Image-guided in situ cancer vaccination with combination of multi-functional nano-adjuvant and an irreversible electroporation technique.

Cancer immunotherapy is a next-generation treatment strategy; however, its side effects limit its clinical translation. Here, a novel combination of a multi-functional nano-adjuvant (M-NA) prepared with an iron oxide/gold core and a cationic polymer shell via multilayer synthesis with CpG oligodeoxynucleotide (CpG-ODN) electrostatically complexed on its surface, and irreversible electroporation (IRE) technique was developed for effective image-guided in situ cancer vaccination. The M-NA can be retained long-term in the dense tumoral extracellular matrix after intratumoral injection and internalized by antigen-presenting cells (APCs). The IRE can induce immunogenic cell death. Indeed, in a mouse tumor model, the M-NA showed longer tumor retention time than free CpG-ODN. Compared with other treatments, the combined treatment significantly inhibited tumor growth with 100% survival rate for ∼60 days. The therapy induced the activation of cytotoxic lymphocytes and the maturation of APCs in vivo. This treatment could be effective in image-guided local cancer immunotherapy.

Effect of layer thickness and printing orientation on the color stability and stainability of a 3D-printed resin material.

STATEMENT OF PROBLEM: Although 3-dimensional (3D)-printed resin prostheses are widely used, studies on the effects of the manufacturing parameters of 3D printing on the color stability and stainability of these prostheses are lacking. PURPOSE: The purpose of this in vitro study was to investigate the effects of layer thickness and printing orientation on the color stability and stainability of a 3D-printed resin. In addition, the influence of roughness and water contact angle was evaluated. MATERIAL AND METHODS: Color changes (ΔE00) in tooth-colored resin specimens produced by 3D printing with 2 different layer thicknesses and 3 different printing orientations and immersed in 3 types of aging media (distilled water, coffee solution, and wine) were evaluated (n=10). The CIELab color values were measured with a spectrophotometer at baseline and different time points (1, 3, 7, 15, and 30 days). The surface roughness (Ra) of resin specimens was measured at various time points (baseline, 7, 15, and 30 days) by confocal laser scanning microscopy after immersion in coffee solution (n=15). The water contact angle was determined by using the sessile drop method (n=10). The ΔE00 values were analyzed by using the 3-way repeated measures ANOVA followed by the Bonferroni test and Dunnett T3 test (α=.05). Ra values were analyzed by 3-way repeated measures ANOVA (α=.05). The water contact angle data were analyzed by 2-way ANOVA (α=.05). RESULTS: The 3-way repeated measures ANOVA showed that layer thickness, printing orientation, and storage time significantly influenced the ΔE00 values of the 3D-printed resin specimens in each aging medium (P<.001). The ΔE00 values in the 0-degree subgroups were significantly lower than those in the 45- and 90-degree subgroups (P<.05). The ΔE00 values in the 25-µm thick groups were significantly higher than those in the 100-µm thick groups (P<.05). The ΔE00 values demonstrated an increase up to 15 days in all aging media. In distilled water, the ΔE00 values of the specimens increased or decreased depending on the groups, whereas in the coffee solution, the values decreased after 15 days (P<.001); in red wine, the values demonstrated a continuous increase up to 30 days in all groups (P<.001). The 3-way repeated measures ANOVA showed that the Ra values did not change significantly with immersion time (P=.444). The 2-way ANOVA showed that the water contact angle was not significantly affected by layer thickness (P=.921) or printing orientation (P=.062). CONCLUSIONS: Layer thickness and printing orientation affected the color stability and stainability of the 3D-printed resin. The discoloration of the 3D-printed resin differed with time, depending on the type of aging media used.

Effect of post-curing time on the color stability and related properties of a tooth-colored 3D-printed resin material.

