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The brain is a common target organ for breast cancer metastasis, and the risk of brain metastasis is usually high for patients with HER2-positive breast cancer. While T-DXd showed positive results in HER2-positive breast cancer brain metastasis (BCBM), its activity and blood-brain barrier (BBB) permeability in active BCBM need to be further validated (TUXEDO-1 included 15 patients with active brain metastasis). Tucatinib plus Trastuzumab and Capecitabine triplet showed efficacy in patients with brain metastasis, but Tucatinib alone has poor BBB penetration. There is still an unmet medical need for active HER2-positive BCBM. VRN101099 is a highly selective kinase inhibitor of HER2 (Eurofins scanMAX Kinase Profiling, S-score (35) of 0.01). VRN101099 has single- to double-digit nanomolar (IC50) cellular potency in HER2-dependent cancer cells, and Ba/F3 cells expressing HER2 wild type or mutations with selectivity over wildtype EGFR. VRN101099 inhibited proliferation of BT474 with 3.6 nM IC50 but HaCaT with 829.2 nM IC50. VRN101099 binds HER2 kinase by forming a covalent bond to the Cys805 and its irreversible inhibition resulted in a longer target resident time than Tucatinib, confirmed by in vitro washout experiments. Robust in vivo activity of VRN101099 was observed in HER2-positive BT474 xenograft models. Moreover, once daily oral administration of VRN101099 significantly regressed intracranial BT474 tumor, demonstrating greater efficacy than twice daily oral administration of Tucatinib. These results were well explained by the superior brain to plasma exposure of VRN101099 to Tucatinib. Also, VRN101099 showed high exposure in the target organ, the fat pad, which potentiated better clinical translation. These anti-tumor efficacies are correlated with pharmacodynamic responses, as confirmed by decreased HER2, AKT, and ERK phosphorylation. In summary, VRN101099 is a brain penetrant, orally bioavailable, irreversible, and highly selective inhibitor of HER2 with therapeutic potential in HER2-positive BCBM. These data support the clinical development of VRN101099 in HER2-driven cancers. Citation Format: Yikyung Ko, Jihye yoo, Hong-ryul Jung, Hyerim Lim, YeongDeok Lee, Se Hyuk Kim, Dong Guk Shin, Serin Cho, Myung hoe Heo, Haelee Kim, Ha Yeon Cho, Ah Reum Han, Eunhwa Ko, Hwan Geun Choi, Deakwon Kim, Sunghwan Kim. VRN101099, Brain Permeable HER2 Kinase Inhibitor, Shows the Anti-tumor Activity in Preclinical Models of HER2-positive Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-03.

Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) are indispensable analytical tools to provide chemical fingerprints in metabolomics studies. The present study evaluated radiation breeding wheat lines for chemical changes by non-targeted NMR-based metabolomics analysis of bran extracts. Multivariate analysis following spectral binning suggested pyrrole-2-carbaldehydes as chemical markers of four mutant lines with distinct NMR fingerprints in a δ

The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1), primarily produced by hepatocytes and neutrophils, is a multifunctional protein that modulates various signaling cascades, mainly TGFβ signaling. Serum LRG1 and neutrophil-derived LRG1 have different molecular weights due to differences in glycosylation, but the impact of the differential glycan composition in LRG1 on its cellular function is largely unknown. We previously reported that LRG1 can promote both angiogenic and neurotrophic processes under hyperglycemic conditions by interacting with LPHN2. Here, we determined the crystal structure of LRG1, identifying the horseshoe-like solenoid structure of LRG1 and its four N-glycosylation sites. In addition, our biochemical and cell-biological analyses found that the deglycosylation of LRG1, particularly the removal of glycans on N325, is critical for the high-affinity binding of LRG1 to LPHN2 and thus promotes LRG1/LPHN2-mediated angiogenic and neurotrophic processes in mouse tissue explants, even under normal glucose conditions. Moreover, the intracavernous administration of deglycosylated LRG1 in a diabetic mouse model ameliorated vascular and neurological abnormalities and restored erectile function. Collectively, these data indicate a novel role of LRG1 glycans as molecular switches that can tune the range of LRG1’s cellular functions, particularly the LRG1/LPHN2 signaling axis.

