.

Pharmaceutics 2020 Aug 11;12(8). Epub 2020 Aug 11.

College of Pharmacy, Sahmyook University, Seoul 01795, Korea.

The aim of this study was to control the dissolution rate and permeability of cilostazol. To enhance the dissolution rate of the active pharmaceutical ingredient (API), hot-melt extrusion (HME) technology was applied to prepare a solid dispersion (SD). To control permeability in the gastrointestinal tract regardless of food intake, the HME process was optimized based on physiologically based pharmacokinetic (PBPK) simulation. The extrudates were produced using a laboratory-scale twin-screw hot-melt extruder with co-rotatory screws and a constant feeding rate. Next, for PBPK simulation, parameter-sensitive analysis (PSA) was conducted to determine the optimization approach direction. As demonstrated by the dissolution test, the solubility of extrudate was enhanced comparing cilostazol alone. Based on the PSA analysis, the surfactant induction was a crucial factor in cilostazol absorption; thus, an extrudate with an even distribution of lipids was produced using hot-melt extrusion technology, for inducing the bile salts in the gastrointestinal tract. In vivo experiments with rats demonstrated that the optimized hot-melt extruded formulation was absorbed more rapidly with lower deviation and regardless of the meal consumed when compared to marketed cilostazol formulations.
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http://dx.doi.org/10.3390/pharmaceutics12080757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463902PMC
August 2020

Inhibition of cytochrome P450 2B6 by Astragalus extract mixture HT042.

Toxicol Res 2020 Jul 4;36(3):195-201. Epub 2019 Dec 4.

Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 05025 South Korea.

Astragalus extract mixture (AEM) HT042 is a functional food approved by the MFDS (Korean FDA) for increasing height. It comprises a mixture of three standardized extracts from root, stem, and root. In this study, drug-functional food interaction was analyzed using six major human cytochrome P450 enzymes. The inhibitory effect of AEM HT042 on P450 activities was studied using a P450-NADPH P450 reductase reconstitution system. Among the six P450 enzymes (1A2, 2A6, 2B6, 2D6, 2C9, and 3A4), only P450 2B6 activity was markedly decreased by AEM HT042 addition. The bupropion hydroxylation activity of P450 2B6 was analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). A calculated IC value of 10.62 µg/ml was obtained. To identify the inhibitory compounds in the mixture, four active compounds in AEM HT042 were analyzed. Shanzhiside methylester exhibited inhibitory effects on P450 2B6, whereas formononetin, eleutheroside E, and sesamoside did not affect P450 2B6 activity at all. Our results suggest that shanzhiside methylester in AEM HT042 is responsible for the inhibitory effect on P450 2B6 metabolism. Characterization of the inhibitory effect on P450 can help determine the safe administration of functional foods along with many clinical drugs that are metabolized by P450.
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http://dx.doi.org/10.1007/s43188-019-00027-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351922PMC
July 2020

Enzymatic reaction mechanism of cis-aconitate decarboxylase based on the crystal structure of IRG1 from Bacillus subtilis.

Sci Rep 2020 07 9;10(1):11305. Epub 2020 Jul 9.

College of Pharmacy, Chung-Ang University, Seoul, 06974, Republic of Korea.

Itaconate, which is formed by decarboxylation of cis-aconitate-an intermediate metabolite in the tricarboxylic acid cycle-has been used as a building block in polymer synthesis and is an important chemical in several biomedical and industrial applications. Itaconate is an immunometabolite with antibacterial, antiviral, immunoregulatory, and tumor-promoting activities. Recent focus has been on the role of itaconate in the field of immunology, with immune-responsive gene 1 (IRG1) being identified as the cis-aconitate decarboxylase responsible for itaconate production. We solved the structure of IRG1 from Bacillus subtilis (bsIRG1) and showed that IRG1 adopts either a closed or an open conformation; bsIRG1 was in the open form. A1 and A2 loops around the active site are flexible and can control the formation of the open and closed forms of IRG1. An in silico docking simulation showed that only the open form of IRG1 can accommodate the substrate. The most energetically favorable position of cis-aconitate in the active site of bsIRG1 involved the localization of C2 and C5 of cis-aconitate into the H102 region and H151 region of bsIRG1, respectively. Based on the structural study of bsIRG1, compared with IDS epimerase, and in silico docking simulation, we proposed two tentative enzymatic reaction mechanisms of IRG1, a two-base model and a one-base model.
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http://dx.doi.org/10.1038/s41598-020-68419-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347537PMC
July 2020

Morphologic Characteristics and Clinical Significance of Computed Tomography and Magnetic Resonance Imaging Findings of Spinal Epidural Gas.

