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As an obstinate cancer pancreatic cancer (PC) poses a major challenge due to limited treatment options which include resection surgery, radiation therapy, and gemcitabine-based chemotherapy. In cancer cells, protein kinase C βI (PKCβI) participates in diverse cellular processes, including cell proliferation, invasion, and apoptotic pathways. In the present study, we created a scaffold to develop PKCβI inhibitors using evodiamine-based synthetic molecules. Among the candidate inhibitors, Evo312 exhibited the highest antiproliferative efficacy against PC cells, PANC-1, and acquired gemcitabine-resistant PC cells, PANC-GR. Additionally, Evo312 robustly inhibited PKCβI activity. Mechanistically, Evo312 effectively suppressed the upregulation of PKCβI protein expression, leading to the induction of cell cycle arrest and apoptosis in PANC-GR cells. Furthermore, Evo312 exerted an antitumor activity in a PANC-GR cell-implanted xenograft mouse model. These findings position Evo312 as a promising lead compound for overcoming gemcitabine resistance in PC through novel mechanisms.

Two new proton-deficient metabolites, tandocyclinones A and B ( 1 and 2 ), were discovered via the chemical profiling of the Streptomyces sp. strain TDH03, which was isolated from a marine sediment sample collected from the intertidal mudflat in Tando Port, the Republic of Korea. The structures of 1 and 2 were elucidated as new ether-bridged C -glycosyl benz[ a ]anthracenes by using a combination of spectroscopic analyses of ultraviolet (UV) and mass spectrometry (MS) data, along with nuclear magnetic resonance (NMR) spectra, which were acquired in tetrahydrofuran (THF)- d 8 selected after an extensive search for a solvent, resulting in mostly observable exchangeable protons in the 1 H NMR spectrum. Their configurations were successfully assigned by applying a J -based configuration analysis, rotating-frame Overhauser enhancement spectroscopy (ROESY) NMR correlations, chemical derivatization methods based on NMR (a modified version of Mosher's method) and circular dichroism (CD) (Snatzke's method using Mo 2 (OAc) 4 -induced CD), as well as quantum-mechanics-based computational methods, to calculate the electronic circular dichroism (ECD). Tandocyclinones A and B ( 1 and 2 ) were found to have weak antifungal activity against Trichophyton mentagrophytes IFM40996 with an MIC value of 128 μg/mL (244 and 265 μM for 1 and 2 , respectively). A further biological evaluation revealed that tandocyclinone A ( 1 ) displayed inhibitory activity against Mycobacterium avium (MIC 50 = 40.8 μM) and antiproliferative activity against SNU638 and HCT116 cancer cells, with IC 50 values of 31.9 µM and 49.4 µM, respectively.

A targeted and logical discovery method was devised for natural products containing piperazic acid (Piz), which is biosynthesized from ornithine by l-ornithine N -hydroxylase (KtzI) and N - N bond formation enzyme (KtzT). Genomic signature-based screening of a bacterial DNA library (2020 strains) using polymerase chain reaction (PCR) primers targeting ktzT identified 62 strains (3.1%). The PCR amplicons of KtzT-encoding genes were phylogenetically analyzed to classify the 23 clades into two monophyletic groups, I and II. Cultivating hit strains in media supplemented with 15 NH 4 Cl and applying 1 H- 15 N heteronuclear multiple bond correlation (HMBC) along with 1 H- 15 N heteronuclear single quantum coherence (HSQC) and 1 H- 15 N HSQC-total correlation spectroscopy (HSQC-TOCSY) NMR experiments detected the spectroscopic signatures of Piz and modified Piz. Chemical investigation of the hit strains prioritized by genomic and spectroscopic signatures led to the identification of a new azinothricin congener, polyoxyperuin B seco acid ( 1 ), previously reported chloptosin ( 2 ) in group I, depsidomycin D ( 3 ) incorporating two dehydropiperazic acids (Dpz), and lenziamides A and B ( 4 and 5 ), structurally novel 31-membered cyclic decapeptides in group II. By consolidating the phylogenetic and chemical analyses, clade-structure relationships were elucidated for 19 of the 23 clades. Lenziamide A ( 4 ) inhibited STAT3 activation and induced G 2 /M cell cycle arrest, apoptotic cell death, and tumor growth suppression in human colorectal cancer cells. Moreover, lenziamide A ( 4 ) resensitized 5-fluorouracil (5-FU) activity in both in vitro cell cultures and the in vivo 5-FU-resistant tumor xenograft mouse model. This work demonstrates that the genomic and spectroscopic signature-based searches provide an efficient and general strategy for new bioactive natural products containing specific structural motifs.