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia, which causes endothelial dysfunction and peripheral neuropathy, ultimately leading to multiple complications. One prevalent complication is diabetic erectile dysfunction (ED), which is more severe and more resistant to treatment than nondiabetic ED. The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1) is a modulator of TGF-β-mediated angiogenesis and has been proposed as a biomarker for a variety of diseases, including DM. Here, we found that the adhesion GPCR latrophilin-2 (LPHN2) is a TGF-β-independent receptor of LRG1. By interacting with LPHN2, LRG1 promotes both angiogenic and neurotrophic processes in mouse tissue explants under hyperglycemic conditions. Preclinical studies in a diabetic ED mouse model showed that LRG1 administration into the penile tissue, which exhibits significantly increased LPHN2 expression, fully restores erectile function by rescuing vascular and neurological abnormalities. Further investigations revealed that PI3K, AKT, and NF-κB p65 constitute the key intracellular signaling pathway of the LRG1/LPHN2 axis, providing important mechanistic insights into LRG1-mediated angiogenesis and nerve regeneration in DM. Our findings suggest that LRG1 can be a potential new therapeutic option for treating aberrant peripheral blood vessels and neuropathy associated with diabetic complications, such as diabetic ED.

(1) Background: Three isolated compounds from Physalis alkekengi var. franchetii (PAF) have been investigated to possess a variety of biological activities. Their structures were elucidated by spectroscopic analysis (Ultraviolet (UV), High-resolution electrospray mass spectrometry (HR-ESI-Ms), and their anti-inflammatory effects were evaluated in vitro; (2) Methods: To investigate the mechanisms of action of PAF extracts and their isolated compounds, their anti-inflammatory effects were assessed in RAW 264.7 macrophages stimulated by lipopolysaccharide (LPS). RAW 264.7 cells were treated with different concentrations of Physalis alkekengi var. franchetii three isolated compounds of PAF for 30 min prior to stimulation with or without LPS for the indicated times. The inflammatory cytokines, interleukin (IL)-1β and tumor necrosis factor (TNF)-α were determined using reverse transcription-polymerase chain (RT-PCR); (3) Results Treatment of RAW 264.7 cells with LPS alone resulted in significant increases in inflammatory cytokine production as compared to the control group (p < 0.001). However, with the treatment of isophysalin B 100 μg/mL, there was a significant decrease in the mRNA expression levels of TNF-α in LPS-stimulated raw 264.7 cells (p < 0.001). With treatment of physalin 1–100 μg/mL, there was a markedly decrease in the mRNA expression levels of TNF-α in LPS stimulated raw 264.7 (p < 0.05). Moreover, TNF-α mRNA (p < 0.05) and IL-1β mRNA (p < 0.001) mRNA levels were significantly suppressed after treatment with 3′,7-dimethylquercetin in LPS stimulated Raw 264.7 cells; (4) Conclusions: These findings suggest that three isolated compounds from can suppress inflammatory responses in LPS stimulated macrophage.

Vibrio vulnificus MO6-24/O has three genes annotated as debranching enzymes or pullulanase genes. Among them, the gene encoded by VVMO6_03032 (vvde1) shares a higher similarity at the amino acid sequence level to the glycogen debranching enzymes, AmyX of Bacillus subtilis (40.5%) and GlgX of Escherichia coli (55.5%), than those encoded by the other two genes. The vvde1 gene encoded a protein with a molecular mass of 75.56 kDa and purified Vvde1 efficiently hydrolyzed glycogen and pullulan to shorter chains of maltodextrin and maltotriose (G3), respectively. However, it hydrolyzed amylopectin and soluble starch far less efficiently, and β-cyclodextrin (β-CD) only rarely. The optimal pH and temperature of Vvde1 was 6.5 and 25°C, respectively. Vvde1 was a cold-adapted debranching enzyme with more than 60% residual activity at 5°C. It could maintain stability for 2 days at 25°C and 1 day at 35°C, but it destabilized drastically at 40°C. The Vvde1 activity was inhibited considerably by Cu