World Neurosurg 2020 09 12;141:e792-e800. Epub 2020 Jun 12.

Department of Radiology, Wooridul Spine Hospital, Seoul, Republic of Korea.

Objective: To evaluate the morphologic characteristics and clinical significance of epidural gas based on computed tomography (CT) and magnetic resonance imaging (MRI) findings and to determine their relationship with radiculopathy.

Materials And Methods: Between March 2009 and November 2018, 110 epidural gas lesions were identified in 103 patients who underwent both CT and MRI for suspected herniated disc in the authors' institution. Patterns of epidural gas were classified as air pseudocyst, air cyst, air-contained disc herniation, and honeycomb-like air cyst. These gas patterns were compared, and possible correlations between these gas patterns and radiculopathy were evaluated.

Results: Overall agreement between CT and MRI findings for evaluation of all lesions and for differentiation of epidural gases was good (kappa [κ] = 0.775). Air pseudocysts demonstrated a moderate correlation (κ = 0.496) and air cysts showed a good correlation (κ = 0.661) with radiculopathy on MRI, whereas air-contained disc herniation and honeycomb-like cysts demonstrated a strong correlation (κ = 0.810 and 0.927, respectively) with radiculopathy on MRI.

Conclusions: This study's results help delineate new classifications of epidural gases. In addition, lumbar epidural gas with disc material (e.g., air-contained disc herniation and honeycomb-like cysts) on MRI was associated with radiculopathy.
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http://dx.doi.org/10.1016/j.wneu.2020.06.009DOI Listing
September 2020

Phase Selection of Cesium Lead Triiodides through Surface Ligand Engineering.

J Phys Chem Lett 2020 May 12;11(10):4232-4238. Epub 2020 May 12.

Department of Materials Science and Engineering, Hanbat National University, 125 Dongseo-daero, Yuseong-Gu, Daejeon 34158, Korea.

The cesium lead triiodide (CsPbI) perovskite is a promising candidate for stable light absorbers and red-light-emitting sources due to its outstanding stability. Phase engineering is the most important approach for the commercialization of CsPbI because the optically inactive nonperovskite structure is more stable than three-dimensional (3-D) perovskite lattices at ambient temperature. This study presents an in-depth evaluation to find the optimum surface ligand and to reveal the mechanism of phase stabilization by surface ligands. Thermodynamic evaluations combined with density functional theory calculations indicate the criteria for forming stable 3-D CsPbI perovskites under surface and volume free energy competition between perovskite and nonperovskite phases. Comparative calculations for ammonium, alcohol, and thiol groups show that ammonium groups enhance the phase stability of 3-D perovskites the most. In addition, ammonium-passivated CsPbI is relatively robust against defect formation and HO adsorption.
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http://dx.doi.org/10.1021/acs.jpclett.0c00499DOI Listing
May 2020

Epigenetically Upregulated T-Type Calcium Channels Contribute to Abnormal Proliferation of Embryonic Neural Progenitor Cells Exposed to Valproic Acid.

Biomol Ther (Seoul) 2020 Sep;28(5):389-396

Departments of Pharmacology and Advanced Translational Medicine, School of Medicine, Konkuk University, Seoul 05029, Republic of Korea.

Valproic acid is a clinically used mood stabilizer and antiepileptic drug. Valproic acid has been suggested as a teratogen associated with the manifestation of neurodevelopmental disorders, such as fetal valproate syndrome and autism spectrum disorders, when taken during specific time window of pregnancy. Previous studies proposed that prenatal exposure to valproic acid induces abnormal proliferation and differentiation of neural progenitor cells, presumably by inhibiting histone deacetylase and releasing the condensed chromatin structure. Here, we found valproic acid up-regulates the transcription of T-type calcium channels by inhibiting histone deacetylase in neural progenitor cells. The pharmacological blockade of T-type calcium channels prevented the increased proliferation of neural progenitor cells induced by valproic acid. Differentiated neural cells from neural progenitor cells treated with valproic acid displayed increased levels of calcium influx in response to potassium chloride-induced depolarization. These results suggest that prenatal exposure to valproic acid up-regulates T-type calcium channels, which may contribute to increased proliferation of neural progenitor cells by inducing an abnormal calcium response and underlie the pathogenesis of neurodevelopmental disorders.
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http://dx.doi.org/10.4062/biomolther.2020.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457173PMC
September 2020

Anti‑inflammatory role of Prunus persica L. Batsch methanol extract on lipopolysaccharide‑stimulated glial cells.