This study investigated the effect of post-curing time on the color stability and related properties, such as degree of conversion (DC), surface roughness, water contact angle, water sorption (Wsp), and water solubility (Wsl) of 3D-printed resin for dental restorations. The 3D-printed specimens were divided into four groups according to the post-curing time (0, 5, 10, and 20 min). Color changes (ΔE00) of the specimens immersed in aging media were measured using a spectrophotometer at different aging times. The DC of the resin was measured using a FTIR. The surface roughness (Ra) of the resin immersed in coffee was measured at different aging times. Water contact angle was evaluated using the sessile drop method, and Wsp and Wsl were tested according to the ISO 4049:2019. The ΔE00 values of the specimens immersed in coffee and red wine decreased with increasing post-curing time. As the post-curing time increased up to 10 min, the DC increased and water contact angle decreased. The Ra value of the group without post-curing (0 min) increased gradually for 30 days, except between 7 and 15 days. However, when the post-curing time increased to greater than 10 min, no apparent change in Ra value was detected. The Wsp and Wsl of the group without post-curing were significantly lower and larger than that of the other groups, respectively. The longer the post-curing time of the tooth-colored 3D-printed resin, the better the color stability. The post-curing time of the 3D-printed resin affected the DC, surface roughness after aging in the staining media, water contact angle, water sorption, and water solubility.

Mobile Phone Use and Time Trend of Brain Cancer Incidence Rate in Korea.

This study evaluated the time trends in mobile phone subscriber number by mobile network generation (G) and brain cancer incidence by type in Korea. We obtained data from the Information Technology Statistics of Korea (1984-2017) and Korea Central Cancer Registry (1999-2017). The average annual percent change was estimated using Joinpoint regression analysis. We evaluated 29,721 brain cancer cases with an age-standardized incidence rate (ASR) of 2.89/100,000 persons. The glioma and glioblastoma annual ASR significantly increased in 2.6% and 3.9% of males and 3.0% and 3.8% of females, respectively. The ASR for frontal lobe involvement was the highest. The ASR of gliomas of unspecified grade annually increased by 7.8%; those for unspecified topology and histology decreased. The incidence of glioma, glioblastoma, frontal, temporal, and high-grade glioma increased among those aged ≥60 years. No association was observed between the mobile phone subscriber number and brain cancer incidence in Korea. Furthermore, long-term research is warranted because of the latency period of brain cancer. © 2021 Bioelectromagnetics Society.

Activation of mitochondrial TUFM ameliorates metabolic dysregulation through coordinating autophagy induction.

Disorders of autophagy, a key regulator of cellular homeostasis, cause a number of human diseases. Due to the role of autophagy in metabolic dysregulation, there is a need to identify autophagy regulators as therapeutic targets. To address this need, we conducted an autophagy phenotype-based screen and identified the natural compound kaempferide (Kaem) as an autophagy enhancer. Kaem promoted autophagy through translocation of transcription factor EB (TFEB) without MTOR perturbation, suggesting it is safe for administration. Moreover, Kaem accelerated lipid droplet degradation in a lysosomal activity-dependent manner in vitro and ameliorated metabolic dysregulation in a diet-induced obesity mouse model. To elucidate the mechanism underlying Kaem's biological activity, the target protein was identified via combined drug affinity responsive target stability and LC-MS/MS analyses. Kaem directly interacted with the mitochondrial elongation factor TUFM, and TUFM absence reversed Kaem-induced autophagy and lipid degradation. Kaem also induced mitochondrial reactive oxygen species (mtROS) to sequentially promote lysosomal Ca2+ efflux, TFEB translocation and autophagy induction, suggesting a role of TUFM in mtROS regulation. Collectively, these results demonstrate that Kaem is a potential therapeutic candidate/chemical tool for treating metabolic dysregulation and reveal a role for TUFM in autophagy for metabolic regulation with lipid overload.

Novel BuChE-IDO1 inhibitors from sertaconazole: Virtual screening, chemical optimization and molecular modeling studies.