Four new chlorinated cycloaromatized enediyne compounds, jejucarbosides B-E ( 1 - 4 ), were discovered together with previously-identified jejucarboside A from a marine actinomycete strain. Compounds 1 - 4 were identified as new chlorinated cyclopenta[ a ]indene glycosides based on 1D and 2D nuclear magnetic resonance, high-resolution mass spectrometry, and circular dichroism (CD) spectra. Jejucarbosides B and E bear a carbonate functional group whereas jejucarbosides C and D are variants possessing 1,2-diol by losing the carbonate functionality. It is proposed that the production of 1 - 4 occurs via Bergman cycloaromatization capturing Cl - and H + in the alternative positions of a p -benzyne intermediate derived from a 9-membered enediyne core. Jejucarboside E ( 4 ) displayed significant cytotoxicity against human cancer cell lines including SNU-638, SK-HEP-1, A549, HCT116, and MDA-MB-231, with IC 50 values of 0.31, 0.40, 0.25, 0.29, and 0.48 μM, respectively, while jejucarbosides B-D ( 1 - 3 ) showed moderate or no cytotoxic effects.

Colorectal cancer (CRC) is one of the most prevalent tumors with high metastatic potential; consequently, finding new drug candidates that suppress tumor metastasis is essential. Apoptolidin A is a macrocyclic lactone produced by Amycolatopsis sp. DW02G. It exhibits significant cytotoxicity against several cancer cell lines, but its effects on CRC cells remain unknown. Therefore, the present study investigated the antiproliferative and antimetastatic activities of apoptolidin A and its underlying molecular mechanisms in CRC cells. Apoptolidin A effectively inhibited CRC cell growth and colony formation. The induction of G 0 /G 1 phase cell cycle arrest was associated with the downregulation of cyclin D1 and CDK4/6 expression. Long-term exposure to apoptolidin A also induced apoptosis as confirmed by the downregulation and upregulation of Bcl-2 and Bax expression, respectively. Moreover, apoptolidin A effectively upregulated the suppressed expression of N-Myc downstream-regulated gene 1 (NDRG1), a tumor suppressor gene, in a concentration-dependent manner in CRC cells. The antimetastatic potential of apoptolidin A was also correlated with the expression of epithelial-mesenchymal transition (EMT) biomarkers, including the upregulation of E-cadherin and downregulation of N-cadherin, vimentin, snail, and MMP9 in CRC cells. These findings suggest that apoptolidin A exerts antiproliferative and antimetastatic activities by regulating the NDRG1-activated EMT pathway in CRC cells.

Diabetes mellitus is a chronic disease with high economic and social burdens. This study aimed to determine the risk factors of microalbuminuria among patients with type 2 diabetes mellitus. Microalbuminuria is predictive of early-stage renal complications and subsequent progression to renal dysfunction. We collected data on type 2 diabetes patients who participated in the 2019-2020 Korea National Health and Nutrition Examination Survey. The risk factors for microalbuminuria among patients with type 2 diabetes were analyzed using logistic regression. As a result, the odds ratios were 1.036 (95% confidence interval (CI) = 1.019-1.053, p < 0.001) for systolic blood pressure, 0.966 (95% CI = 0.941-0.989, p = 0.007) for high-density lipoprotein cholesterol level, 1.008 (95% CI = 1.002-1.014, p = 0.015) for fasting blood sugar level, and 0.855 (95% CI = 0.729-0.998, p = 0.043) for hemoglobin level. A significant strength of this study is the identification of low hemoglobin level (i.e., anemia) as a risk factor for microalbuminuria in patients with type 2 diabetes. This finding implies that the early detection and management of microalbuminuria can prevent the development of diabetic nephropathy.

Metastatic triple-negative breast cancer (mTNBC) is a fatal type of breast cancer (BC), and signal transducer and activator of transcription 3 (STAT3) has emerged as an effective target for mTNBC. In the present study, compound MC0704 was found to be a novel synthetic STAT3 pathway inhibitor, and its potential antitumor activity was demonstrated using in vitro and in vivo models in docetaxel-resistant TNBC cells. Based on marinacarboline (MC), a series β-carboline derivatives were synthesized and investigated for their antitumor activities against docetaxel-resistant MDA-MB-231 (MDA-MB-231-DTR) cells. Combining antiproliferation and STAT3 inhibitory activities, MC0704 was selected as the most promising β-carboline compound. MC0704 effectively impeded the metastatic potential of MDA-MB-231-DTR cells in vitro , and the combination of MC0704 and docetaxel exhibited potent antitumor activities in a xenograft mouse model. These findings suggested that MC0704 can be a lead candidate as a target therapeutic agent for TNBC patients with docetaxel resistance.