Mol Med Rep 2020 05 10;21(5):2030-2040. Epub 2020 Mar 10.

College of Pharmacy, Chung‑Ang University, Seoul 06974, Republic of Korea.

Glial cells are the resident immune cells of the central nervous system. Reactive glial cells release inflammatory mediators that induce neurotoxicity or aggravate neurodegeneration. Regulation of glial activation is crucial for the initiation and progression of neuropathological conditions. Constituents of the peach tree (Prunus persica L. Batsch), which has a global distribution, have been found to exert therapeutic effects in pathological conditions, such as rashes, eczema and allergies. However, the therapeutic potential of its aerial parts (leaves, fruits and twigs) remains to be elucidated. The present study aimed to evaluate the anti‑inflammatory role of P. persica methanol extract (PPB) on lipopolysaccharide (LPS)‑stimulated glial cells. High‑performance liquid chromatography coupled with tandem mass spectrometry analysis showed that PPB contained chlorogenic acid and catechin, which have antioxidant properties. Western blot and reverse transcription polymerase chain reaction results indicated that PPB reduced the transcription of various proinflammatory enzymes (nitric oxide synthase and cyclooxygenase‑2) and cytokines [tumor necrosis factor‑α, interleukin (IL)‑1β and IL‑6] in LPS‑stimulated BV2 cells. In addition, PPB inhibited the activation of NF‑κB and various mitogen‑activated protein kinases required for proinflammatory mediator transcription. Finally, nitrite measurement and immunocytochemistry results indicated that PPB also suppressed nitrite production and NF‑κB translocation in LPS‑stimulated primary astrocytes. Thus, PPB may be used as a potential therapeutic agent for neurodegenerative diseases and neurotoxicity via the suppression of glial cell activation.
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http://dx.doi.org/10.3892/mmr.2020.11016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7115241PMC
May 2020

Skin-interfaced biosensors for advanced wireless physiological monitoring in neonatal and pediatric intensive-care units.

Nat Med 2020 03 11;26(3):418-429. Epub 2020 Mar 11.

Center for Bio-integrated Electronics, Northwestern University, Evanston, IL, USA.

Standard clinical care in neonatal and pediatric intensive-care units (NICUs and PICUs, respectively) involves continuous monitoring of vital signs with hard-wired devices that adhere to the skin and, in certain instances, can involve catheter-based pressure sensors inserted into the arteries. These systems entail risks of causing iatrogenic skin injuries, complicating clinical care and impeding skin-to-skin contact between parent and child. Here we present a wireless, non-invasive technology that not only offers measurement equivalency to existing clinical standards for heart rate, respiration rate, temperature and blood oxygenation, but also provides a range of important additional features, as supported by data from pilot clinical studies in both the NICU and PICU. These new modalities include tracking movements and body orientation, quantifying the physiological benefits of skin-to-skin care, capturing acoustic signatures of cardiac activity, recording vocal biomarkers associated with tonality and temporal characteristics of crying and monitoring a reliable surrogate for systolic blood pressure. These platforms have the potential to substantially enhance the quality of neonatal and pediatric critical care.
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http://dx.doi.org/10.1038/s41591-020-0792-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315772PMC
March 2020

Glucose Exerts an Anti-Melanogenic Effect by Indirect Inactivation of Tyrosinase in Melanocytes and a Human Skin Equivalent.

Int J Mol Sci 2020 Mar 3;21(5). Epub 2020 Mar 3.

Department of Beauty and Cosmetic Science, Eulji University, Seongnam City, 13135, Gyunggi-do, Korea.