Proanthocyanidins (PAs) are major phytochemicals in rice, and accumulate abundantly in red pericarp (RP) rice. Consumers and rice breeders are increasingly showing interest in PAs because of their beneficial health effects; however, PA biosynthesis in rice is not well-understood. Therefore, to gain insights into this process, we performed comparative transcriptome analysis of grains harvested at 14 days after flowering (DAF; i.e., the stage at which active PA biosynthesis occurs without pericarp color change) and 28 DAF (the stage of late seed development with pericarp color change) from RP and white pericarp rice. In RP rice at 14 DAF, the expression levels of six structural genes (OsCHS, OsF3H, OsF3′H, OsDFR, OsANS, and OsLAR), one modification gene (OsUGT), and one transport gene (OsGSTU34) were significantly upregulated, along with the activation of Rc, the key regulator of PA accumulation in the pericarp. Functional enrichment analysis of 56 differentially expressed genes specifically upregulated in RP rice at 28 DAF revealed the presence of three laccase genes known to cause the browning reaction through oxidation. These results expand our understanding of PA biosynthesis in rice, and provide a genetic basis that will lead to further studies on the genes and underlying molecular mechanisms associated with this process.

The Golgi apparatus is a critical intracellular organelle that is responsible for modifying, packaging, and transporting proteins to their destinations. Golgi homeostasis involving the acidic pH, ion concentration, and membrane potential, is critical for proper functions and morphology of the Golgi. Although transporters and anion channels that contribute to Golgi homeostasis have been identified, the molecular identity of cation channels remains unknown. Here we identify TMEM87A as a novel Golgi-resident cation channel that contributes to pH homeostasis and rename it as GolpHCat (GolgipH-sensitiveCation channel). The genetic ablation of GolpHCat exhibits an impaired resting pH in the Golgi. Heterologously expressed GolpHCat displays voltage- and pH-dependent, non-selective cationic, and inwardly rectifying currents, with potent inhibition by gluconate. Furthermore, reconstitution of purified GolpHCat in liposomes generates functional channel activities with unique voltage-dependent gating and ion permeation. GolpHCat is expressed in various cell types such as neurons and astrocytes in the brain. In the hippocampus, GolpHCat-knockout mice show dilated Golgi morphology and altered glycosylation and protein trafficking, leading to impaired spatial memory with significantly reduced long-term potentiation. We elucidate that GolpHCat, by maintaining Golgi membrane potential, regulates ionic and osmotic homeostasis, protein glycosylation/trafficking, and brain functions. Our results propose a new molecular target for Golgi-related diseases and cognitive impairment.

TMEM87 family is evolutionarily conserved eukaryotic transmembrane proteins residing in the Golgi1. TMEM87 members play a role in retrograde transport in Golgi and are also proposed mechanosensitive ion channel implicated in cancer and heart disease2–7. In an accompanying study, TMEM87A is described as a voltage-gated, pH-sensitive, non-selective cation channel whose genetic ablation in mice disrupts Golgi morphology, alters glycosylation and protein trafficking, and impairs hippocampal memory. Despite the pivotal functions of TMEM87s in Golgi, underlying molecular mechanisms of channel gating and ion conduction have remained unknown. Here, we present a high-resolution cryo-electron microscopy structure of human TMEM87A (hTMEM87A). Compared with typical ion channels, the architecture of hTMEM87A is unique: a monomeric cation channel consisting of a globular extracellular/luminal domain and a seven-transmembrane domain (TMD) with close structural homology to channelrhodopsin. The central cavity within TMD is occupied by endogenous phosphatidylethanolamine, which seals a lateral gap between two TMs exposed to the lipid bilayer. By combining electrophysiology and molecular dynamics analysis, we identify a funnel-shaped electro-negative luminal vestibule that effectively attracts cations, and phosphatidylethanolamine occludes ion conduction. Our findings suggest that a conformational switch of highly conserved positively-charged residues on TM3 and displacement of phosphatidylethanolamine are opening mechanisms for hTMEM87A, providing an unprecedented insight into the molecular basis for voltage-gated ion conduction in Golgi.

