Cell Membrane-Cloaked Nanotherapeutics for Targeted Drug Delivery.

Cell membrane cloaking technique is bioinspired nanotechnology that takes advantage of naturally derived design cues for surface modification of nanoparticles. Unlike modification with synthetic materials, cell membranes can replicate complex physicochemical properties and biomimetic functions of the parent cell source. This technique indeed has the potential to greatly augment existing nanotherapeutic platforms. Here, we provide a comprehensive overview of engineered cell membrane-based nanotherapeutics for targeted drug delivery and biomedical applications and discuss the challenges and opportunities of cell membrane cloaking techniques for clinical translation.

Angiotensin AT1 receptor antagonism by losartan stimulates adipocyte browning via induction of apelin.

Adipocyte browning appears to be a potential therapeutic strategy to combat obesity and related metabolic disorders. Recent studies have shown that apelin, an adipokine, stimulates adipocyte browning and has negative cross-talk with angiotensin II receptor type 1 (AT1 receptor) signaling. Here, we report that losartan, a selective AT1 receptor antagonist, induces browning, as evidenced by an increase in browning marker expression, mitochondrial biogenesis, and oxygen consumption in murine adipocytes. In parallel, losartan up-regulated apelin expression, concomitant with increased phosphorylation of protein kinase B and AMP-activated protein kinase. However, the siRNA-mediated knockdown of apelin expression attenuated losartan-induced browning. Angiotensin II cotreatment also inhibited losartan-induced browning, suggesting that AT1 receptor antagonism-induced activation of apelin signaling may be responsible for adipocyte browning induced by losartan. The in vivo browning effects of losartan were confirmed using both C57BL/6J and ob/ob mice. Furthermore, in vivo apelin knockdown by adeno-associated virus carrying-apelin shRNA significantly inhibited losartan-induced adipocyte browning. In summary, these data suggested that AT1 receptor antagonism by losartan promotes the browning of white adipocytes via the induction of apelin expression. Therefore, apelin modulation may be an effective strategy for the treatment of obesity and its related metabolic disorders.

Impact of Endoscopists' Personality Traits on Adenoma and Polyp Detection Rates in Colonoscopy: A KASID Multicenter Study.

BACKGROUND: The personality traits of endoscopists have been suggested to affect the adenoma detection rate (ADR). We thus evaluated the relationship between endoscopists' personality traits and the ADR during colonoscopy using the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). METHODS: In total, 1230 patients (asymptomatic and aged 50-80 years) who underwent screening or surveillance (≥ 5 years) colonoscopy were recruited from 13 university hospitals by 20 endoscopists between September 2015 and December 2017. We retrospectively measured the ADR, polyp detection rate (PDR), and number of adenomas per colonoscopy (APC). All 20 endoscopists completed all 567 true/false MMPI-2 items. RESULTS: The overall mean colonoscopy withdrawal time, PDR, ADR, and APC were 7.3 ± 2.8 min, 55%, 45.3%, and 0.97 ± 1.58, respectively. No significant difference was observed in the MMPI-2 clinical scales (e.g., hypochondriasis and psychasthenia), content scales (e.g., obsessiveness and type A character), or supplementary scales (e.g., dominance and social responsibility) between the high ADR group (ADR ≥45%, n = 10) and the low ADR group (ADR < 45%, n = 10). In multivariate logistic regression analysis, the ADR was associated significantly with patient age and sex. The ADR was related significantly to endoscopists' colonoscopy experience and the per-minute increase in the colonoscopy withdrawal time (OR 1.21, 95% CI 1.06-1.38, p = 0.005). In a logistic regression analysis adjusted for patient factors, the ADR was associated significantly with ego strength (OR 1.04, 95% CI 1.00-1.09, p = 0.044), as measured by the MMPI-2. CONCLUSIONS: With the exception of ego strength, the endoscopists' personality traits were not associated with adenoma or polyp detection.

The Impact of Surgical Intervention on Neurodevelopmental Outcomes in Very Low Birth Weight Infants: a Nationwide Cohort Study in Korea.