Two new macrocyclic secondary metabolites, glycosyl-migrastatin (1) and 5-hydroxy-migrastatin (2), were isolated from a gut bacterium Kitasatospora sp. JL24 in dung beetle Onthophagus lenzii. Based on a comprehensive analysis of the nuclear magnetic resonance (NMR), MS, and UV spectroscopic data, the planar structures of 1 and 2 were successfully identified as new derivatives of migrastatin. Compound 1 was the first glycosylated member of the migrastatin family. The absolute configuration of the sugar moiety was determined to be d-glucose through the analysis of coupling constants and ROESY correlations, followed by chemical derivatization and chromatographic comparison with authentic d- and l-glucose. Compound 2, identified as 5-hydroxy-migrastatin possessing an additional hydroxy group with a previously unreported chiral center, was assigned using Mosher's method through 19F NMR chemical shifts and confirmed with the modified Mosher's method. Genomic analysis of Kitasatospora sp. strain JL24 revealed a putative biosynthetic pathway involving an acyltransferase-less type I polyketide synthase biosynthetic gene cluster., One-Sentence Summary: Two secondary metabolites, glycosyl-migrastatin (1) and 5-hydroxy-migrastatin (2), were discovered from the gut bacterium Kitasatospora sp. JL24 in the dung beetle Onthophagus lenzii., (© The Author(s) 2023. Published by Oxford University Press on behalf of Society of Industrial Microbiology and Biotechnology.)

Although gemcitabine-based chemotherapy is common and effective for pancreatic cancer (PC), acquired drug resistance is one of the major reasons for treatment failure. Therefore, a novel therapeutic approach for gemcitabine-resistant PC is required. Nuclear factor erythroid 2-related factor 2 (Nrf2) is an oxidative stress-responsive transcription factor regulating antioxidant responses and plays a crucial role in chemoresistance. In the present study, the antitumor activity of periplocin, a natural cardiac glycoside, was evaluated in an established gemcitabine-resistant PC cell line (PANC-GR). Nrf2 was overexpressed in gemcitabine-resistant cells, and Nrf2 knockdown recovered gemcitabine sensitivity in PANC-GR cells. The antiproliferative activity of periplocin was highly associated with Nrf2 downregulation and Nrf2-mediated signaling pathways in PANC-GR cells. Periplocin also increased reactive oxygen species production inducing G 0 /G 1 cell cycle arrest and apoptosis in PANC-GR cells. Periplocin and gemcitabine combined significantly inhibited tumor growth in a PANC-GR cells-implanted xenograft mouse model via Nrf2 downregulation. Overall, these findings suggest that periplocin might be a novel therapeutic agent against gemcitabine resistance, as it could recover sensitivity to gemcitabine by regulating Nrf2-mediated signaling pathways in gemcitabine-resistant PC cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Piceamycin ( 1 ), a macrocyclic lactam isolated from the silkworm's gut ( Streptomyces sp. SD53 strain), reportedly possesses antibacterial activity. However, the potential anticancer activity and molecular processes underlying 1 have yet to be reported. Colorectal cancer (CRC) is high-risk cancer and accounts for 10% of all cancer cases worldwide. The high prevalence of resistance to radiation or chemotherapy means that patients with advanced CRC have a poor prognosis, with high recurrence and metastasis potential. Therefore, the present study investigated the antitumor effect and underlying mechanisms of 1 in CRC cells. The growth-inhibiting effect of 1 in CRC cells was correlated with the upregulation of a tumor suppressor, N-myc downstream-regulated gene 1 (NDRG1). Additionally, 1 induced G 0 /G 1 cell cycle arrest and apoptosis and inhibited the migration of CRC cells. Notably, 1 disrupted the interaction between NDRG1 and c-Myc in CRC cells. In a mouse model with HCT116-implanted xenografts, the antitumor activity of 1 was confirmed by NDRG1 modulation. Overall, these findings show that 1 is a potential candidate for CRC treatment through regulation of NDGR1-mediated functionality.

A genomic and spectroscopic signature-based search revealed a cycloaromatized enediyne, jejucarboside A ( 1 ), from a marine actinomycete strain. The structure of 1 was determined as a new cyclopenta[ a ]indene glycoside bearing carbonate functionality by nuclear magnetic resonance, high-resolution mass spectrometry (MS), MS/MS, infrared spectroscopy, and a modified Mosher's method. An iterative enediyne synthase pathway has been proposed for the putative biosynthesis of 1 by genomic analysis. Jejucarboside A exhibited cytotoxicity against the HCT116 colon carcinoma cells.