The serum glycoprotein leucine-rich ɑ-2-glycoprotein 1 (LRG1), primarily produced by hepatocytes and neutrophils, is a multifunctional protein that can modulate various signalling cascades, mainly TGFβ signalling. Serum LRG1 and neutrophil-derived LRG1 have different molecular weights due to differences in glycosylation, but what impact the differential glycan composition in LRG1 has on its cellular function is largely unknown. We previously reported that LRG1 can promote both angiogenic and neurotrophic processes under hyperglycemic conditions by interacting with LPHN2. Here, we determined the crystal structure of LRG1, identifying the horseshoe-like solenoid structure of LRG1 and its four N-glycosylation sites. In addition, our biochemical and cell-biological analysis found that de-glycosylation of LRG1, particularly the removal of glycans on N325, is critical for high-affinity binding of LRG1 to LPHN2, thereby promoting LRG1/LPHN2-mediated angiogenic and neurotrophic processes in mouse tissue explants, even under normal glucose conditions. Moreover, intracavernous administration of de-glycosylated LRG1 in a diabetic mouse model ameliorated vascular and neurological abnormalities and restored erectile function. Collectively, these data indicate a novel role of LRG1’s glycans as molecular switches that can tune the range of LRG1’s cellular functions, particularly the LRG1/LPHN2 signalling axis.

TMEM43 is a transmembrane protein with four transmembrane (TM) domains. TheTMEM43gene has been reported to play supportive but critical roles in many human diseases, such as cancer, arrhythmogenic right ventricular cardiomyopathy (ARVC), and auditory neuropathy spectrum disorder (ANSD). However, the direct characterization of the TMEM43 protein is missing. In this study, we examined the function of TMEM43in vitro. Heterologous expression of TMEM43 demonstrated that TMEM43 is permeable to Na+, K+, and Cs+ions, indicating that TMEM43 is a nonselective cation channel. The TMEM43-mediated current decreased gradually with lowering external solution pH, further characterizing TMEM43 as an external-pH sensing channel. Utilizing the endogenous cysteine residue at TM3, we could predict that the pore-forming residue of TMEM43 lies near TM3 and Loop2 domain. Importantly, stochastic channel openings from the lipid bilayer-reconstituted purified TMEM43 protein were observed, strengthening the proposal of TMEM43 as an ion channel. Lastly, the heterologous expression ofTMEM43-p.(Arg372Ter) resulted in a loss of channel activity in a dominant-negative fashion, as in the hearing loss phenotype in humans. These results together disclose the molecular and functional properties of TMEM43 and identify TMEM43 as a novel ion channel. The physiological identity of TMEM43 provided in this study will promote future research on TMEM43-related diseases.

Esculeoside A and tomatine are two major steroidal alkaloids in tomato fruit (

Skin wound healing is essential for recovery from injury, and delayed or impaired wound healing is a severe therapeutic challenge. Keratinocytes, a major component of the epidermis, play crucial roles in reepithelialization during wound healing including cell proliferation. Recent studies have shown that compounds from natural products have candidates for healing skin injury. Isoegomaketone (IK), isolated from leaves of Perilla frutescens var. crispa (Lamiaceae), has various bioactivities. However, the effect of IK on cutaneous wound healing processes has not been studied yet. In this study, we demonstrated that IK exhibits therapeutic wound healing effects using the human keratinocyte cell line HaCaT. Notably, IK promoted cell proliferation and migration in a dose-dependent manner in vitro, and treatment with 10 μM IK upregulated these processes by approximately 1.5-fold after 24 h compared with the control. IK induced the activation of the MAPK/ERK pathway and cell cycle progression to the S and G2/M phases. Thus, this study demonstrates IK as a potential candidate to upregulate wound healing that may provide therapeutic benefits to patients with delayed wound healing.

