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ABSTRACTPatients with inflammatory bowel disease (IBD), including ulcerative colitis (UC), show an increased incidence of anxiety and depression; however, the association between UC-associated psychiatric disorders and the gut microbiota is unclear. This study aimed to examine whether gut microbiota from patients with UC can alter colonic gene expression, leading to anxiety- and depression-like behavior in mice receiving fecal microbiota transplantation (FMT). RNA sequencing transcriptome analyses revealed a difference in colonic gene expression between mice receiving FMT from patients with UC (UC-FMT mice) and those receiving FMT from healthy controls (HC-FMT mice). Gene ontology analysis revealed the downregulation of neuropeptide signaling pathways, including neuropeptide Y (NPY) expression, in the colons of UC-FMT mice. The protein levels of NPY also decreased in the colon and plasma of UC-FMT mice compared to those in HC-FMT mice. The oral administration of Enterococcus mundtii (EM), a bacterium isolated from the feces of patients with UC, reduced NPY expression in the colons of mice and induced intestinal inflammation, anxiety, and depression-like behavior. Reduced NPY protein levels were also observed in the plasma and hippocampus of EM-treated mice. Intraperitoneal administration of NPY significantly alleviated anxiety- and depressive-like behaviors induced by EM in mice. Capsular polysaccharide in EM was associated with EM-induced NPY downregulation in the colon. Analysis of Gene Expression Omnibus datasets showed markedly reduced NPY expression in the inflamed colons of patients with UC compared with that in the colons of healthy controls. In summary, EM-induced reduction in the colonic expression of NPY may be associated with a decrease in hippocampal NPY and anxiety- and depression-like behavior in mice.

Milling can affect the distribution of mycotoxins in small grains. To investigate the effects on barley, seven hulled barley and three naked barley samples naturally contaminated with trichothecenes and zearalenone were obtained and milled at commonly used rates. Both barleys were simultaneously contaminated with deoxynivalenol and its acetyl derivatives (98.1–2,197.8 µg/kg), nivalenol and its acetyl derivative (468.5–3,965.1 µg/kg), and zearalenone (4.1–274.2 µg/kg). Milling hulled barleys at a rate of 67% reduced the mycotoxins in the grain by 90.9% for deoxynivalenol, 87.7% for nivalenol, and 93.2% for zearalenone. The reduction in naked barleys (milled at a rate of 70%) was slightly lower than in hulled barleys, with 88.6% for deoxynivalenol, 80.2% for nivalenol, and 70.1% for zearalenone. In both barleys, the acetyl derivatives of deoxynivalenol and nivalenol were reduced by 100%. However, barley bran had significantly higher mycotoxin concentrations than the pre-milled grains: bran from hulled barley had a 357% increase in deoxynivalenol, 252% increase in nivalenol, and 169% increase in zearalenone. Similarly, bran from naked barley had a 337% increase in deoxynivalenol, 239% increase in nivalenol, and 554% increase in zearalenone. These results show that mycotoxins present in the outer layers of barley grain can be effectively removed through the milling process. As milling redistributes mycotoxins from the grain into the bran, however, it shows that advance monitoring of barley bran is recommended when using barley bran for human or animal consumption.

In this review, the mycotoxin contamination of Korean cereals and their products is analyzed by crop based on scientific publications since 2000. Barley, rice, and corn were investigated heavier than the others. The common mycotoxins occurred in all cereals and their products were deoxynivalenol and zearalenone. Nivalenol was detected in all samples analyzed but more frequently or mainly in barley, rice, and oat. Fumonisin was commonly detected in corn and sorghum but also in adlay, millet, and rice. Adlay and millet were similar in the contamination pattern that fumonisin and zearalenone were the most frequently detected mycotoxins. Zearalenone was the most commonly detected mycotoxin with concentrations higher than the national standards (maximum limit), followed by deoxynivalenol, and aflatoxin. However, most occurrence levels were below the maximum limits for respective mycotoxins. This result shows that barley, rice, corn, sorghum, millet, and adlay are more vulnerable to mycotoxin contamination than other cereals and therefore continuous monitoring and safety management are necessary.

Fusarium head blight is an important disease of small grains. It is mainly caused by members of the Fusarium graminearum species complex (FGSC). Barley and wheat growers spray fungicides, especially demethylation-inhibitor fungicides, to suppress the disease. The objective of this study was to examine the changes in the sensitivity of the FGSC population to the triazole fungicide, propiconazole. A total of 124 and 350 isolates of FGSC were obtained from barley and wheat in Jeolla Province during 2010-2016 and 2020-2021, respectively. The species identity and trichothecene chemotypes of the FGSC isolates were determined based on polymerase chain reaction assays targeting translation elongation factor 1-alpha and TRI12 genes, respectively. Sensitivity to propiconazole was determined based on the effective concentration that reduced 50% of the mycelial growth (EC50) using the agar dilution method. Of all isolates, F. asiaticum with the nivalenol chemotype was the most common (83.9% in 2010-2016 and 96.0% in 2020-2021), followed by F. asiaticum with the 3-acetyl deoxynivalenol chemotype (12.1% in 2010-2016 and 2.9% in 2020-2021). The EC50 values of the isolates collected in 2010-2016 and 2020-2021 ranged from 0.0180 to 11.0166 μg/mL and 1.3104 to 17.9587 μg/mL, respectively. The mean EC50 value of the isolates increased from 3.8648 μg/mL in 2010-2016 to 5.9635 μg/mL in 2020-2021. The baseline resistance to propiconazole was determined to be 7 μg/mL, based on the EC50 value of isolates collected in 2010-2016, and the ratio of resistant isolates increased from 9.7% in 2010-2016 to 28.6% in 2020-2021.