BACKGROUND: To investigate the incidence of surgical intervention in very low birth weight (VLBW) infants and the impact of surgery on neurodevelopmental outcomes at corrected ages (CAs) of 18-24 months, using data from the Korean Neonatal Network (KNN). METHODS: Data from 7,885 VLBW infants who were born and registered with the KNN between 2013 to 2016 were analyzed in this study. The incidences of various surgical interventions and related morbidities were analyzed. Long-term neurodevelopmental outcomes at CAs of 18-24 months were compared between infants (born during 2013 to 2015, n = 3,777) with and without surgery. RESULTS: A total of 1,509 out of 7,885 (19.1%) infants received surgical interventions during neonatal intensive care unit (NICU) hospitalization. Surgical ligation of patent ductus arteriosus (n = 840) was most frequently performed, followed by laser therapy for retinopathy of prematurity and laparotomy due to intestinal perforation. Infants who underwent surgery had higher mortality rates and greater neurodevelopmental impairment than infants who did not undergo surgery (P value < 0.01, both). On multivariate analysis, single or multiple surgeries increased the risk of neurodevelopmental impairment compared to no surgery with adjusted odds ratios (ORs) of 1.6 with 95% confidence interval (CI) of 1.1-2.6 and 2.3 with 95% CI of 1.1-4.9. CONCLUSION: Approximately one fifth of VLBW infants underwent one or more surgical interventions during NICU hospitalization. The impact of surgical intervention on long-term neurodevelopmental outcomes was sustained over a follow-up of CA 18-24 months. Infants with multiple surgeries had an increased risk of neurodevelopmental impairment compared to infants with single surgeries or no surgeries after adjustment for possible confounders.

One-year Cohort Follow-up on the Diagnosis and Posttraumatic Symptoms in Child Sexual Assault Victims in Korea.

OBJECTIVE: The victims and their families of child sexual abuse (CSA) may confront persistent psychological sequela. We aimed to investigate the psychological symptoms, diagnosis, and family functions in children and adolescents with CSA. METHODS: We assessed the symptom scales at 6-month intervals, and conducted diagnostic re-assessments at 1-year intervals. Trauma Symptom Checklist for Children (TSCC), Trauma Symptom Checklist for Young Children (TSCYC), Family Adaptability and Cohesion Evaluation Scales IV (FACES-IV), and Family Communication Scale (FCS) scores were reported by children or parents. RESULTS: We found in parent-reported TSCYC, that posttraumatic stress symptoms domain scores significantly decreased with time progression. The scores decreased more in the evidence-based treatment group over time in anxiety and posttraumatic stress symptom domains of TSCC. In FACES-IV and FCS scores, indices of family function have been gradually increasing both after 6 months and after 1 year compared to the initial evaluation. Further, about 64% of the children diagnosed with psychiatric diseases, including posttraumatic stress disorder (PTSD) at the initial assessment maintained the same diagnosis at follow-up. CONCLUSION: We observed changes in psychological symptoms and family functioning in sexually abused children with time progression during 1 year. It is postulated that PTSD may be a persistent major mental illness in the victims of CSA.

Adapalene induces adipose browning through the RARß-p38 MAPK-ATF2 pathway.

Adipose browning has recently been reported to be a novel therapeutic strategy for obesity. Because the retinoic acid receptor (RAR) is a potential target involved in browning, adapalene (AD), an anti-acne agent with RAR agonism, was examined in detail for its effects on adipose browning and the underlying mechanisms in vitro and in vivo. AD upregulated the expression of adipose browning-related markers in a concentration-dependent manner, promoted mitochondrial biogenesis, increased oxygen consumption rates, and lowered lipid droplet sizes in differentiated 3T3/L1 white adipocytes. Among the three retinoic acid receptors (RARα, RARß, and RARγ), knockdown of the gene encoding RARß mitigated AD-induced adipose browning. Similarly, LE135 (a selective RARß antagonist) attenuated AD action, suggesting that AD promotes adipose browning through RARß. Sequential phosphorylation of p38 mitogen-activated protein kinase (MAPK) and activating transcription factor 2 (ATF2) was critical for AD-induced adipose browning, based on the observations that either SB203580 (a p38 MAPK inhibitor) or ATF2 siRNA reduced the effects of AD. In vivo browning effects of AD were confirmed in C57BL/6J mice and high-fat diet-induced obese (DIO) mice after oral administration of AD either acutely or chronically. This study identifies new actions of AD as an adipose browning agent and demonstrates that RARß activation followed by increased phosphorylation of p38 MAPK and ATF2 appears to be a key mechanism of AD action.