Many studies have focussed on modulating the activity of γ-aminobutyric acid transaminase (GABA-T), a GABA-catabolizing enzyme, for treating neurological diseases, such as epilepsy and drug addiction. Nevertheless, human GABA-T synthesis and purification have not been established. Thus, biochemical and drug design studies on GABA-T have been performed by using porcine GABA-T mostly and even bacterial GABA-T. Here we report an optimised protocol for overexpression of 6xHis-tagged human GABA-T in human cells followed by a two-step protein purification. Then, we established an optimised human GABA-T (0.5 U/mg) activity assay. Finally, we compared the difference between human and bacterial GABA-T in sensitivity to two irreversible GABA-T inhibitors, gabaculine and vigabatrin. Human GABA-T in homodimeric form showed 70-fold higher sensitivity to vigabatrin than bacterial GABA-T in multimeric form, indicating the importance of using human GABA-T. In summary, our newly developed protocol can be an important first step in developing more effective human GABA-T modulators.

The scaly bulbs of Lilium longiflorum (Liliaceae) are used as a food ingredient and a traditional medicine in East Asia. A preliminary study revealed that treatment with 100 μg/mL of the ethyl acetate fraction of this plant material inhibited dipeptidyl peptidase IV (DPP-IV) to 58.99%. Phytochemical studies were conducted to identify the active ingredient, and five compounds, namely, 1 (2.9 mg, 75.8% purity at 320 nm), 2 (12.2 mg, 97.9% purity at 320 nm), 3 (3.1 mg, 66.5% purity at 320 nm), 4 (6.8 mg, 96.9% purity at 320 nm), and 5 (6.2 mg, 90.2% purity at 320 nm) were purified from 200 mg of the ethyl acetate fraction of L. longiflorum via centrifugal partition chromatography (CPC) with a two-phase solvent system composed of chloroform/methanol/isopropanol/water (5:2:2:4, v/v/v/v) in an ascending mode. Their structures were identified as 1-O-p-coumaroyl-2-O-β-glucopyranosylglycerol (regaloside D, 1), 3,6'-O-diferuloylsucrose (2), 1-O-p-coumaroyl-2-O-β-glucopyranosyl-3-O-acetylglycerol (regaloside B, 3), 1-O-p-coumaroylglycerol (4), and 4-O-acetyl-3,6'-O-diferuloylsucrose (5), respectively, by 1H and 13C NMR and MS analysis. Compounds 2 and 5 exhibited DPP-IV inhibitory activities with IC50 values of 46.19 and 63.26 μM, respectively. Compounds 1, 3, and 4 did not show activities, indicating that biphenylpropanoids linked via the sugar moiety are more effective than phenylpropanoids with glycerol or glyceryl glucoside. This is the first report of simultaneous separation of five phenylpropanoids from L. longiflorum by CPC and evaluation of their DPP-IV inhibitory activities.

Recently, wheat has attracted attention as a functional food, rather than a simple dietary energy source. Accordingly, whole-grain intake increases with an understanding of bioactive phytochemicals in bran. The development of colored wheat has drawn more attention to the value of bran owing to its nutritional quality, as well as the antioxidant properties of the colorant. The present 1H NMR-based chemometric study evaluated the compositional improvement of radiation-induced mutants in purple wheat by focusing on the predominant metabolites with high polarity. A total of 33 metabolites, including three choline derivatives, three sugar alcohols, four sugars, 13 amino acids, eight organic acids, and two nucleosides, were identified throughout the 1H NMR spectra, and quantification data were obtained for the identified metabolites via peak shape-based quantification. Principal component and hierarchical cluster analyses were conducted for performing multivariate analyses. The colored original wheat was found to exhibit improvements compared to yellow wheat in terms of the contents of primary metabolites, thus highlighting the importance of conducting investigations of polar metabolites. The chemometrics studies further revealed mutant lines with a compositional enhancement for metabolites, including lysine, proline, acetate, and glycerol.