Ovarian cancer, which ranks eighth among global female cancers and fifth in fatality, poses a significant health challenge owing to its asymptomatic early stages. Understanding the pathogenesis requires extensive research. Recent studies have emphasized the role of the gut and cervicovaginal microbiota in ovarian cancer. This review explores the current understanding of the relationship between the microbiome and ovarian cancer, considering the potential of biomarkers in the serum and various tissues. Insights into the influence of the microbiome on treatments, including surgery and chemotherapy, open doors to innovative approaches, such as fecal microbiome transplantation. This synthesis of recent findings provides crucial insights into the intricate interplay between the microbiome and ovarian cancer, thereby shaping diagnostic and treatment strategies.

The regulation of the immune environment within the tumor microenvironment has provided new opportunities for cancer treatment. However, an important microenvironment surrounding cancer that is often overlooked despite its significance in cancer progression is the neural environment surrounding the tumor. The release of neurotrophic factors from cancer cells is implicated in cancer growth and metastasis by facilitating the infiltration of nerve cells into the tumor microenvironment. This nerve–tumor interplay can elicit cancer cell proliferation, migration, and invasion in response to neurotransmitters. Moreover, it is possible that cancer cells could establish a network resembling that of neurons, allowing them to communicate with one another through neurotransmitters. The expression levels of players in the neural circuits of cancers could serve as potential biomarkers for cancer aggressiveness. Notably, the upregulation of certain players in the neural circuit has been linked to poor prognosis in specific cancer types such as breast cancer, pancreatic cancer, basal cell carcinoma, and stomach cancer. Targeting these players with inhibitors holds great potential for reducing the morbidity and mortality of these carcinomas. However, the efficacy of anti-neurogenic agents in cancer therapy remains underexplored, and further research is necessary to evaluate their effectiveness as a novel approach for cancer treatment. This review summarizes the current knowledge on the role of players in the neural circuits of cancers and the potential of anti-neurogenic agents for cancer therapy.

Peanuts in storage were estimated for mycotoxigenic fungi and mycotoxins. Peanut samples collected from storages in Gochang were mainly contaminated with Fusarium (17.2±28.0%), Penicillium (12.4±28.0%), and Aspergillus (8.0±7.6%). Other genera, including Talaromyces, Rhizopus, Rhizoctonia, Trichocladium, Clonostachys, Mucor, Chaetomium, Trametes, Epicoccum, and Humicola, were also found. Although aflatoxins were not detected in the peanut samples, 29 strains of Aspergillus flavus were identified using molecular marker genes. Among them, 17 selected isolates produced aflatoxins in solid culture media ranging from 0.61–187.82 μg/kg. All of them could produce both aflatoxin B1 and B2 and some (n=5) produced additional G1, G2, or both. This study is the first report that A. flavus stains obtained from Korean stored peanut are aflatoxigenic.

Sedum middendorffianum Maxim (SMM) is a Korean endemic plant belonging to the Crassulaceae family. This study aimed to investigate the antitumor effects of the SMM extract on human ovarian cancer cells. Among five endemic plants grown in Korea, the SMM extract showed the most potent cytotoxicity in ovarian cancer cells and had little effect on normal ovarian surface epithelial cells. Furthermore, we revealed that the SMM extract dose-dependently induced apoptosis in human ovarian cancer A2780 and SKOV3 cells. The SMM extract markedly stimulated the activation of caspase-3/8, while the broad-spectrum caspase inhibitor and caspase-8 selective inhibitor significantly reversed SMM extract-induced apoptosis. In addition, the SMM extract significantly inhibited cell invasion and the expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 in ovarian cancer cells. Notably, the SMM extract increased the generation of intracellular ROS, and pretreatment with antioxidant N-acetyl-L-cysteine (NAC) significantly suppressed SMM-induced cytotoxicity and anti-invasive activity. Moreover, NAC treatment reversed the SMM-induced inhibition of MMP-2/9 expression. Taken together, these data suggest that the SMM extract induces caspase-dependent apoptotic cell death and inhibits MMP-dependent invasion via ROS regulation.

Ovarian cancer is a metastatic disease that frequently exhibits extensive peritoneal dissemination. Recent studies have revealed that noncancerous cells inside the tumor microenvironment, such as macrophages and mesothelial cells, may play a role in ovarian cancer metastasis. In this study, we found that human ovarian cancer cells (A2780 and SKOV3) adhered more to human mesothelial Met5A cells stimulated by macrophages (M-Met5A) in comparison to unstimulated control Met5A cells. The mRNA sequencing revealed that 94 adhesion-related genes, including FMN1, ITGA2, COL13A1, VEGFC, and NRG1, were markedly upregulated in M-Met5A cells. Knockdown of ITGA2 and VEGFC in M-Met5A cells significantly inhibited the adhesion of ovarian cancer cells. Inhibition of the JNK and Akt signaling pathways suppressed ITGA2 and VEGFC expression in M-Met5A cells as well as ovarian cancer-mesothelial cell adhesion. Furthermore, increased production of CC chemokine ligand 2 (CCL2) and CCL5 by macrophages elevated ovarian cancer-mesothelial cell adhesion. These findings imply that macrophages may play a significant role in ovarian cancer-mesothelial cell adhesion by inducing the mesothelial expression of adhesion-related genes via the JNK and Akt pathways.