Alkaloids derived from natural products have been traditionally used to treat various diseases, including cancers. Rutaecarpine ( 1 ), a β-carboline-type alkaloid obtained from Evodia rutaecarpa , has been previously reported as an anti-inflammatory agent. Nonetheless, its anticancer activity and the underlying molecular mechanisms remain to be explored. In the procurement of Wnt/β-catenin inhibitors from natural alkaloids, 1 was found to exhibit activity against the Wnt/β-catenin-response reporter gene. Since the abnormal activation of Wnt/β-catenin signaling is highly involved in colon carcinogenesis, the antitumor activity and molecular mechanisms of 1 were investigated in colorectal cancer (CRC) cells. The antiproliferative activity of 1 was associated with the suppression of the Wnt/β-catenin-mediated signaling pathway and its target gene expression in human CRC cells. 1 also induced G 0 /G 1 cell cycle arrest and apoptotic cell death, and the antimigration and anti-invasion potential of 1 was confirmed through epithelial-mesenchymal transition biomarker inhibition by the regulation of Wnt signaling. The antitumor activity of 1 was supported in an Ls174T-implanted xenograft mouse model via Wnt target gene regulation. Overall, these findings suggest that targeting the Wnt/β-catenin signaling pathway by 1 is a promising therapeutic option for the treatment of human CRC harboring β-catenin mutation.

Streptomyces sp. GET02.ST and Achromobacter sp. GET02.AC were isolated together from the gut of the wharf roach, Ligia &nbsp; exotica , inhabiting the intertidal zone of the west coast of Korea. The co-cultivation of these two strains significantly induced the production of two new metabolites, ligiamycins A ( 1 ) and B ( 2 ), which were barely detected in the single culture of Streptomyces sp. GET02.ST. The planar structures of ligiamycins A ( 1 ) and B ( 2 ) were elucidated as new decalins coupled with amino-maleimides by the analysis of various spectroscopic data, including nuclear magnetic resonance (NMR), ultraviolet (UV), and mass (MS) data. The assignment of two nitrogen atoms in amino-maleimide in 1 was accomplished based on 1 H- 15 N heteroatom single quantum coherence spectroscopy (HSQC) NMR experiments. The relative configurations of the ligiamycins were determined using rotating frame Overhauser effect spectroscopy (ROESY) NMR data, and their absolute configurations were deduced by comparing their experimental and calculated optical rotations. Ligiamycin A ( 1 ) displayed antibacterial effects against Staphylococcus aureus and Salmonella enterica , while ligiamycin B ( 2 ) exhibited mild cell cytotoxicity against human colorectal cancer cells.

Systematic inactivation of nonribosomal peptide synthetase (NRPS) domains and translocation of the thioesterase (TE) domain revealed several unprecedented nonlinear NRPS assembly processes during the biosynthesis of the cyclodepsipeptide WS9326A in Streptomyces sp. SNM55. First, two sets of type ΙΙ TE (TEΙΙ)-like enzymes mediate the shuttling of activated amino acids between two sets of stand-alone adenylation (A)-thiolation (T) didomain modules and an "A-less" condensation (C)-T module with distinctive specificities and flexibilities. This was confirmed by the elucidation of the affinities of the A-T didomains for the TEΙΙs and its structure. Second, the C-T didomain module operates iteratively and independently from other modules in the same protein to catalyze two chain elongation cycles. Third, this biosynthetic pathway includes the first example of module skipping, where the interpolated C and T domains are required for chain transfer., (© 2021 Wiley-VCH GmbH.)

Although docetaxel-based regimens are common and effective for early-stage triple-negative breast cancer (TNBC) treatment, acquired drug resistance frequently occurs. Therefore, a novel therapeutic strategy for docetaxel-resistant TNBC is urgently required. Signal transducer and activator of transcription 3 (STAT3) plays a pivotal role in the tumorigenesis and metastasis of numerous cancers, and STAT3 signaling is aberrantly activated in TNBC cells. In this study, a docetaxel-resistant TNBC cell line (MDA-MB-231-DTR) was established, and mechanisms for the antitumor activity of pulvomycin, a novel STAT3 inhibitor isolated from marine-derived actinomycete, were investigated. Levels of activated STAT3 (p-STAT3 (Y705)) increased in docetaxel-resistant cells, and knockdown of STAT3 recovered the sensitivity to docetaxel in MDA-MB-231-DTR cells. Pulvomycin effectively inhibited the proliferation of both cell lines. In addition, pulvomycin suppressed the activation of STAT3 and subsequently induced G 0 /G 1 cell cycle arrest and apoptosis. Pulvomycin also significantly inhibited the invasion and migration of MDA-MB-231-DTR cells through the modulation of epithelial-mesenchymal transition markers. In an MDA-MB-231-DTR-bearing xenograft mouse model, the combination of pulvomycin and docetaxel effectively inhibited tumor growth through STAT3 regulation. Thus, our findings demonstrate that the combination of docetaxel and STAT3 inhibitors is an effective strategy for overcoming docetaxel resistance in TNBC.