Lentil (Lens culinaris; Fabaceae), one of the major pulse crops in the world, is an important source of proteins, prebiotics, lipids, and essential minerals as well as functional components such as flavonoids, polyphenols, and phenolic acids. To improve crop nutritional and medicinal traits, hybridization and mutation are widely used in plant breeding research. In this study, mutant lentil populations were generated by γ-irradiation for the development of new cultivars by inducing genetic diversity. Molecular networking via Global Natural Product Social Molecular Networking web platform and dipeptidyl peptide-IV inhibitor screening assay were utilized as tools for structure-based discovery of active components in active mutant lines selected among the lentil population. The bioactivity-based molecular networking analysis resulted in the annotation of the molecular class of phosphatidylcholine (PC) from the most active mutant line. Among PCs, 1-stearoyl-2-hydroxy-sn-glycero-3-phosphocholine (18:0 Lyso PC) was selected for further in vivo study of anti-obesity effect in a high-fat diet (HFD)-induced obese mouse model. The administration of 18:0 Lyso PC not only prevented body weight gain and decreased relative gonadal adipose tissue weight, but also attenuated the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and leptin in the sera of HFD-induced obese mice. Additionally, 18:0 Lyso PC treatment inhibited the increase of adipocyte area and crown-like structures in adipose tissue. Therefore, these results suggest that 18:0 Lyso PC is a potential compound to have protective effects against obesity, improving obese phenotype induced by HFD.

Angiopoietin (Angpt)-Tie receptor 2 (Tie2) plays key roles in vascular development and homeostasis as well as pathological vascular remodeling. Therefore, Tie2-agonistic antibody and engineered Angpt1 variants have been developed as potential therapeutics for ischemic and inflammatory vascular diseases. However, their underlying mechanisms for Tie2 clustering and activation remain elusive and the poor manufacturability and stability of Angpt1 variants limit their clinical application. Here, we develop a human Tie2-agonistic antibody (hTAAB), which targets the membrane proximal fibronectin type III domain of Tie2 distinct from the Angpt-binding site. Our Tie2/hTAAB complex structures reveal that hTAAB tethers the preformed Tie2 homodimers into polygonal assemblies through specific binding to Tie2 Fn3 domain. Notably, the polygonal Tie2 clustering induced by hTAAB is critical for Tie2 activation and are resistant to antagonism by Angpt2. Our results provide insight into the molecular mechanism of Tie2 clustering and activation mediated by hTAAB, and the structure-based humanization of hTAAB creates a potential clinical application., Angiopoietin (Angpt)-Tie receptor 2 (Tie2) regulates vascular stability and is thus a potential therapeutic target in vascular diseases. Here, the authors report a Tie2-agonistic antibody which targets a site distinct from the Angpt 1-binding site and which influences Tie2 clustering and activation in an Angpt2 inhibition-resistant manner.

Under certain conditions, numerous soluble proteins possess an inherent tendency to convert into insoluble amyloid aggregates, which are associated with several sporadic and genetic human diseases. Transthyretin (TTR) is one of the more than 30 human amyloidogenic proteins involved in conditions such as senile systemic amyloidosis, familial amyloid polyneuropathy, and familial amyloid cardiomyopathy. Considerable effort has been focused on identifying the native tetrameric TTR stabilizers to inhibit rate-limiting tetramer dissociation and, consequently, ameliorate TTR amyloidogenesis. Here, we describe the design and synthesis of quinolin-2(1H)-one derivatives that could be structurally complementary to the thyroxine-binding site within tetrameric TTR. Among these quinolin-2(1H)-one derivatives, compound 7a allowed 16.7% of V30M-TTR (3.6 μM) fibril formation at the same concentration and 49.6% at a concentration of 1.8 μM. Compound 7a exhibited much greater potency in complex biological samples like human plasma than that observed with tafamidis, the drug approved for the treatment of TTR amyloid cardiomyopathy for wild-type or hereditary TTR-mediated amyloidosis. Furthermore, the unique spectral properties of compound 7a demonstrated its high potential for TTR quantification, imaging sensors, and fluorescent tools to study the mechanism of TTR amyloidogenesis.