In our effort towards the identification of novel BuChE-IDO1 dual-targeted inhibitor for the treatment of Alzheimer's disease (AD), sertaconazole was identified through a combination of structure-based virtual screening followed by MM-GBSA rescoring. Preliminary chemical optimization was performed to develop more potent and selective sertaconazole analogues. In consideration of the selectivity and the inhibitory activity against target proteins, compounds 5c and 5d were selected for the next study. Further modification of compound 5c led to the generation of compound 10g with notably improved selectivity towards BuChE versus AChE. The present study provided us with a good starting point to further design potent and selective BuChE-IDO1 inhibitors, which may benefit the treatment of late stage AD.

Extract of high hydrostatic pressure-treated danshen (Salvia miltiorrhiza) ameliorates atherosclerosis via autophagy induction.

Danshen (Salvia miltiorrhiza) is a traditional medicinal plant widely used in Asian countries for its pharmacological activities (e.g., amelioration of cardiovascular diseases). In this study, we investigated the anti-atherosclerotic activity of raw danshen root extract prepared using high hydrostatic pressure (HHP) at 550 MPa for 5 min and hot water extraction. This method was useful for elimination of bacteria from cultured danshen plants and for better extraction yield of active principles. The HHPtreated danshen extract (HDE) inhibited proliferation of human umbilical vein endothelial cells (HUVECs) and induced autophagy that was assessed by LC3 conversion and p62 degradation. HDE suppressed foam cell formation in oxLDL-induced RAW264.7 macrophages; lysosomal activity simultaneously increased, measured by acridine orange staining. HDE also reduced atherosclerotic plaque development in vivo in apolipoprotein E knock-out (ApoE-/-) mice fed a high cholesterol diet. Taken together, these results indicated that HDE exhibited anti-atherosclerotic activity via autophagy induction. [BMB Reports 2020; 53(12): 652-657].

Identification and Validation of VEGFR2 Kinase as a Target of Voacangine by a Systematic Combination of DARTS and MSI.

Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.

Current State of Research on the Risk of Morbidity and Mortality Associated with Air Pollution in Korea.

PURPOSE: The effects of air pollution on health can vary regionally. Our goal was to comprehensively review previous epidemiological studies on air pollution and health conducted in Korea to identify future areas of potential study. MATERIALS AND METHODS: We systematically searched all published epidemiologic studies examining the association between air pollution and occurrence of death, diseases, or symptoms in Korea. After classifying health outcomes into mortality, morbidity, and health impact, we summarized the relationship between individual air pollutants and health outcomes. RESULTS: We analyzed a total of 27 studies that provided 104 estimates of the quantitative association between risk of mortality and exposure to air pollutants, including particulate matter with aerodynamic diameter less than 10 µm, particulate matter with aerodynamic diameter less than 2.5 µm, sulfur dioxide, nitrogen dioxide, ozone, and carbon monoxide in Korea between January 1999 and July 2018. Regarding the association with morbidity, there were 38 studies, with 98 estimates, conducted during the same period. Most studies examined the short-term effects of air pollution using a time series or case-crossover study design; only three cohort studies that examined long-term effects were found. There were four health impact studies that calculated the attributable number of deaths or disability-adjusted life years due to air pollution. CONCLUSION: There have been many epidemiologic studies in Korea regarding air pollution and health. However, the present review shows that additional studies, especially cohort and experimental studies, are needed to provide more robust and accurate evidence that can be used to promote evidence-based policymaking.

A prospective randomised comparison of fixation methods in Tamai's zone I amputation.