Diabetic bone regeneration with nanoceria-tailored scaffolds by recapitulating cellular microenvironment: Activating integrin/TGF-ß co-signaling of MSCs while relieving oxidative stress.

Regenerating defective bone in patients with diabetes mellitus remains a significant challenge due to high blood glucose level and oxidative stress. Here we aim to tackle this issue by means of a drug- and cell-free scaffolding approach. We found the nanoceria decorated on various types of scaffolds (fibrous or 3D-printed one; named nCe-scaffold) could render a therapeutic surface that can recapitulate the microenvironment: modulating oxidative stress while offering a nanotopological cue to regenerating cells. Mesenchymal stem cells (MSCs) recognized the nanoscale (tens of nm) topology of nCe-scaffolds, presenting highly upregulated curvature-sensing membrane protein, integrin set, and adhesion-related molecules. Osteogenic differentiation and mineralization were further significantly enhanced by the nCe-scaffolds. Of note, the stimulated osteogenic potential was identified to be through integrin-mediated TGF-ß co-signaling activation. Such MSC-regulatory effects were proven in vivo by the accelerated bone formation in rat calvarium defect model. The nCe-scaffolds further exhibited profound enzymatic and catalytic potential, leading to effectively scavenging reactive oxygen species in vivo. When implanted in diabetic calvarium defect, nCe-scaffolds significantly enhanced early bone regeneration. We consider the currently-exploited nCe-scaffolds can be a promising drug- and cell-free therapeutic means to treat defective tissues like bone in diabetic conditions.

TLR4 downregulation by the RNA-binding protein PUM1 alleviates cellular aging and osteoarthritis.

Dysfunction of mRNA or RNA-binding proteins (RBPs) causes cellular aging and age-related degenerative diseases; however, information regarding the mechanism through which RBP-mediated posttranscriptional regulation affects cellular aging and related disease processes is limited. In this study, PUM1 was found to be associated with the self-renewal capacity and aging process of human mesenchymal stem cells (MSC). PUM1 interacted with the 3'-untranslated region of Toll-like receptor 4 (TLR4) to suppress TLR4 mRNA translation and regulate the activity of nuclear factor-κB (NF-κB), a master regulator of the aging process in MSCs. PUM1 overexpression protected MSCs against H2O2-induced cellular senescence by suppressing TLR4-mediated NF-κB activity. TLR4-mediated NF-κB activation is a key regulator in osteoarthritis (OA) pathogenesis. PUM1 overexpression enhanced the chondrogenic potential of MSCs even under the influence of inflammation-inducing factors, such as lipopolysaccharide (LPS) or interleukin-1ß (IL-1ß), whereas the chondrogenic potential was reduced following the PUM1 knockdown-mediated TLR4 activation. PUM1 levels decreased under inflammatory conditions in vitro and during OA progression in human and mouse disease models. PUM1 knockdown in human chondrocytes promoted chondrogenic phenotype loss, whereas PUM1 overexpression protected the cells from inflammation-mediated disruption of the chondrogenic phenotype. Gene therapy using a lentiviral vector encoding mouse PUM1 showed promise in preserving articular cartilage integrity in OA mouse models. In conclusion, PUM1 is a novel suppressor of MSC aging, and the PUM1-TLR4 regulatory axis represents a potential therapeutic target for OA.

Antioxidant Properties and Protective Effects of Aerial Parts from Cnidium officinale Makino on Oxidative Stress-Induced Neuronal Cell Death.