Two new secondary metabolites, svalbamides A ( 1 ) and B ( 2 ), were isolated from a culture extract of Paenibacillus sp. SVB7 that was isolated from surface sediment from a core (HH17-1085) taken in the Svalbard archipelago in the Arctic Ocean. The combinational analysis of HR-MS and NMR spectroscopic data revealed the structures of 1 and 2 as being lipopeptides bearing 3-amino-2-pyrrolidinone, d-valine, and 3-hydroxy-8-methyldecanoic acid. The absolute configurations of the amino acid residues in svalbamides A and B were determined using the advanced Marfey's method, in which the hydrolysates of 1 and 2 were derivatized with l- and d- forms of 1-fluoro-2,4-dinitrophenyl-5-alanine amide (FDAA). The absolute configurations of 1 and 2 were completely assigned by deducing the stereochemistry of 3-hydroxy-8-methyldecanoic acid based on DP4 calculations. Svalbamides A and B induced quinone reductase activity in Hepa1c1c7 murine hepatoma cells, indicating that they represent chemotypes with a potential for functioning as chemopreventive agents.

Colorectal cancer (CRC) is a common and intractable malignancy with a high mortality risk. Conventional chemotherapeutics are effective for patients with early stage CRC, but the majority of deaths of CRC patients are linked to acquired drug resistance or metastasis occurrence. Asperphenin B ( 1 ), a lipopeptidyl benzophenone isolated from a marine-derived Aspergillus sp. fungus, reportedly possesses antiproliferative activity against cancer cells. However, its antitumor activity and the underlying molecular mechanisms remain unexplored. In this study, 1 induced G 2 /M phase cell cycle arrest and subsequent apoptotic cell death and inhibited tumor growth in a xenograft model. The 1 -induced G 2 /M phase arrest was associated with the regulation of checkpoint proteins, including Chk1/2 and Cdc25c. The 1 -induced apoptosis was correlated with an upregulation of p53 and cleaved caspases and a downregulation of survivin. Further experiments revealed that 1 -mediated suppression of migration and invasion of metastatic HCT116 cells was partially associated with the downregulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. The antimetastatic potential of 1 was also confirmed by E-cadherin upregulation and N-cadherin and Snail downregulation, which were in turn associated with the GAPDH regulation. These findings highlight the potential use of 1 as a novel candidate for treating metastatic CRC with the modulation of GAPDH function.

Coprisamides C and D ( 1 and 2 ) were isolated from a gut bacterium, Micromonospora sp. UTJ3, of the carrion beetle Silpha perforata . Based on the combined analysis of UV, MS, and NMR spectral data, the planar structures of 1 and 2 were elucidated to be unreported derivatives of coprisamides A and B, cyclic depsipeptides bearing a 2-alkenylcinnamic acid unit and the unusual amino acids β-methylaspartic acid and 2,3-diaminopropanoic acid. The absolute configuration of 1 was determined using the advanced Marfey's method, phenylglycine methyl ester derivatization, and J -based configuration analysis. The biosynthetic gene clusters for the coprisamides were investigated based on genomic data from coprisamide-producing strains Micromonospora sp. UTJ3 and Streptomyces sp. SNU533. Coprisamide C ( 1 ) was active against the Mycobacterium tuberculosis mc 2 6230 strain.