Fusarium asiaticum of the F. graminearum species complex causes head blight in small-grain cereals. The nivalenol (NIV) chemotypes of F. asiaticum is more common than the deoxynivalenol (DON) chemotypes of F. asiaticum or F. graminearum in Korea. To understand the prevalence of F. asiaticum–NIV in Korean cereals, we characterized the biological traits of 80 cereal isolates of F. asiaticum producing NIV or 3-acetyl-deoxynivalenol (3-ADON), and 54 F. graminearum with 3-ADON or 15-acetyl-deoxynivalenol (15-ADON). There was no significant difference in mycelial growth between the chemotypes, but F. asiaticum isolates grew approximately 30% faster than F. graminearum isolates on potato dextrose agar. Sexual and asexual reproduction capacities differed markedly between the two species. Both chemotypes of F. graminearum (3-ADON and 15-ADON) produced significantly higher numbers of perithecia and conidia than F. asiaticum–NIV. The highest level of mycotoxins (sum of trichothecenes and zearalenone) was produced by F. graminearum–3-ADON on rice medium, followed by F. graminearum–15-ADON, F. asiaticum–3-ADON, and F. asiaticum–NIV. Zearalenone levels were correlated with DON levels in some chemotypes, but not with NIV levels. Disease assessment on barley, maize, rice, and wheat revealed that both F. asiaticum and F. graminearum isolates were virulent toward all crops tested. However, there is a tendency that virulence levels of F. asiaticum–NIV isolates on rice were higher than those of F. graminearum isolates. Taken together, the phenotypic traits found among the Korean F. asiaticum–NIV isolates suggest an association with their host adaptation to certain environments in Korea.

A total of 1,159 Fusarium strains were isolated from sorghum grown in Danyang and Youngwol in 2017 and 2018. The isolates were analyzed to reveal genetic, toxigenic and pathogenic characteristics. Phylogenetic analysis using TEF-1α and RPB2 genes showed that the samples were contaminated with at least 17 Fusarium species. Among them, F. graminearum, F. proliferatum, F. thapsinum, F. incarnatum, and F. asiaticum were dominant species. In F. graminearum and F. asiaticum, F. graminearum-15-acetyl deoxynivalenol chemotype and F. asiaticum-nivalenol chemotype were frequent. Six Fusarium species tested produced one or more mycotoxins, except F. thapsinum and FTSC 11. F. proliferatum and F. fujikuroi had FUM1 gene (76.0% and 81.6%, respectively) and some isolates produced high level of fumonisin (over 1,000 μg/g). F. proliferatum and F. thapsinum were more virulent than other species on sorghum. These results indicate that Fusarium species in sorghum might produce multiple mycotoxins.

This study aimed to assess the incidence and distribution of toxigenic fungi in Korean oat. Toxigenic fungi were isolated from oat samples collected from 12 oat fields from heading to harvest in 2017 and 2018. A total of 745 fungal colonies were isolated based on morphology and identified using marker genes. About 92% of the fungal isolates were Fusarium spp. and others were Penicillium (5.9%) and Aspergillus (2.1%). Fusarium isolates comprised mostly of F. asiaticum (83.1%), followed by F. incarnatum (5.4%), F. proliferatum (3.5%), F. fujikuroi (2.8%), F. tricinctum species complex (FTSC) 11 (1.5%) and F. graminearum (1.0%). About 97% of F. asiaticum was nivalenol type, and 3-acetyl deoxynivalenol (3.2%) and 15-acetyl deoxynivalenol (0.4%) types also were found. Pathogenicity test of the selected Fusarium isolates revealed that F. asiaticum isolates have a wide range of virulence depending on the tested plants. F. graminearum and FTSC 11 isolates from blighted spikelets were the most virulent in naked oat. All Fusarium isolates (n=18) except one (FTSC 11) produced nivalenol (0.2–7.6 μg/g), deoxynivalenol (0.03–6.1 μg/g), and zearalenone (0.1–27.0 μg/g) on rice medium. This study is first report that F. asiaticum causes Fusarium head blight disease of oat in Korea. These findings demonstrate the dominance of F. asiaticum in oat agroecosystems as in rice, wheat and barley in Korea.