BACKGROUND: The treatment of choice for fingertip amputation is replantation to restore function and aesthetics. The purpose of this study was to compare the success rates and salvage periods between patients with Tamai's zone I amputation injuries treated with bony fixation and suture fixation. METHODS: Fifty-five patients with Tamai's zone I amputations with bony involvement were included in this study. The patients were allocated randomly to two groups treated by bony fixation with Kirschner (K-)wire and suture fixation, respectively. In the bony fixation group (n = 21), the distal phalangeal bone was fixed with K-wire; in the suture fixation group (n = 34), the amputated portion was fixed with sutures alone. The success rate was defined as the percentage of fully viable replanted cases, and the salvage period was defined as extending from the first postoperative day to the cessation of salvation. RESULTS: The success rates for the bony and suture fixation groups were 90.0% and 91.1%, respectively, with no significant difference. The average salvage period was longer in the bony fixation group than in the suture fixation group (8.7 ± 1.25 vs. 6.4 ± 0.98 days; P = 0.01). No case of non-union of the distal phalangeal bone, limitation of motion, or disfigurement was observed in either group. CONCLUSION: The average salvage period was significantly longer for the bony fixation group, but the success rates did not differ between groups. We suggest that bony fixation is not mandatory in the treatment of Tamai's zone I amputation.

Curcumin and Curcuma longa L. extract ameliorate lipid accumulation through the regulation of the endoplasmic reticulum redox and ER stress.

For this study, we examined the effects of curcumin against acute and chronic stress, paying specific attention to ROS. We also aimed to clarify the differences between acute and chronic stress conditions. We investigated the effects of curcumin against acute stress (once/1 day CCl4 treatment) and chronic-stress (every other day/4week CCl4 treatment). Compared with acute stress, in which the antioxidant system functioned properly and aspartate transaminase (AST) and ROS production increased, chronic stress increased AST, alanine aminotransferase (ALT), hepatic enzymes, and ROS more significantly, and the antioxidant system became impaired. We also found that ER-originated ROS accumulated in the chronic model, another difference between the two conditions. ER stress was induced consistently, and oxidative intra-ER protein folding status, representatively PDI, was impaired, especially in chronic stress. The PDI-associated client protein hepatic apoB accumulated with the PDI-binding status in chronic stress, and curcumin recovered the altered ER folding status, regulating ER stress and the resultant hepatic dyslipidemia. Throughout this study, curcumin and curcumin-rich Curcuma longa L. extract promoted recovery from CCl4-induced hepatic toxicity in both stress conditions. For both stress-associated hepatic dyslipidemia, curcumin and Curcuma longa L. extract might be recommendable to recover liver activity.

The effects of postnatal phthalate exposure on the development of auditory temporal processing in rats.

OBJECTIVE: The central auditory pathway is known to continue its development during the postnatal critical periods and is shaped by experience and sensory inputs. Phthalate, a known neurotoxic material, has been reported to be associated with attention deficits in children, impacting many infant neurobehaviors. The objective of this study was to investigate the potential effects of neonatal phthalate exposure on the development of auditory temporal processing. METHODS: Neonatal Sprague-Dawley rats were randomly assigned into two groups: The phthalate group (n = 6), and the control group (n = 6). Phthalate was given once per day from postnatal day 8 (P8) to P28. Upon completion, at P28, the Auditory Brainstem Response (ABR) and Gap Prepulse Inhibition of Acoustic Startle response (GPIAS) at each gap duration (2, 5, 10, 20, 50 and 80 ms) were measured, and gap detection threshold (GDT) was calculated. These outcomes were compared between the two groups. RESULTS: Hearing thresholds by ABR showed no significant differences at all frequencies between the two groups. Regarding GPIAS, no significant difference was observed, except at a gap duration of 20 ms (p = 0.037). The mean GDT of the phthalate group (44.0 ms) was higher than that of the control group (20.0 ms), but without statistical significance (p = 0.065). Moreover, the phthalate group tended to demonstrate more of a scattered distribution in the GDT group than the in the control group. CONCLUSION: Neonatal phthalate exposure may disrupt the development of auditory temporal processing in rats.

Antiplatelet and antithrombotic effects of cordycepin-enriched WIB-801CE from Cordyceps militaris ex vivo, in vivo, and in vitro.