Cellular senescence is important for the maintenance of tissue homeostasis during normal development. In this study, we aimed to investigate the effect of renin angiotensin system (RAS) blockade on renal cell senescence in the developing rat kidney. Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for seven days after birth. We investigated the intrarenal expressions of cell cycle regulators p21 and p16 with immunoblots and immunohistochemistry at postnatal day 8. For the determination of renal cellular senescence, immunostaining for senescence-associated β-galactosidase (SA-β-gal) and telomerase reverse transcriptase (TERT) was also performed. Enalapril treatment showed significant alterations in cellular senescence in neonatal rat kidneys. In the enalapril-treated group, intrarenal p16 and p21 protein expressions decreased compared to controls. The expressions of both p21 and p16 were reduced throughout the renal cortex and medulla of enalapril-treated rats. The immunoreactivity of TERT in enalapril-treated kidneys was also weaker than that in control kidneys. Control kidneys revealed a clear positive SA-β-gal signal in the cortical tubules; however, SA-β-gal activity was noticeably lower in the enalapril-treated kidneys than in control kidneys. Interruption of the RAS during postnatal nephrogenesis may disrupt physiologic renal cellular senescence in the developing rat kidney., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Stem cell transplantation has been proposed as an alternative treatment for intractable optic nerve disorders characterized by irrecoverable loss of cells. Mesenchymal stem cells, with varying tissue regeneration and recovery capabilities, are being considered for potential cell therapies. To overcome the limitations of cell therapy, we isolated exosomes from human placenta-derived mesenchymal stem cells (hPMSCs) and investigated their therapeutic effects in R28 cells (retinal precursor cells) exposed to CoCl 2 ., Method: After 9 h of exposure to CoCl 2 , the hypoxic damaged R28 cells were divided into the non-treatment group (CoCl 2 + R28 cells) and treatment group (CoCl 2 + R28 cells treated with exosome). Immunoblot analysis was performed for Pcna, Hif-1α, Vegf, Vimentin, Thy-1, Gap43, Ermn, Neuroflament, Wnt3a, β-catenin, phospo-GSK3β, Lef-1, UBA2, Skp1, βTrcp, and ubiquitin. The proteomes of each group were analyzed by liquid chromatography/tandem mass (LC-MS/MS) spectrometry. Differentially expressed proteins (DEPs) were detected by label-free quantification, and the interactions of the proteins were examined through signal transduction pathway and gene ontology analysis., Result: We observed that exosome could significantly recover proliferation damaged by CoCl 2 treatment. In addition, the treatment group presented the decreased expression of Hif-1α protein (P < 0.05) and increased expression of proliferation marker, Pcna, and nerve regeneration-related factors such as Vimentin, Thy-1, and Neuroflament (P < 0.05) compared with the non-treatment group. In total, 200 DEPs were identified in the non-treatment group and treatment group (fold change ≥ 2, p < 0.05). Catenin and ubiquitin systems (UBA2, UBE2E3, UBE2I) were found in both the DEP lists of downregulated proteins from the non-treatment group and upregulated proteins from the treatment group. The mRNA expressions of ubiquitin systems were significantly decreased under hypoxic conditions. Moreover, UBA2 and Wnt/β-catenin protein were associated with the rescue of the hypoxic damaged R28 cells. Using a siRNA system, we could find it out that hPMSC exosomes could not repair altered expressions of target proteins by CoCl 2 in lacking UBA2 R28 cells., Conclusion: This study reported that hypoxic damaged expression of regeneration markers in R28 cells was significantly recovered by hPMSC exosomes. We could also demonstrate that UBA2 played a key role in activating the Wnt/β-catenin signaling pathway during protection of hypoxic damaged R28 cells, induced by hPMSC exosomes.

Colorectal cancer (CRC) is one of the most malignant type of cancers and its incidence is steadily increasing, due to life style factors that include western diet. Abnormal activation of canonical Wnt/β-catenin signaling pathway plays an important role in colorectal carcinogenesis. Therefore, targeting Wnt/β-catenin signaling has been considered a crucial strategy in the discovery of small molecules for CRC. In the present study, we found that Nodosin, an ent -kaurene diterpenoid isolated from Isodon serra , effectively inhibits the proliferation of human colon cancer HCT116 cells. Mechanistically, Nodosin effectively inhibited the overactivated transcriptional activity of β-catenin/T-cell factor (TCF) determined by Wnt/β-catenin reporter gene assay in HEK293 and HCT116 cells. The expression of Wnt/β-catenin target genes such as Axin2, cyclin D1, and survivin were also suppressed by Nodosin in HCT116 cells. Further study revealed that a longer exposure of Nodosin induced the G 2 /M phase cell cycle arrest and subsequently apoptosis in HCT116 cells. These findings suggest that the anti-proliferative activity of Nodosin in colorectal cancer cells might in part be associated with the regulation of Wnt/β-catenin signaling pathway.

Chemical profiling of the Streptomyces sp. strain SUD119, which was isolated from a marine sediment sample collected from a volcanic island in Korea, led to the discovery of three new metabolites: donghaecyclinones A-C ( 1 - 3 ). The structures of 1 - 3 were found to be rearranged, multicyclic, angucyclinone-class compounds according to nuclear magnetic resonance (NMR) and mass spectrometry (MS) analyses. The configurations of their stereogenic centers were successfully assigned using a combination of quantum mechanics-based computational methods for calculating the NMR shielding tensor (DP4 and CP3) as well as electronic circular dichroism (ECD) along with a modified version of Mosher's method. Donghaecyclinones A-C ( 1 - 3 ) displayed cytotoxicity against diverse human cancer cell lines (IC 50 : 6.7-9.6 μM for 3 ).

Triple-negative breast cancer (TNBC) is the most intractable cancer in women with a high risk of metastasis. While hyper-methylation of histone H3 catalyzed by disruptor of telomeric silencing 1-like (DOT1L), a specific methyltransferase for histone H3 at lysine residue 79 (H3K79), is reported as a potential target for TNBCs, early developed nucleoside-type DOT1L inhibitors are not sufficient for effective inhibition of growth and metastasis of TNBC cells. We found that TNBC cells had a high expression level of DOT1L and a low expression level of E-cadherin compared to normal breast epithelial cells and non-TNBC cells. Here, a novel psammaplin A analog (PsA-3091) exhibited a potent inhibitory effect of DOT1L-mediated H3K79 methylation. Consistently, PsA-3091 also significantly inhibited the proliferation, migration, and invasion of TNBC cells along with the augmented expression of E-cadherin and the suppression of N-cadherin, ZEB1, and vimentin expression. In an orthotopic mouse model, PsA-3091 effectively inhibited lung metastasis and tumor growth by the regulation of DOT1L activity and EMT biomarkers. Together, we report here a new template of DOT1L inhibitor and suggest that targeting DOT1L-mediated H3K79 methylation by a novel PsA analog may be a promising strategy for the treatment of metastatic breast cancer patients., (© 2019 The Author(s).)