Although C17 polyacetylenes from Panax ginseng exhibit cytotoxic properties against various tumor cells, there have been few experiments on epithelial ovarian carcinoma cells. This study aimed to investigate the cytotoxic effects of C17 polyacetylenes from P. ginseng against ovarian cancer cell lines. Four unreported (1–4) and fifteen known (5–19) C17 polyacetylenes were obtained from the roots of P. ginseng using repeated chromatography (open column, MPLC, and preparative HPLC). The chemical structures of all the compounds were determined by analyzing their spectroscopic data (NMR, IR, and optical rotation) and HR-MS. The structures of new polyacetylenes were elucidated as (3S,8S,9R,10R)-(-)-heptadeca-9,10-epoxy-4,6-diyne-3,8-diyl diacetate (1), (3S,8S,9R,10R)-(−)-heptadeca-1-en-9,10-epoxy-4,6-diyne-3,8-diyl diacetate (2), (−)-haptadeca-9,10-epoxy-8-methoxy-4,6-diyne-3,11-diol (3), and (3R,9R,10R)-(+)-3-acetoxy-9,10-dihydroxyheptadeca-1-en-4,6-diyne (4), named ginsenoynes O, P, and Q, and 3-acetyl panaxytriol, respectively. Subsequently, in vitro experiments on A2780 and SKOV3 human epithelial ovarian carcinoma cells were performed to assess the cytotoxic properties of the isolates. Among the isolates, panaquinquecol 4 (15) exhibited the most remarkable cytotoxic effects on both human ovarian cancer cells A2780 (IC50 value of 7.60 μM) and SKOV3 (IC50 value of 27.53 μM). Therefore, C17 polyacetylenes derived from P. ginseng may warrant further investigation for their therapeutic potential in epithelial ovarian cancer.

Background/Aims After endoscopic treatment of common bile duct (CBD) stones, recurrence of choledocholithiasis due to small stone fragments and post-endoscopic retrograde cholangiopancreatography (post-ERCP) cholangitis can occur. We determined the effect of biliary stenting after removal of CBD stones on the recurrence of CBD stones and the incidence of post-ERCP cholangitis. Methods We performed a retrospective single-center study involving 483 patients who underwent ERCP for the removal of CBD stones. The patients were classified into two groups according to their biliary stenting status. The primary outcome was the rate of CBD stone recurrence and the secondary outcome was the incidence of post-ERCP cholangitis. Results Among the 483 patients, 219 and 264 did and did not receive a biliary stent after CBD stone removal, respectively. The incidence of stone recurrence was 15.5% and 7.6% in the non-stenting and stenting groups (p = 0.006), respectively, while the incidence of post-ERCP cholangitis was 4.6% and 2.7% (p = 0.256). In a multivariate analysis, biliary stenting significantly reduced the stone recurrence rate (odds ratio, 0.30; p = 0.004). Conclusions Biliary stenting after the removal of CBD stones reduces the stone recurrence rate and assisted recovery. For patients with large and multiple stones who undergo lithotripsy, preventive biliary stent insertion can reduce the rate of stone recurrence.

In our previous study, we reported the isolation of pennogenin-3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-β-D-glucopyranoside (spiroconazol A), a steroidal saponin, from the flowers of Dioscorea bulbifera L. var. sativa. In the present study, we aimed to investigate the effects of spiroconazol A on autophagy and its underlying mechanisms in A549 and NCI-H358 human non-small cell lung cancer (NSCLC) cells. Spiroconazol A inhibited the proliferation of NSCLC cells in a concentration- and time-dependent manner. To determine the type of programmed cell death induced by spiroconazol A, we performed a characterization of apoptosis in spiroconazol A-treated A549 cells. Our results showed that spiroconazol A significantly suppressed A549 cell viability but did not influence cell apoptosis because phosphatidylserine and caspase activation were not detected. Furthermore, spiroconazol A treatment upregulated the expression of LC3-II and autophagy-related Beclin-1 protein, suggesting that spiroconazol A induces autophagy in A549 cells. Moreover, spiroconazol A activated the phosphorylation of p38 mitogen-activated protein kinase (MAPK) but did not affect the phosphorylation of Janus kinase or ERK1/2. Notably, SB203580, a p38 MAPK inhibitor, had a significant inhibitory effect on spiroconazol A-induced autophagic cell death in A549 cells. Our results indicated that spiroconazol A-induced autophagy is dependent on p38 MAPK signaling and has potential as a therapeutic target in NSCLC.

The flower of Pueraria lobata (Puerariae Flos) is a reddish-purple to violet-purple flower that blooms between July and September. In our preliminary study, Puerariae Flos extract exhibited significant activity against a human ovarian cancer cell line. This research aims to identify the active compounds in Pueraria Flos. By repeated chromatography, one new tryptophan derivative (1), two new flavanones (4 and 5), and 19 known compounds, including tryptophan derivatives (2 and 3), flavonoids (6–9), isoflavonoids (10–20), a flavonolignan (21), and a phenolic compound (22), were isolated from a methanol extract of Puerariae Flos. The structures of new compounds were elucidated as 13-N-benzoyl-l-tryptophan-1-N-β-d-glucopyranoside (1), 2-hydroxy-5-methoxy-naringenin (4), and 2-hydroxy-5-methoxy-naringenin 7-O-β-d-glucopyranoside (5). Among the isolates, afromosin (17), tectorigenin (11), apigenin (8), glycitein (16), (-)-hydnocarpin (21), irilin D (12), irisolidone 7-O-glucoside (14), and genistein (10) showed cytotoxicity against human ovarian cancer cell line A2780. Apigenin (8) and (-)-hydnocarpin (21) were the most active (IC50 values of 9.99 and 7.36 μM, respectively).