The epithelial–mesenchymal transition (EMT) of cancer cells is a crucial process in cancer cell metastasis. An Aquimarina sp. MC085 extract was found to inhibit A549 human lung cancer cell invasion, and caprolactin C (1), a new natural product, α-amino-ε-caprolactam linked to 3-methyl butanoic acid, was purified through bioactivity-guided isolation of the extract. Furthermore, its enantiomeric compound, ent-caprolactin C (2), was synthesized. Both 1 and 2 inhibited the invasion and γ-irradiation-induced migration of A549 cells. In transforming growth factor-β (TGF-β)-treated A549 cells, 2 inhibited the phosphorylation of Smad2/3 and suppressed the EMT cell marker proteins (N-cadherin, β-catenin, and vimentin), as well as the related messenger ribonucleic acid expression (N-cadherin, matrix metalloproteinase-9, Snail, and vimentin), while compound 1 did not suppress Smad2/3 phosphorylation and the expression of EMT cell markers. Therefore, compound 2 could be a potential candidate for antimetastatic agent development, because it suppresses TGF-β-induced EMT.

Coreopsis species have been developed to produce cultivars of various floral colors and sizes and are also used in traditional medicine. To identify and evaluate mutant cultivars of C. rosea and C. verticillata, their phytochemical profiles were systematically characterized using ultra-performance liquid chromatography time-of-flight mass spectrometry, and their anti-diabetic effects were evaluated using the dipeptidyl peptidase (DPP)-IV inhibitor screening assay. Forty compounds were tentatively identified. This study is the first to provide comprehensive chemical information on the anti-diabetic effect of C. rosea and C. verticillata. All 32 methanol extracts of Coreopsis cultivars inhibited DPP-IV activity in a concentration-dependent manner (IC50 values: 34.01–158.83 μg/mL). Thirteen compounds presented as potential markers for distinction among the 32 Coreopsis cultivars via principal component analysis and orthogonal partial least squares discriminant analysis. Therefore, these bio-chemometric models can be useful in distinguishing cultivars as potential dietary supplements for functional plants.

The Dendrobium species (Orchidaceae) has been cultivated as an ornamental plant as well as used in traditional medicines. In this study, the chemical profiles of Dendrobii Herba, used as herbal medicine, Dendrobium in two different species, their hybrid, and the gamma-irradiated mutant lines of the hybrid, were systematically investigated via ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QToF MS). Among the numerous peaks detected, 17 peaks were unambiguously identified. Gigantol (1), (1R,2R)-1,7-hydroxy-2,8-methoxy-2,3-dihydrophenanthrene-4(1H)-one (2), tristin (3), (−)-syringaresinol (4), lusianthridin (5), 2,7-dihydroxy-phenanthrene-1,4-dione (6), densiflorol B (7), denthyrsinin (8), moscatilin (9), lusianthridin dimer (10), batatasin III (11), ephemeranthol A (12), thunalbene (13), dehydroorchinol (14), dendrobine (15), shihunine (16), and 1,5,7-trimethoxy-2-phenanthrenol (17), were detected in Dendrobii Herba, while 1, 2, and 16 were detected in D. candidum, 1, 11, and 16 in D. nobile, and 1, 2, and 16 in the hybrid, D. nobile × candidum. The methanol extract taken of them was also examined for cytotoxicity against FaDu human hypopharynx squamous carcinoma cells, where Dendrobii Herba showed the greatest cytotoxicity. In the untargeted metabolite analysis of 436 mutant lines of the hybrid, using UPLC-QToF MS and cytotoxicity measurements combined with multivariate analysis, two tentative flavonoids (M1 and M2) were evaluated as key markers among the analyzed metabolites, contributing to the distinction between active and inactive mutant lines.