The chemical analysis of a Streptomyces strain, from a Korean volcanic island, discovered new benz[ a]anthracene dimers linked by a thioether bond. The structures of donghaesulfins A and B (1 and 2) were elucidated by spectroscopic analysis including energy-dispersive X-ray. Their configurations were determined by ROESY NMR data, DP4 calculations, the modified Mosher's method, and ECD calculations. Donghaesulfins A (1) induced quinone reductase, whereas donghaesulfin B (2) displayed antiangiogenesis activity.

Background: Renin-angiotensin system (RAS) blockade during nephrogenesis causes a broad range of renal mal-development. Here, we hypothesized that disruption of renal lymphangiogenesis may contribute to tubulointerstitial alterations after RAS blockade during kidney maturation., Methods: Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle for 7 days after birth. Lymphangiogenesis was assessed via immunostaining and/or immunoblots for vascular endothelial growth factor (VEGF)-C, VEGF receptor (VEGFR)-3, Podoplanin, and Ki-67. The intrarenal expression of fibroblast growth factor (FGF)-1, FGF-2, FGF receptor (R)-1, α-smooth muscle actin (α-SMA), and fibroblast-specific protein (FSP)-1 was also determined. Sirius Red staining was performed to evaluate interstitial collagen deposition., Results: On postnatal day 8, renal lymphangiogenesis was disrupted by neonatal enalapril treatment. The expression of podoplanin and Ki-67 decreased in enalapril-treated kidneys. While the expression of VEGF-C was decreased, the levels of VEGFR-3 receptor increased following enalapril treatment. Enalapril treatment also reduced the renal expression of FGF-1, FGF-2, and FGFR-1. Enalapril-treated kidneys exhibited profibrogenic properties with increased expression of α-SMA and FSP-1 and enhanced deposition of interstitial collagen., Conclusion: Enalapril treatment during postnatal renal maturation can disrupt renal lymphangiogenesis along with tubulointerstitial changes, which may result in a pro-fibrotic environment in the developing rat kidney.

WS9326H (1), a new cyclic peptide, was isolated from a mudflat-derived Streptomyces strain. Based on analysis by 1D/2D NMR, UV spectroscopy, and mass spectrometry, compound 1 was determined to have the gross structure of a cyclic heptapeptide bearing an unprecedented pyrazolone ring connected to a d-arabinitol via an amide bond. The absolute configuration of 1 was established by multistep chemical derivatizations, comprehensive NMR, and LC/MS analyses of the derivatives and quantum mechanics-based computational methods. WS9326H (1) displayed significant antiangiogenesis activity.

Proper and timely assembly of the kidney vasculature with their respective nephrons is crucial during normal kidney development. In this study, we investigated the effects of enalapril (angiotensin-converting enzyme inhibitor) on angiogenesis-related gene expression and microvascular endothelium related to glomeular and tubular changes in the neonatal rat kidney. Enalapril-treated rats had higher tubular injury scores and lower glomerular maturity grades than those of untreated rats. In the enalapril-treated group, intrarenal angiopoietin-2, Tie-2, and thrombospondin-1 protein expression increased, whereas intrarenal angiopoietin-1 protein expression decreased. JG12-positive glomerular and peritubular capillary staining was reduced in the enalapril-treated rat kidney. The number of JG12-positive capillary endothelial cells was directly correlated with glomerular maturation grade and was inversely related with the tubular injury. Our findings suggest the imbalance between pro- and anti-angiogenic factors may be implicated in the loss of capillaries in associated with impaired nephrogenesis after angiotensin II blockade in the developing rat kidney.