Recently, microorganisms and their metabolites in the Antarctic marine environment have attracted attention as useful sources for novel therapeutics, including anticancer drugs. Here, we investigated the effects of citromycin, isolated from the Antarctic marine-derived fungus, Sporothrix sp., on human ovarian cancer cells. Citromycin inhibited the migration and invasion of human ovarian cancer SKOV3 and A2780 cells, but had no cytotoxic activity against them. Additionally, it inhibited the expression of epithelial–mesenchymal transition (EMT) markers and the activation of matrix metalloproteinase (MMP)-2 and MMP9. Moreover, extracellular signal-regulated kinase (ERK)-1/2 signaling was inhibited after citromycin treatment, and the ectopic expression of ERK negated the anti-invasive activity of citromycin. Our findings suggest that citromycin inhibits the migration and invasion of human ovarian cancer cells by downregulating the expression levels of EMT markers and MMP-2/9 via inhibition of the ERK1/2 pathway.

Rhizomes of Cyperus rotundus have been widely used as a traditional medicine in Asia for the treatment of gynecological diseases. However, there is no scientific evidence demonstrating the effect of C. rotundus rhizomes on endometriosis, which is characterized by the adhesion of endometrial tissues outside the uterus, resulting in chronic and severe pelvic pain. The aim of this study was to investigate the effects of Cyperi rhizoma extract (CRE) on cell adhesion and the expression of pain-related factors (neurotrophins) in endometriotic cells, and to elucidate the underlying molecular mechanisms. CRE inhibited the adhesion of human endometriotic 12Z cells to peritoneal mesothelial Met5A cells using by adhesion assays. The mRNA expression of adhesion molecules [P-cadherin and matrix metalloproteinase (MMP)-2] was downregulated by CRE treatment. In addition, CRE significantly inhibited the mRNA expression of neurotrophins (BDNF, NGF, NT-3 and NT-4/5) in 12Z cells. Moreover, Akt overexpression markedly neutralized the inhibition of cell adhesion by CRE and expression of neurotrophins in 12Z cells. Furthermore, it was found that CRE suppressed NF-kB activation through the Akt pathway. These data suggest that CRE exerts anti-endometriotic activities by the inhibition of cell adhesion and neurotrophin expression, through the negative regulation of the Akt and NF-kB pathways in endometriotic cells.

Endometriosis: a sweet and sticky mechanism uncovered A growth factor involved in cell differentiation and proliferation contributes to the development of endometriosis by stimulating a protein modification mechanism that increases the adhesiveness of cells lining the uterus. Endometriosis results when these cells, known as endometrial cells, start growing outside the uterus causing pelvic pain, heavy periods and, in some cases, infertility. Ki-Tae Ha at Pusan National University, Yangsan, South Korea, and colleagues found that transforming growth factor-β1 signaling promoted the addition of sialic acid sugar units onto endometrial cell surface proteins. This modification enhanced the adhesion of endometrial cells to mesothelial cells, which line other internal organs, and the formation of endometriosis lesions in mice. Preventing sialic acid binding to its mesothelial cell receptor reduced lesion formation. The findings reveal a new molecular mechanism underlying endometriosis and a potential treatment strategy.

Background: Extended endoplasmic reticulum (ER) stress may initiate apoptotic pathways in cancer cells, and ER stress has been reported to possibly increase tumor death in cancer therapy. We previously reported that caspase-8 played an important role in compound K-induced apoptosis via activation of caspase-3 directly or indirectly through Bid cleavage, cytochrome c release, and caspase-9 activation in HL-60 human leukemia cells. The mechanisms leading to apoptosis in A549 and SK-MES-1 human lung cancer cells and the role of ER stress have not yet been understood. Methods: The apoptotic effects of compound K were analyzed using flow cytometry, and the changes in protein levels were determined using Western blot analysis. The intracellular calcium levels were monitored by staining with Fura-2/AM and Fluo-3/AM. Results: Compound K-induced ER stress was confirmed through increased phosphorylation of eIF2α and protein levels of GRP78/BiP, XBP-1S, and IRE1α in human lung cancer cells. Moreover, compound-K led to the accumulation of intracellular calcium and an increase in m-calpain activities that were both significantly inhibited by pretreatment either with BAPTA-AM (an intracellular Ca2+ chelator) or dantrolene (an RyR channel antagonist). These results were correlated with the outcome that compound K induced ER stress-related apoptosis through caspase-12, as z-ATAD-fmk (a specific inhibitor of caspase-12) partially ameliorated this effect. Interestingly, 4-PBA (ER stress inhibitor) dramatically improved the compound K-induced apoptosis. Conclusion: Cell survival and intracellular Ca2+ homeostasis during ER stress in human lung cancer cells are important factors in the induction of the compound K-induced apoptotic pathway. Keywords: apoptosis, calcium, compound K, ER stress, lung cancer cells

Ovarian cancers often display elevated TGF-β signaling but repressed miRNA expression. Here the authors identify that non-coding RNA nc886 expression is induced by TGF-β, which then binds to DICER and impairs miRNA maturation.