The rhizomes of Cnidium officinale Makino have been used as a traditional medicine for many purposes, however, use of its aerial parts is very limited. We investigated the antioxidant properties and protective effects of the aerial parts (leaves and stems) from C. officinale on H2O2-induced toxicity in SH-SY5Y neuroblastoma. C. officinale methanol extracts (70%) were sequentially fractionated using hexane (non-polar fraction, NF), ethyl acetate (intermediate polar fraction, IF), and water (polar fraction, PF). Total phenolics and flavonoids contents were highest in IF, followed by PF. IF also showed the strongest radical scavenging activities against 2,2-diphenyl-2-picrylhydrazyl and 2,2'-azinobis(3-ethylbenzo-thiazoline-6-sulfonic acid), as well as superoxide, with the half maximal inhibitory concentrations of 13.2, 23.2, and 12.8 mg/mL, respectively. Furthermore, all fractions significantly inhibited linoleic acid peroxidation induced by the Fenton reaction or by UV irradiation. Both PF and IF protected against H2O2-induced SH-SY5Y neuronal cell death by increasing the cell survival by 22.1∼47.7 and 35.9∼50.3% at concentrations of 25∼100 and 25∼400 µg/mL, respectively, whereas NF was toxic to the cells at these concentrations. IF also significantly decreased intracellular levels of reactive oxygen species by 7.72∼47.47% at a concentration of 25∼200 µg/mL. Our results indicate that compounds from the aerial parts of C. officinale have potent antioxidant activities, which may help rescue neuronal cells from oxidative stress-induced injury. Therefore, the aerial parts, as well as the rhizomes, of C. officinale may have medicinal applications.

MicroRNAs Regulating Hippo-YAP Signaling in Liver Cancer.

Liver cancer is one of the most common cancers worldwide, and its prevalence and mortality rate are increasing due to the lack of biomarkers and effective treatments. The Hippo signaling pathway has long been known to control liver size, and genetic depletion of Hippo kinases leads to liver cancer in mice through activation of the downstream effectors yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Both YAP and TAZ not only reprogram tumor cells but also alter the tumor microenvironment to exert carcinogenic effects. Therefore, understanding the mechanisms of YAP/TAZ-mediated liver tumorigenesis will help overcome liver cancer. For decades, small noncoding RNAs, microRNAs (miRNAs), have been reported to play critical roles in the pathogenesis of many cancers, including liver cancer. However, the interactions between miRNAs and Hippo-YAP/TAZ signaling in the liver are still largely unknown. Here, we review miRNAs that influence the proliferation, migration and apoptosis of tumor cells by modulating Hippo-YAP/TAZ signaling during hepatic tumorigenesis. Previous findings suggest that these miRNAs are potential biomarkers and therapeutic targets for the diagnosis, prognosis, and treatment of liver cancer.

Biomaterials-assisted spheroid engineering for regenerative therapy.

Cell-based therapy is a promising approach in the field of regenerative medicine. As cells are formed into spheroids, their survival, functions, and engraftment in the transplanted site are significantly improved compared to single cell transplantation. To improve the therapeutic effect of cell spheroids even further, various biomaterials (e.g., nano- or microparticles, fibers, and hydrogels) have been developed for spheroid engineering. These biomaterials not only can control the overall spheroid formation (e.g., size, shape, aggregation speed, and degree of compaction), but also can regulate cell-to-cell and cell-to-matrix interactions in spheroids. Therefore, cell spheroids in synergy with biomaterials have recently emerged for cell-based regenerative therapy. Biomaterials-assisted spheroid engineering has been extensively studied for regeneration of bone or/and cartilage defects, critical limb ischemia, and myocardial infarction. Furthermore, it has been expanded to pancreas islets and hair follicle transplantation. This paper comprehensively reviews biomaterials-assisted spheroid engineering for regenerative therapy. [BMB Reports 2021; 54(7): 356-367].

The Effect of Selenium Nanoparticles on the Osteogenic Differentiation of MC3T3-E1 Cells.

Reactive oxygen species (ROS) regulate various functions of cells, including cell death, viability, and differentiation, and nanoparticles influence ROS depending on their size and shape. Selenium is known to regulate various physiological functions, such as cell differentiations and anti-inflammatory functions, and plays an important role in the regulation of ROS as an antioxidant. This study aims to investigate the effect of selenium nanoparticles (SeNPs) on the differentiation of osteogenic MC3T3-E1 cells. After fabrication of SeNPs with a size of 25.3 ± 2.6 nm, and confirmation of its oxidase-like activity, SeNPs were added to MC3T3-E1 cells with or without H2O2: 5~20 µg/mL SeNPs recovered cells damaged by 200 µM H2O2 via the intracellular ROS downregulating role of SeNPs, revealed by the ROS staining assay. The increase in osteogenic maturation with SeNPs was gradually investigated by expression of osteogenic genes at 3 and 7 days, Alkaline phosphatase activity staining at 14 days, and Alizarin red S staining at 28 days. Therefore, the role of SeNPs in regulating ROS and their therapeutic effects on the differentiation of MC3T3-E1 cells were determined, leading to possible applications for bone treatment.