BACKGROUND: A species of the fungal genus Cordyceps has been used as a complementary and alternative medicine of traditional Chinese medicine, and its major component cordycepin and cordycepin-enriched WIB-801CE are known to have antiplatelet effects in vitro. However, it is unknown whether they have also endogenous antiplatelet and antithrombotic effects. In this study, to resolve these doubts, we prepared cordycepin-enriched WIB-801CE, an ethanol extract from Cordyceps militaris-hypha, then evaluated its ex vivo, in vivo, and in vitro antiplatelet and antithrombotic effects. METHODS: Ex vivo effects of WIB-801CE on collagen- and ADP-induced platelet aggregation, serotonin release, thromboxane A2 (TXA2) production and its associated activities of enzymes [cyclooxygenase-1 (COX-1), TXA2 synthase (TXAS)], arachidonic acid (AA) release and its associated phosphorylation of phospholipase Cß3, phospholipase Cγ2 or cytosolic phospholipase A2, mitogen-activated protein kinase (MAPK) [p38 MAPK, extracellular signal-regulated kinase (ERK)], and blood coagulation time in rats were investigated. In vivo effects of WIB-801CE on collagen plus epinephrine-induced acute pulmonary thromboembolism, and tail bleeding time in mice were also inquired. In vitro effects of WIB-801CE on cytotoxicity, and fibrin clot retraction in human platelets, and nitric oxide (NO) production in RAW264.7 cells or free radical scavenging activity were studied. RESULTS: Cordycepin-enriched WIB-801CE inhibited ex vivo platelet aggregation, TXA2 production, AA release, TXAS activity, serotonin release, and p38 MAPK and ERK2 phosphorylation in collagen- and ADP-activated rat platelets without affecting blood coagulation. Furthermore, WIB-801CE manifested in vivo inhibitory effect on collagen plus epinephrine-induced pulmonary thromboembolism mice model. WIB-801CE inhibited in vitro NO production and fibrin clot retraction, but elevated free radical scavenging activity without affecting cytotoxicity against human platelets. CONCLUSION: WIB-801CE inhibited collagen- and ADP-induced platelet activation and its associated thrombus formation ex vivo and in vivo. These were resulted from down-regulation of TXA2 production and its related AA release and TXAS activity, and p38MAPK and ERK2 activation. These results suggest that WIB-801CE has therapeutic potential to treat platelet activation-mediated thrombotic diseases in vivo.

Turmeric extract and its active compound, curcumin, protect against chronic CCl4-induced liver damage by enhancing antioxidation.

BACKGROUND: Curcumin, a major active component of turmeric, has previously been reported to alleviate liver damage. Here, we investigated the mechanism by which turmeric and curcumin protect the liver against carbon tetrachloride (CCl4)-induced injury in rats. We hypothesized that turmeric extract and curcumin protect the liver from CCl4-induced liver injury by reducing oxidative stress, inhibiting lipid peroxidation, and increasing glutathione peroxidase activation. METHODS: Chronic hepatic stress was induced by a single intraperitoneal injection of CCl4 (0.1 ml/kg body weight) into rats. Turmeric extracts and curcumin were administered once a day for 4 weeks at three dose levels (100, 200, and 300 mg/kg/day). We performed ALT and AST also measured of total lipid, triglyceride, cholesterol levels, and lipid peroxidation. RESULT: We found that turmeric extract and curcumin significantly protect against liver injury by decreasing the activities of serum aspartate aminotransferase and alanine aminotransferase and by improving the hepatic glutathione content, leading to a reduced level of lipid peroxidase. CONCLUSIONS: Our data suggest that turmeric extract and curcumin protect the liver from chronic CCl4-induced injury in rats by suppressing hepatic oxidative stress. Therefore, turmeric extract and curcumin are potential therapeutic antioxidant agents for the treatment of hepatic disease.

The Use of Topical Lidocaine Gel During Intermaxillary Fixation Procedure.