Sugars are ubiquitous in organisms and well-known cosmetic ingredients for moisturizing skin with minimal side-effects. Glucose, a simple sugar used as an energy source by living cells, is often used in skin care products. Several reports have demonstrated that sugar and sugar-related compounds have anti-melanogenic effects on melanocytes. However, the underlying molecular mechanism by which glucose inhibits melanin synthesis is unknown, even though glucose is used as a whitening as well as moisturizing ingredient in cosmetics. Herein, we found that glucose significantly reduced the melanin content of α-melanocyte-stimulating hormone (MSH)-stimulated B16 cells and darkly pigmented normal human melanocytes with no signs of cytotoxicity. Furthermore, topical treatment of glucose clearly demonstrated its whitening efficacy through photography, Fontana-Masson (F&M) staining, and multi-photon microscopy in a pigmented 3D human skin model, MelanoDerm. However, glucose did not alter the gene expression or protein levels of major melanogenic proteins in melanocytes. While glucose potently decreased intracellular tyrosinase activity in melanocytes, it did not reduce mushroom tyrosinase activity in a cell-free experimental system. However, glucose was metabolized into lactic acid, which can powerfully suppress tyrosinase activity. Thus, we concluded that glucose indirectly inhibits tyrosinase activity through conversion into lactic acid, explaining its anti-melanogenic effects in melanocytes.
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http://dx.doi.org/10.3390/ijms21051736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084727PMC
March 2020

Differences of Spinal Curvature, Thoracic Mobility, and Respiratory Strength Between Chronic Neck Pain Patients and People Without Cervical Pain.

Ann Rehabil Med 2020 Feb 29;44(1):58-68. Epub 2020 Feb 29.

Department of Rehabilitation Medicine, Kwangju Christian Hospital, Gwangju, Korea.

Objective: To investigate the differences of spinal curvature, thoracic sagittal mobility, and respiratory strength between patients with chronic neck pain (CNP) and people without cervical pain, and to determine the correlation between respiratory strength and thoracic mobility in CNP patients.

Methods: A total of 78 participants were finally included in this study, of whom 30 had no cervical pain and 48 had CNP. The Neck Disability Index (NDI), cervical lordotic curvature, thoracic kyphotic curvature, thoracic sagittal range of motion (ROM), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were measured and analyzed.

Results: In males, thoracic sagittal ROMMEP-MIP and MEP showed a significant difference between the no cervical pain group and the CNP group. In females, thoracic kyphotic curvature, thoracic sagittal ROMMEP-MIP, MIP, and MEP were significantly different between the no cervical pain group and the CNP group. Thoracic kyphotic curvature was significantly correlated with MEP and MIP in all population groups, and significantly correlated with NDI in the female group. Thoracic sagittal ROMMEP-MIP had a significant linear relationship with NDI, MEP, and MIP in all population groups.

Conclusion: The thoracic mobility during forced respiration was reduced in patients with CNP and was correlated with respiratory strength. Changes in the biomechanics of the cervicothoracic spine and rib cage due to CNP may contribute to impairment of respiratory strength.
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http://dx.doi.org/10.5535/arm.2020.44.1.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056330PMC
February 2020

Characterization of the Anti-Cancer Activity of the Probiotic Bacterium Using 2D vs. 3D Culture in Colorectal Cancer Cells.

Biomolecules 2019 10 1;9(10). Epub 2019 Oct 1.

Center for Bioanalysis, Korea Research Institute of Standards and Science (KRISS), Daejeon 34113, Korea.

The aim of this study was to investigate the potential anti-cancer effects of probiotic cell-free supernatant (CFS) treatment using for colorectal cancer (CRC) in 3D culture systems. Cell viability was assessed using MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2-tetrazolium, inner salt) assays, whereas apoptosis was monitored through RT-qPCR analysis of Bax, Bak, Noxa, and Bid mRNA expressions in addition to flow cytometry analysis of cell-free supernatant (LCFS) treatment. Our results showed that the anti-cancer effect of LCFS on cell viability was pronouncedly enhanced in 3D-cultured HCT-116 cells, which was linked to the increased level of cleaved caspase 3. Additionally, upregulation of apoptotic marker gene mRNA transcription was dramatically increased in 3D cultured cells compared to 2D systems. In conclusion, this study suggests that LCFS enhances the activation of intrinsic apoptosis in HCT-116 cells and the potential anti-cancer effects of Lactobacilli mixtures in 3D culture systems. All in all, our study highlights the benefits of 3D culture models over 2D culture modeling in studying the anti-cancer effects of probiotics.
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http://dx.doi.org/10.3390/biom9100557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843223PMC
October 2019
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