Dual actions of osteoclastic-inhibition and osteogenic-stimulation through strontium-releasing bioactive nanoscale cement imply biomaterial-enabled osteoporosis therapy.

Repair of defective hard-tissues in osteoporotic patients faces significantly challenges with limited therapeutic options. Although biomedical cements are considered promising materials for healthy bone repair, their uses for healing osteoporotic fracture are clinically limited. Herein, strontium-releasing-nanoscale cement was introduced to provide dual therapeutic-actions (pro-osteogenesis and anti-osteoclastogenesis), eventually for the regeneration of osteoporotic bone defect. The Sr-nanocement hardened from the Sr-doped nanoscale-glass particles was shown to release multiple ions including silicate, calcium and strontium at doses therapeutically relevant over time. When the Sr-nanocement was treated to pre-osteoblastic cells, the osteogenic mRNA level (Runx2, Opn, Bsp, Ocn), alkaline phosphatase activity, calcium deposition, and target luciferase reporter were stimulated with respect to the case with Sr-free-nanocement. When treated to pre-osteoclastic cells, the Sr-nanocement substantially reduced the osteoclastogenesis, such as osteoclastic mRNA level (Casr, Nfatc1, c-fos, Acp, Ctsk, Mmp-9), tartrate-resistant acid trap activity, and bone resorption capacity. In particular, the osteoclastic inhibition resulted in part from the interactive effect of osteoblasts which were activated by the Sr-nanocement, i.e., blockage of RANKL (receptor activator of nuclear factor-κB ligand) binding by enhanced osteoprotegerin and the deactivated Nfatc1. The Sr-nanocement, administered to an ovariectomized tibia defect (osteoporotic model) in rats, exhibited profound bone regenerative potential in cortical and surrounding trabecular area, including increased bone volume and density, enhanced production of osteopromotive proteins, and more populated osteoblasts, together with reduced signs of osteoclastic bone resorption. These results demonstrate that Sr-nanocement, with its dual effects of osteoclastic inhibition and osteogenic-stimulation, can be considered an effective nanotherapeutic implantable biomaterial platform for the treatment of osteoporotic bone defects.

Electricity auto-generating skin patch promotes wound healing process by activation of mechanosensitive ion channels.

Electricity constitutes a natural biophysical component that preserves tissue homeostasis and modulates many biological processes, including the repair of damaged tissues. Wound healing involves intricate cellular events, such as inflammation, angiogenesis, matrix synthesis, and epithelialization whereby multiple cell types sense the environmental cues to rebuild the structure and functions. Here, we report that electricity auto-generating glucose-responsive enzymatic-biofuel-cell (EBC) skin patch stimulates the wound healing process. Rat wounded-skin model and in vitro cell cultures showed that EBC accelerated wound healing by modulating inflammation while stimulating angiogenesis, fibroblast fuctionality and matrix synthesis. Of note, EBC-activated cellular bahaviors were linked to the signalings involved with calcium influx, which predominantly dependent on the mechanosensitive ion channels, primarily Piezo1. Inhibition of Piezo1-receptor impaired the EBC-induced key functions of both fibroblasts and endothelial cells in the wound healing. This study highlights the significant roles of electricity played in wound healing through activated mechanosensitive ion channels and the calcium influx, and suggests the possibility of the electricity auto-generating EBC-based skin patch for use as a wound healing device.

A Study on Myogenesis by Regulation of Reactive Oxygen Species and Cytotoxic Activity by Selenium Nanoparticles.