This study was aimed to investigate the association of candidate gene polymorphisms and obesity or overweight in young Korean children. A total of 190 Korean preschool children (96 control, 48 overweight, and 46 obese children) were genotyped for the angiotensin converting enzyme (ACE) insertion (I)/deletion (D), angiotensin II type 2 receptor (AT2) C3123A, transforming growth factor (TGF)-β1 T869C, vascular endothelial growth factor (VEGF) T460C, and tumor necrosis factor (TNF)-α G308A polymorphisms. No differences were found among the groups with respect to age, sex, birth weight, blood pressure levels, and serum concentrations of glucose and total cholesterol. Obese children showed a higher incidence of ACE DD genotype and D allelic frequency compared to the controls (odds ratio [OR], 2.7, 95% confidence interval [CI], 1.01-7.21; OR, 2.5, 95% CI, 1.49-4.19; all P < 0.05). The frequency of TC genotype and C allele in the TGF-β1 T869C polymorphism (OR, 2.08, 95% CI, 1.01-4.27; OR, 1.93, 95% CI, 1.15-3.21) and that in the VEGF T460C polymorphism (OR, 2.5, 95% CI, 1.19-5.28; OR, 2.15, 95% CI, 1.26-3.68) was also higher in obese children than in control subjects (all P < 0.05). Overweight children exhibited a higher frequency of the A allele in the AT2 C3123A polymorphism compared to the controls (OR, 1.72, 95% CI, 1.03-2.88, P < 0.05). There were no differences in the TNF-α G308A polymorphism among the groups. The ACE I/D, AT2 C3123A, TGF-β1 T869C, and VEGF T460C polymorphisms can affect susceptibility to obesity or overweight in Korean children., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2017 The Korean Academy of Medical Sciences.)

Purpose: Nephrogenesis is normally accompanied by a tightly regulated and efficient vascularization. We investigated the effect of angiotensin II inhibition on angiogenesis in the developing rat kidney., Methods: Newborn rat pups were treated with enalapril (30 mg/kg/day) or vehicle (control) for 7 days after birth. Renal histological changes were checked using Hematoxylin & Eosin staining. We also investigated the intrarenal expression of vascular endothelial growth factor (VEGF)-A, VEGF receptor 1 (VEGFR1), VEGFR2, platelet-derived growth factor (PDGF)-B, and PDGF receptor-β with Western blotting and immunohistochemical staining at postnatal day 8. Expression of the endothelial cell marker CD31 was examined to determine glomerular and peritubular capillary density., Results: Enalapril-treated rat kidneys showed disrupted tubules and vessels when compared with the control rat kidneys. In the enalapril-treated group, intrarenal VEGF-A protein expression was significantly higher, whereas VEGFR1 protein expression was lower than that in the control group (P<0.05). The expression of VEGFR2, PDGF-B, and PDGF receptor-β was not different between the 2 groups. The increased capillary CD31 expression on the western blots of enalapril-treated rat kidneys indicated that the total endothelial cell protein level was increased, while the cortical capillary density, assessed using CD31 immunohistochemical staining, was decreased., Conclusion: Impaired VEGF-VEGFR signaling and altered capillary repair may play a role in the deterioration of the kidney vasculature after blocking of angiotensin II during renal development.

Background: Early predictive biomarkers for the diagnosis and management of febrile urinary tract infections (UTIs) can be valuable diagnostic tools in children., Methods: The study cohort comprised 73 pediatric patients with febrile UTIs [46 with acute pyelonephritis (APN) and 27 with lower UTIs] and 56 healthy children. Urine neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (uKIM-1) levels and serum cystatin C (sCysC) levels were measured., Results: The uNGAL/creatinine (Cr) and uKIM-1/Cr levels were higher in the UTI group than in the controls (P < 0.05). uNGAL/Cr and sCysC levels were higher in patients with APN than in those with lower UTIs (P < 0.05). uNGAL/Cr levels in both the APN and UTI groups decreased following the administration of antibiotics compared to those before treatment (P < 0.05). The uNGAL/Cr level was correlated with serum levels of white blood cells, C-reactive protein, CysC and with uKIM-1/Cr (P < 0.05). uKIM-1/Cr was also correlated with sCysC (P < 0.05). Receiver operating curve analyses showed good diagnostic profiles of uNGAL/Cr and uKIM-1/Cr for identifying UTIs [area under the curve (AUC) 0.9 and 0.66, respectively) and of uNGAL/Cr and sCysC for predicting APN (AUC 0.78 and 0.72, respectively)., Conclusions: Our results suggest that uNGAL, uKIM-1 and sCysC levels may be useful for predicting and managing febrile UTIs in children.

Purpose: This study was aimed to develop a computerized reminder system and evaluate it's effect in terms of percent age change of screening, and satisfaction., Method: It was conducted through 6 phases : Analyzing the job and defining the basic input data, developing the information system, collecting and inputing data, testing the system, working with the system, and evaluating it's effect. Participants were 787 people (female 30-69 years, and males 40-49 years) in 2 dong of Suyoung gu, Busan, who haven't had cancer screening for the stomach, breast, or cervix since Dec. 2000. There were three experimental groups: a letter; calling and calling after the letter reminder, and a non-equivalent control group. To determine whether services were obtained, a telephone survey was done after two months of follow-up., Result: A cancer screening information system with five DB modules was developed. Overall compliance with screening was not statistically significantly changed before and after applying computerized reminders for all three screening sites. Only 16% were satisfied with the reminder., Conclusion: This data didn't show that a reminder effort was effective of screening. However, because the evaluation interval was too short to find a difference in screening rate, we recommend additional longer prospective follow up studies.