This study aimed to validate the usefulness of lidocaine gel during intermaxillary fixation using arch bars in patients with mandible fracture by comparing 2 patient groups: one group using lidocaine gel in intermaxillary fixation and the other group undergoing traditional local infiltration.Subjects were patients with mandible fracture undergoing intermaxillary fixation using arch bars from March 2003 to February 2007. Twenty-three patients were anesthetized in the upper and lower gingiva by 2% local lidocaine solution injection; another 23 underwent topical anesthesia with 2% lidocaine hydrochloride gel applied to the upper and lower gingiva. The convenience of fixation was measured in terms of operation time and degree of pain according to the visual analog scale; arch bar loosening rate was assessed postoperatively.The mean operation times were 63 and 47 minutes in the groups undergoing local infiltration and using topical lidocaine gel, respectively. For pain degree according to the visual analog scale, the mean scores were 6.4 and 3.2 in the groups using local infiltration and topical lidocaine gel, respectively. When the arch bar loosening rate was measured postoperatively, the 2 groups differed significantly, with a rate of 26% in the group using local infiltration and 13% in the group using topical lidocaine gel.Application of topical lidocaine gel during intermaxillary fixation using arch bars in patients with mandible fracture relieves pain and offers convenience in performing the procedure. It can be a useful alternative method for patients who are sensitive to pain or have needle phobia.

Honokiol suppresses lung tumorigenesis by targeting EGFR and its downstream effectors.

Since epidermal growth factor receptor (EGFR) is commonly deregulated in pre-malignant lung epithelium, targeting EGFR may arrest the development of lung cancer. Here, we showed that honokiol (2.5-7.5 µM), a bioactive compound of Magnolia officinalis, differentially suppressed proliferation (up to 93%) and induced apoptosis (up to 61%) of EGFR overexpressing tumorigenic bronchial cells and these effects were paralleled by downregulation of phospho-EGFR, phospho-Akt, phospho-STAT3 and cell cycle-related proteins as early as 6-12 h post-treatment. Autocrine secretion of EGF sensitized 1170 cells to the effects of honokiol. Molecular docking studies indicated that honokiol binds to the tyrosine kinase domain of EGFR although it was less efficient than erlotinib. However, the anti-proliferative and pro-apoptotic activities of honokiol were stronger than those of erlotinib. Upon combinatory treatment, honokiol sensitized bronchial cells and erlotinib resistant H1650 and H1975 cells to erlotinib. Furthermore, in a mouse lung tumor bioassay, intranasal instillation of liposomal honokiol (5 mg/kg) for 14 weeks reduced the size and multiplicity (49%) of lung tumors and the level of total- and phospho-EGFR, phospho-Akt and phospho-STAT3. Overall, our results indicate that honokiol is a promising candidate to suppress the development and even progression of lung tumors driven by EGFR deregulation.

Ulmus davidiana ethanol extract inhibits monocyte adhesion to tumor necrosis factor-alpha-stimulated endothelial cells.

BACKGROUND: Ulmus davidiana var. japonica Rehder (UD) has long been used in traditional folk medicine in Asia. This study is designed to investigate the antiadhesive activity of the ethanol extract of UD (UDE) and its underlying mechanisms in cultured endothelial cells. METHODS: The dried root bark of UD was extracted with 80% (v/v) ethanol. The antiadhesive activity of the UDE was investigated in cultured human umbilical vein endothelial cells and human embryonic kidney epithelial 293T (HEK 293T) cells stably transfected with pGL3-vascular cell adhesion molecule (VCAM)-1-luc. Monocyte adhesion in endothelial cells was induced by tumor necrosis factor-alpha (TNF-α), and the protective effects of UDE on monocyte-endothelial cell adhesion, VCAM-1 expression, reactive oxygen species production, and nuclear factor-κB activity were determined. RESULTS: Exposure to UDE at a concentration of 3-30 µg/mL for 24 hours produced no detectable cytotoxicity in human umbilical vein endothelial cells, but it significantly inhibited TNF-α-induced monocyte adhesion and VCAM-1 expression. TNF-α treatment of HEK 293T/VCAM-1-luc cells resulted in increased luciferase activity of the VCAM-1 promoter, which was inhibited by treatment with UDE. Additionally, TNF-α-induced reactive oxygen species generation, nuclear translocation of nuclear factor-κB, and IκBα degradation in human umbilical vein endothelial cells were effectively reduced by treatment with 30 µg/mL of UDE. CONCLUSION: Our results indicated that UDE treatment inhibited TNF-α-induced monocyte adhesion in endothelial cells, suggesting that UD may reduce vascular endothelial inflammation.