Reactive oxygen species (ROS) are continuously produced by skeletal muscle during contractile activity and even at rest. However, the ROS generated from excessive exercise or traumatic damage may produce more ROS than can be neutralized by an antioxidant capacity, which can be harmful to muscle function. In particular, selenium is a known antioxidant that regulates physiological functions such as cell differentiation and anti-inflammatory function. In this study, we developed nano-sized antioxidative biomaterials using selenium to investigate the protective and differentiation effects against C2C12 myoblasts in an H2O2-induced oxidative stress environment. The selenium nanoparticles (SeNPs) were produced with a size of 35.6 ± 4.3 nm and showed antioxidant effects according to the 3,3',5,5'-tetramethylbenzidine assay. Then, SeNPs were treated to C2C12 cells with or without H2O2. Our results showed that SeNPs reduced C2C12 apoptosis and intracellular ROS levels. Additionally, SeNPs effectively up-regulated in the presence of H2O2, MyoD, MyoG, α-actinin, and myosin heavy chain, which are well known to increase during myoblast differentiation as assayed by qRT-PCR, immunocytochemistry-staining, western blotting. These results demonstrate that SeNPs can accelerate differentiation with its protective effects from the ROS environment and can be applied to the treatment of skeletal muscle in a cellular redox environment.

Antibacterial, proangiogenic, and osteopromotive nanoglass paste coordinates regenerative process following bacterial infection in hard tissue.

Bacterial infection raises serious concerns in tissue repair settings involved with implantable biomaterials, devastating the regenerative process and even life-threatening. When hard tissues are infected with bacteria (called 'osteomyelitis'), often the cases in open fracture or chronic inflammation, a complete restoration of regenerative capacity is significantly challenging even with highly-dosed antibiotics or surgical intervention. The implantable biomaterials are thus needed to be armored to fight bacteria then to relay regenerative events. To this end, here we propose a nanoglass paste made of ~200-nm-sized silicate-glass (with Ca, Cu) particles that are hardened in contact with aqueous medium and multiple-therapeutic, i.e., anti-bacterial, pro-angiogenic and osteopromotive. The nanoglass paste self-hardened via networks of precipitated nano-islands from leached ions to exhibit ultrahigh surface area (~300 m2/g), amenable to fill tunable defects with active biomolecular interactions. Also, the nanoglass paste could release multiple ions (silicate, calcium, and copper) at therapeutically relevant doses and sustainably (for days to weeks), implying possible roles in surrounding cells/tissues as a therapeutic-ions reservoir. The osteopromotive effects of nanoglass paste were evidenced by the stimulated osteogenic differentiation of MSCs. Also, the nanoglass paste promoted angiogenesis of endothelial cells in vitro and vasculature formation in vivo. Furthermore, the significant bactericidal effect of nanoglass paste, as assessed with E. coli and S. aureus, highlighted the role of copper played in elevating ROS level and destroying homeostasis, which salvaged tissue cells from co-cultivated bacteria contamination. When administered topically to rat tibia osteomyelitis defects, the nanoglass paste enhanced in vivo bone healing and fracture resistance. The developed nanoglass paste, given its self-setting property and the coordinated therapeutic actions, is considered to be a promising drug-free inorganic biomaterial platform for the regenerative therapy of bacteria-infected hard tissues.

Korean red ginseng attenuates hyperglycemia-induced renal inflammation and fibrosis via accelerated autophagy and protects against diabetic kidney disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Panax ginseng C.A. Mey. (Korean ginseng) has been widely used in traditional medicine to treat diabetes mellitus for thousands of years. It also plays a key role in health maintenance owing to its anti-oxidant and anti-fatigue properties, and is quite popular as a dietary supplement. AIM OF THE STUDY: This study was designed to offer a complementary and alternative medicine to manage the diabetic kidney disease (DKD), which causes long-term damage to the renal structure. We also investigated the regulation of the autophagy mechanism, which is the underlying the pathogenesis of DKD. MATERIALS AND METHODS: The effect of Korean red ginseng (KRG) on DKD was evaluated using human kidney proximal tubular cells and streptozotocin (STZ)-treated Sprague-Dawley rat models. In vitro experiments were conducted to evaluate the proteins related to fibrosis and autophagy. This was followed by in vivo experiments involving rats treated with single intraperitoneal administration of STZ (60 mg/kg) and then with KRG solution orally for 4 weeks. Proteins related to renal injury, fibrosis, and autophagy were determined by immunoblotting. Hematoxylin and eosin (H&E), Periodic acid-Schiff (PAS), Sirius red, and immunostaining were processed for histological studies. RESULTS: KRG diminished the levels of metabolic measurements and blood parameters. Western blotting showed a decreased expression of proteins, such as TGF-ß1, KIM1, and AGE, which are responsible for renal inflammation, injury, and fibrosis. Histological studies also supported these results and revealed that the KRG-treated groups recovered from renal injury and fibrosis. Furthermore, the autophagy marker, LC3, was upregulated, whereas p62 was downregulated. The levels of proteins related to the autophagy mechanism, such as ATG7, increased, while mammalian target of rapamycin (mTOR) decreased with the KRG treatment and exhibited accelerated autophagy compared to the STZ alone group. CONCLUSIONS: KRG can suppress renal inflammation, injury, and fibrosis by blocking TGF-ß1 activation and can induce cellular autophagy. Therefore, this study strongly suggests that KRG exhibits a renoprotective effect against the STZ-induced DKD.