The rhizomes of Alpinia galanga (Thai ginger) have been used extensively as a spice in Southeast Asian and Arabian cuisines and reported to possess a wide range of biological properties, such as antioxidant, antimicrobial, and antibacterial. However, the specific molecular and cellular mechanisms underlying the anti-tumor effects induced by Thai ginger and its corresponding active compounds have been poorly characterized. We found that upon EtOH extraction, Thai ginger extract exhibits cytotoxic activity (IC50 < 10 μg/mL) and triggers cell death via caspase-dependent apoptosis in human ovarian cancer cells. Among the three major compounds isolated from the extract, 1′-acetoxyeugenol acetate (AEA) exhibited potent cytotoxic activity in human ovarian cancer cells, SKOV3 and A2780. AEA induced apoptotic cell death through the activation of caspases-3 and -9. Notably, AEA enhanced the intracellular levels of reactive oxygen species (ROS), and the application of an antioxidant markedly reversed AEA-induced apoptosis of ovarian cancer cells. The knockdown of p47phox, a subunit of NADPH oxidase, suppressed both the pro-apoptotic and ROS-inducing effects of AEA. Additionally, the activation of the mitogen-activated protein kinase (MAPK) pathway by AEA through ROS regulation was found to be involved in AEA-induced apoptosis. Altogether, these results suggest that AEA exhibits potent apoptosis-inducing activity through the activation of the intrinsic pathway via ROS-mediated MAPK signaling in human ovarian cancer cells.

The present study demonstrated that 2′-hydroxycinnamaldehyde (2′-HCA) induced apoptosis in human promyelocytic leukemia HL-60 cells through the activation of mitochondrial pathways including (1) translocation of Bim and Bax from the cytosol to mitochondria, (2) downregulation of Bcl-2 protein expression, (3) cytochrome c release into the cytosol, (4) loss of mitochondrial membrane potential (ΔΨm), and (5) caspase activation. 2′-HCA also induced the activation of c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase1/2 (ERK1/2) in HL-60 cells. The pharmacological and genetic inhibition of JNK effectively prevented 2′-HCA-induced apoptosis and activator protein-1 (AP-1)-DNA binding. In addition, 2′-HCA resulted in the accumulation of reactive oxygen species (ROS) and depletion of intracellular glutathione (GSH) and protein thiols (PSH) in HL-60 cells. NAC treatment abrogated 2′-HCA-induced JNK phosphorylation, AP-1-DNA binding, and Bim mitochondrial translocation, suggesting that oxidative stress may be required for 2′-HCA-induced intrinsic apoptosis. Xenograft mice inoculated with HL-60 leukemia cells demonstrated that the intraperitoneal administration of 2′-HCA inhibited tumor growth by increasing of TUNEL staining, the expression levels of nitrotyrosine and pro-apoptotic proteins, but reducing of PCNA protein expression. Taken together, our findings suggest that 2′-HCA induces apoptosis via the ROS-dependent JNK pathway and could be considered as a potential therapeutic agent for leukemia.

A new steroidal saponin, 26-O-β-d-glucopyranosyl-(25R)-furost-5-ene-3β,22α,26-triol 3-O-(1−4)-β-d-glucopyranosyl-α-l-rhamnopyranosyl-(1−2)-[α-l-rhamnopyranosyl-(1−4)]-β-d-glucopyranoside [asparacochioside A (1)] was isolated from a hot water extract of the roots of Asparagus cochinchinensis, together with the known steroidal saponins protodioscin (2), methyl protodioscin (3), aspacochioside A (4), aspacochioside C (5), 15−hydroxypseudoprotodioscin (6), and chamaedroside E (7). The structure of the new compound 1 was determined by interpretation of its spectroscopic data (1D- and 2D-NMR and HR−Q−TOF−MS) and sugar analysis. The isolated compounds 1−7 were tested for their in vitro cytotoxicity against human ovarian cancer cell lines (A2780 and SKOV3). Asparacochioside A (1) exhibited a significant cytotoxicity against both A2780 and SKOV3 cells with IC50 values of 5.25 ± 2.2 and 46.82 ± 9.43 μM, respectively. Furthermore, asparacochioside A (1) significantly increased the percentage of Annexin V-positive cells (apoptotic cells), suggesting that asparacochioside A induces ovarian cancer cell death via apoptosis.

The fruits of Schisandra chinensis (Schisandra berries) are used as health food supplements and popular food ingredients in East Asia. Lignans, major and characteristic polyphenol compounds of Schisandra berries, possess various biological activities, including hepatoprotective and anticancer effects. However, the biological activities of gomisin L1, a lignan isolated from Schisandra berries, are less to be investigated. In this study, the antitumor activity of gomisin L1 and its underlying molecular mechanism in human ovarian cancer cells were investigated. Gomisin L1 exhibited potent cytotoxic activity against A2780 and SKOV3 ovarian cancer cells. Flow cytometry analysis revealed that the growth inhibitory effects of gomisin L1 were mediated by the induction of apoptosis. Furthermore, gomisin L1 induced an increase in intracellular reactive oxygen species (ROS) levels, and the antioxidant N-acetyl cysteine significantly negated gomisin L1-induced cell death. Moreover, inhibition of NADPH oxidase (NOX) using an inhibitor and siRNA attenuated gomisin L1-induced death of, and ROS production in, human ovarian cancer cells. Taken together, these data indicate that the lignan gomisin L1 from Schisandra berries induces apoptotic cell death by regulating intracellular ROS production via NOX.