Five new furanocoumarins, dahuribirin H (1), dahuribirin I (2), (2'S)-(+)-5-(2'-hydroxy-3'-methylbut-3'-enyloxy)-8-(3''-methylbut-2″-enyloxy)psoralen (3), (2'R)-(+)-5-(2',3'-epoxy-3'-methylbutoxy)-8-(3″-methylbut-2″-enyloxy)psoralen (4), and 5-methoxy-8-((Z)-4'-(3″-methylbutanoate)-3'-methylbut-2'-enyloxy)psoralen (5), along with 15 known compounds (6-20), were isolated from the roots of Angelica dahurica. The structures of the new compounds were elucidated by spectroscopic analysis, along with electronic circular dichroism calculations and Mosher ester analysis. Compounds 3, 4, 11, 13, and 16 reduced H2O2-induced cell death in HepG2 cells and attenuated reactive oxygen species (ROS) formation without showing cytotoxicity, suggesting that these compounds might have cytoprotective effects against H2O2-induced oxidative damage via ROS scavenging activities.

Inflammatory bowel disease (IBD) is a worldwide health problem. An effective treatment for IBD is unavailable, and potential therapeutic agents should be developed for treating colonic inflammation. In this study, we demonstrated that isoegomaketone (IK), an essential oil component of a mutant cultivar of Perilla frutescens produced through radiation breeding, reduced levels of inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6, interleukin-10, and interleukin-12p40, in lipopolysaccharide-stimulated mouse primary macrophages. Furthermore, when 5 mg/kg IK was administered to mice with dextran sodium sulfate-induced colitis, it ameliorated the severity of the disease as assessed by survival, body weight, and colonic damage. These results suggested that 5 mg/kg IK has a preventive effect in colitis and can be a novel alternative therapy for treating colitis.

The Korean Peninsula is the southern limit of the distribution of Picea jezoensis (Siebold et Zucc.) Carriere, where it occurs only on isolated subalpine mountain tops in South Korea. Global warming is altering habitat environments, threatening the survival of P. jezoensis. This study investigated the seed germination, seedling establishment, and seedling mortality of P. jezoensis on different forest floor substrates (woody debris [WD], litter, and soil from a P. jezoensis habitat on Mt. Gyebang), together with horticultural sand, under control (mimicking habitat condition: day 22.3 °C/night 9.4 °C) and elevated (26.6 °C/13.7 °C) air temperatures to determine the effects of an increase in temperature on P. jezoensis regeneration. Seed germination did not differ significantly between the control and elevated temperature conditions on all substrates. Yet, seedling mortality increased by more than 1.4 times under elevated temperature compared to controls on all substrates. Among the four substrates, WD and litter respectively exhibited the lowest (15.6%) and highest (50%) seedling mortality for P. jezoensis under control conditions, with respective significant increases of 53% and 77% seedling mortality under elevated temperature (p

Zingiber cassumunar Roxb. (Zingiberaceae), is an important medicinal plant known as “Plai (Phlai)” in Thailand, “Bangle” in Indonesia, and “Bulei” in China. Traditionally, this plant has been used to treat inflammation, pain, and respiratory problems. The rhizomes are the primary part of the plant that has been used for medicinal purposes due to their constituents with therapeutic properties, including phenylbutenoids, curcuminoids, and essential oils. Since the 1970s, many studies have been conducted on the phytochemicals and bioactivities of Z. cassumunar to establish fundamental scientific evidence that supports its use in traditional medicine. The accumulated biological studies on the extracts, solvent fractions, and constituents of Z. cassumunar have described their diverse medicinal properties, including antioxidant, anti-inflammatory, anticancer, neuroprotective/neurotrophic, cosmeceutical, and antifungal/antimicrobial bioactivities. In this review, we summarize information on the phytochemicals of Z. cassumunar and the bioactivities of its extracts and constituents.