Author Correction: Telmisartan induces browning of fully differentiated white adipocytes via M2 macrophage polarization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Label-Free Fluorescent Mesoporous Bioglass for Drug Delivery, Optical Triple-Mode Imaging, and Photothermal/Photodynamic Synergistic Cancer Therapy.

Nanomaterials combined with phototherapy and multimodal imaging are promising for cancer theranostics. Our aim is to develop fluorescent mesoporous bioglass nanoparticles (fBGn) based on carbon dots (CD) with delivery, triple-mode imaging, and photothermal (PTT) properties for cancer theranostics. A direct and label-free approach was used to prepare multicolor fluorescent fBGn with 3-aminopropyl triethoxysilane as the surface-functionalizing agent. The calcination at 400 °C provided fBGn with high fluorescence intensity originating from the CD. In particular, a triple-mode emission [fluorescence imaging, two-photon (TP), and Raman imaging] was observed which depended on CD nature and surface properties such as surface oxidation edge state, amorphous region, nitrogen passivation of surface state, and crystalline region. The fBGn also exhibited phototherapeutic properties such as photodynamic (PDT) and PTT effects. The antitumor effect of the combined PDT/PTT therapy was significantly higher than that of individual (PDT or PTT) therapy. The fBGn, due to the mesoporous structure, the anticancer drug doxorubicin could be loaded and released in a pH-dependent way to show chemotherapy effects on cancer cells. The in vivo imaging and biocompatibility of fBGn were also demonstrated in a nude mouse model. The fBGn, with the combined capacity of anticancer delivery, triple-mode imaging, and PTT/PDT therapy, are considered to be potentially useful for cancer theranostics.

Clinical impact of admission hypothermia in very low birth weight infants: results from Korean Neonatal Network.

BACKGROUND: Preterm infants have difficulty maintaining body temperature after birth. However, clinical guidelines advocate that neonatal body temperature should be maintained at 36.5°C-37.5°C. PURPOSE: We aimed to investigate the incidence of admission hypothermia in very low birth weight (VLBW) infants and to determine the association of admission temperature with in-hospital mortality and morbidities. METHODS: A cohort study using prospectively collected data involving 70 neonatal intensive care units (NICUs) that participate in the Korean Neonatal Network. From registered infants born between January 2013 and December 2015, 5,343 VLBW infants born at less than 33 weeks of gestation were reviewed. RESULTS: The mean admission temperature was 36.1°C±0.6°C, with a range of 31.9°C to 38.4°C. Approximately 74.1% of infants had an admission hypothermia of <36.5°C. Lower birth weight, intubation in the delivery room and Apgar score <7 at 5 minutes were significantly related to admission hypothermia. The mortality was the lowest at 36.5°C-37.5°C and adjusted odd ratios for all deaths increased to 1.38 (95% confidence interval [CI], 1.04-1.83), 1.44 (95% CI, 1.05-1.97) and 1.86 (95% CI, 1.22-2.82) for infants with admission temperatures of 36.0°C-36.4°C, 35.0°C-35.9°C, and <35.0°C, respectively. Admission hypothermia was also associated with high likelihoods of bronchopulmonary dysplasia, pulmonary hypertension, proven sepsis, pulmonary hemorrhage, air-leak, seizure, grade 3 or higher intraventricular hemorrhage and advanced retinopathy of prematurity requiring laser therapy. CONCLUSION: A large portion of preterm infants in Korea had hypothermia at NICU admission, which was associated with high mortality and several important morbidities. More aggressive interventions aimed at reducing hypothermia are required in this high-risk population.