Abstract Missense mutations of TP53 are extremely common, and mutant p53 accumulation and gain-of-function play crucial roles in human ovarian cancer. Here, we investigated the role of mutant p53 in cell migration and invasion as well as its underlying molecular mechanisms in human ovarian cancer cells. Overexpression of mutant p53 significantly increased migration and invasion in p53-null SKOV3 cells. In contrast, knockdown of mutant p53 significantly compromised mutant p53-induced cell migration and invasion. Microarray analysis revealed that several migration/invasion-related genes, including S1PR1 (Sphingosine-1-phosphate receptor 1) and THBS1 (Thrombospodin 1), were significantly upregulated in SKOV3 cells that overexpressed mutant p53-R248 (SKOV3R248). We found that Rad21 is involved in the transcriptional regulation of the migration/invasion-related genes induced by mutant p53-R248. Knockdown of Rad21 significantly attenuated the mutant p53-R248-induced invasion and the expressions of S1PR1 and THBS1. Moreover, co-immunoprecipitation and chromatin immunoprecipitation assays revealed that mutant p53 interacts with Rad21 and binds to the Rad21-binding elements in the S1PR1 and THBS1 genes. Finally, downregulation of S1PR1 significantly attenuated the invasion driven by mutant p53-R248. These novel findings reveal that mutant p53-R248 maintains gain-of-function activity to stimulate cell invasion and induces the related gene expressions through an interaction with Rad21 in human ovarian cancer cells.

Fusarium graminearum species complex (FGSC) causes Fusarium head blight in small grain cereals. To date, four species (F. graminearum, F. asiaticum, F. boothii, and F. meridionale ) belonging to FGSC frequently occur in Korean cereals. In addition, we first reported the occurrence of additional species (F. vorosii ) within FGSC, which was isolated from barley, corn, and rice in Korea. Phylogenetic analysis of the Fusarium isolates of this group using combined multi-gene sequences confirmed species identification. Moreover, the macroconidia produced by these isolates were morphologically similar to those of the F. vorosii holotype. Chemical analysis indicated that the F. vorosii isolates produced various trichothecenes such as nivalenol and deoxynivalenol with their acetyl derivatives along with zearalenone. Pathogenicity tests demonstrated that all of the F. vorosii isolates examined were pathogenic on barley, corn, and rice with variation in aggressiveness. This study is the first report of F. vorosii in Korean cereals, their pathogenicity towards barley and corn, and their ability to produce trichothecenes and zearalenone.

Triterpenoids echinocystic acid and its glycosides, isolated from several Eclipta prostrata, have been reported to possess various biological activities such as anti-inflammatory, anti-bacterial, and anti-diabetic activity. However, the cytotoxicity of the triterpenoids in human cancer cells and their molecular mechanism of action are poorly understood. In the present study, we found that eclalbasaponin II with one glucose moiety has potent cytotoxicity in three ovarian cancer cells and two endometrial cancer cells compared to an aglycone echinocystic acid and eclalbasaponin I with two glucose moiety. Eclalbasaponin II treatment dose-dependently increased sub G1 population. Annexin V staining revealed that eclalbasaponin II induced apoptosis in SKOV3 and A2780 ovarian cancer cells. In addition, eclalbasaponin II-induced cell death was associated with characteristics of autophagy; an increase in acidic vesicular organelle content and elevation of the levels of LC3-II. Interestingly, autophagy inhibitor BaF1 suppressed the eclalbasaponin II-induced apoptosis. Moreover, eclalbasaponin II activated JNK and p38 signaling and inhibited the mTOR signaling. We further demonstrated that pre-treatment with a JNK and p38 inhibitor and mTOR activator attenuated the eclalbasaponin II-induced autophagy. This suggests that eclalbasaponin II induces apoptotic and autophagic cell death through the regulation of JNK, p38, and mTOR signaling in human ovarian cancer cells.

Four new eudesmane-type sesquiterpenoids, (1R,5S,6R,7S,9S,10S)-1,6,9-trihydroxy-eudesm-3-ene-1,6-di-O-β-d-glucopyranoside (1), (1R,5S,6S,7R,9S,10S)-1,6,9,11-tetrahydroxy-eudesm-3-ene-1,6-di-O-β-d-glucopyranoside (3), (1R,5S,6R,7S,9S,10R)-9-O-(Z-p-coumaroyl)-1,6,9-trihydroxy-eudesm-3-ene-6-O-β-d-glucopyranoside (6), and (1R,5S,6R,7S,9S,10R)-9-O-(E-feruloyl)-1,6,9-trihydroxy-eudesm-3-ene-6-O-β-d-glucopyranoside (7), were isolated from a 95% EtOH extract of the leaves of Aster koraiensis by repeated chromatography. Moreover, three sesquiterpenoids (2, 4, and 5) and two caffeoylquinic acids (8 and 9) having previously known chemical structures were isolated during the isolation procedure. The four new compounds (1, 3, 6, and 7) were elucidated by spectroscopic data (1D- and 2D-NMR, MS, and ECD) interpretation and hydrolysis. Moreover, the absolute configurations of 2, 4, and 5 were determined for the first time in this study. The compounds isolated were tested for their viability on nitric oxide (NO) and prostaglandin E2 (PGE2) production on LPS-stimulated RAW 264.7 cells. Among them, only 7 presented weak inhibitory effects on both NO and PGE2 production.