Discovery of novel drug targets and their functions using phenotypic screening of natural products.

Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.

Direct vascular actions of quercetin in aorta from renal hypertensive rats

BACKGROUND: Chronic treatment with the dietary flavonoid quercetin is known to lower blood pressure and restore endothelial dysfunction in animal models of hypertension. This study investigated the direct effects of quercetin on vascular response in chronic 2-kidney, 1-clip (2K1C) renal hypertensive rats. The effects of antioxidant vitamin ascorbic acid on the vasoreactivity were also examined. METHODS: 2K1C renal hypertension was induced by clipping the left renal artery; age-matched rats that received sham treatment served as controls. Thoracic aortae were mounted in tissue baths for the measurement of isometric tension. RESULTS: Relaxant responses to acetylcholine were significantly attenuated in 2K1C rats in comparison with sham rats. Quercetin or ascorbic acid augmented acetylcholine-induced relaxation in 2K1C rats, whereas no significant differences were noted in sham rats. The relaxation response to sodium nitroprusside was comparable between 2K1C and sham rats, and sodium nitroprusside-induced relaxation was not altered by quercetin or ascorbic acid in either group. The contractile response to phenylephrine was significantly enhanced in 2K1C rats compared with sham rats. Phenylephrine-induced contraction was inhibited by pretreatment with quercetin or ascorbic acid in 2K1C rats, whereas neither chemical affected responses in sham rats. N(w)-nitro-L-arginine methyl ester markedly augmented the contractile response to phenylephrine in sham rats, whereas no significant differences were observed in 2K1C rats. Quercetin or ascorbic acid did not affect phenylephrine-induced contraction in the presence of N(w)-nitro-L-arginine methyl ester in either 2K1C or sham rats. CONCLUSION: Acute exposure to quercetin appears to improve endothelium-dependent relaxation and inhibit the contractile response, similar to the effect of ascorbic acid in 2K1C hypertension. These results partially explain the vascular beneficial effects of quercetin in renal hypertension.

Korean research project on the integrated exposure assessment of hazardous substances for food safety.

OBJECTIVES: This survey was designed to conduct the first nationwide dietary exposure assessment on hazardous substances including the intakes of functional food and herbal medicine. In this paper, we introduced the survey design and the results of the dietary exposure status and internal exposure levels of lead (Pb), cadmium (Cd), and mercury (Hg). METHODS: We selected 4867 subjects of all ages throughout Korea. We conducted a food survey, dietary survey, biomonitoring, and health survey. RESULTS: Pb and Cd were the highest (median value) in the seaweed (94.2 µg/kg for Pb; 594 µg/kg for Cd), and Hg was the highest in the fish (46.4 µg/kg). The dietary exposure level (median value) of Pb was 0.14 µg/kg body weight (bw)/d, 0.18 µg/kg bw/d for Cd, and 0.07 µg/kg bw/d for Hg. Those with a blood Pb level of less than 5.00 µg/dL (US Centers for Disease Control and Prevention, reference value for those 1 to 5 years of age) were 99.0% of all the subjects. Those with a blood Cd level with less than 0.30 µg/L (German Federal Environmental Agency, reference value for non-smoking children) were 24.5%. For those with a blood Hg level with less than 5.00 µg/L (human biomonitoring I, references value for children and adults, German Federal Environmental Agency) was 81.0 % of all the subjects. CONCLUSIONS: The main dietary exposure of heavy metals occurs through food consumed in a large quantity and high frequency. The blood Hg level and dietary exposure level of Hg were both higher than those in the European Union.