High levels of iron in the peritoneal cavity during menstruation have been implicated in the pathogenesis of endometriosis. However, whether iron directly affects the growth or migration of human endometriotic cells is poorly understood. This study demonstrated the presence of increased levels of the iron storage protein, ferritin, in the endometriotic tissues of patients with endometriosis. Furthermore, iron treatment stimulated the migration and epithelial–mesenchymal transition (EMT), but not growth, of 12Z human endometriotic cells. The expression of matrix metalloproteinase (MMP)-2/-9 was markedly increased through iron treatment in 12Z cells. Interestingly, intracellular reactive oxygen species (ROS) levels were significantly increased by iron in 12Z cells, and N-acetyl-L-cysteine significantly reduced iron-induced migration and MMP-2/-9 expression. Additionally, iron stimulated the activation of the NFκB pathway, and the activation was associated with iron-induced migration and MMP-2/-9 expression in 12Z cells. Moreover, iron markedly increased EMT and MMP-2/-9 expression in endometriotic lesions in an endometriosis mouse model. Taken together, these results suggest that iron may contribute to the migration abilities of human endometriotic cells via MMP expression through the ROS–NFκB pathway.

Marine sponges harbor a range of biologically active compounds. Phorbaketal A is a tricyclic sesterterpenoid isolated from the marine sponge Phorbas sp.; however, little is known about its biological activities and associated molecular mechanisms. In this study, we examined the anti-inflammatory effects and underlying molecular mechanism of phorbaketal A in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We found that phorbaketal A significantly inhibited the LPS-induced production of nitric oxide (NO), but not prostaglandin E2, in RAW 264.7 cells. Further, phorbaketal A suppressed the expression of inducible NO synthase at both the mRNA and protein levels. In addition, phorbaketal A reduced the LPS-induced production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, and monocyte chemotactic protein-1. Treatment with phorbaketal A inhibited the transcriptional activity of nuclear factor-kappaB (NF-κB), a crucial signaling molecule in inflammation. Moreover, phorbaketal A up-regulated the expression of heme oxygenase-1 (HO-1) in LPS-stimulated RAW 264.7 cells. These data suggest that phorbaketal A, isolated from the marine sponge Phorbas sp., inhibits the production of inflammatory mediators via down-regulation of the NF-κB pathway and up-regulation of the HO-1 pathway.

The seeds of Millettia ferruginea are used in fishing, pesticides, and folk medicine in Ethiopia. Here, the anti-cancer effects of isoflavones isolated from M. ferruginea were evaluated in human ovarian cancer cells. We found that isoflavone ferrugone and 6,7-dimethoxy-3’,4’-methylenedioxy-8-(3,3-dimethylallyl)isoflavone (DMI) had potent cytotoxic effects on human ovarian cancer cell A2780 and SKOV3. Ferrugone and DMI treatment increased the sub-G1 cell population in a dose-dependent manner in A2780 cells. The cytotoxic activity of ferrugone and DMI was associated with the induction of apoptosis, as shown by an increase in annexin V-positive cells. Z-VAD-fmk, a broad-spectrum caspase inhibitor, and z-DEVD-fmk, a caspase-3 inhibitor, significantly reversed both the ferrugone and DMI-induced apoptosis, suggesting that cell death stimulated by the isoflavones is mediated by caspase-3-dependent apoptosis. Additionally, ferrugone-induced apoptosis was found to be caspase-8-dependent, while DMI-induced apoptosis was caspase-9-dependent. Notably, DMI, but not ferrugone, increased the intracellular levels of reactive oxygen species (ROS), and antioxidant N-acetyl-L-cysteine (NAC) attenuated the pro-apoptotic activity of DMI. These data suggest that DMI induced apoptotic cell death through the intrinsic pathway via ROS production, while ferrugone stimulated the extrinsic pathway in human ovarian cancer cells.

It has been reported that [3-(1,1'-biphenyl-4-yl)-2-(1-methyl-5-dimethylamino-pentylamino)-3,4-dihydroquinazolin-4-yl]-N-benzylacetamide 2hydrochloride (KYS05090), a selective T-type Ca2+ channel blocker, reduces tumor volume and weight in the A549 xenograft model, but the molecular mechanism of cell death has not yet been elucidated. In this study, KYS05090 induced autophagy- and apoptosis-mediated cell death in human lung adenocarcinoma A549 cells. Although KYS05090 decreased intracellular Ca2+ levels, it was not directly related with KYS05090-induced cell death. In addition, KYS05090 generated intracellular reactive oxygen species (ROS) and reduced glucose uptake, and catalase and methyl pyruvate prevented KYS05090-induced cell death. These results indicate that KYS05090 can lead to autophagy and apoptosis in A549 cells through ROS generation by inhibiting glucose uptake. Our findings suggest that KYS05090 has potential chemotherapeutic value for the treatment of lung cancer.

Chrysanthemum boreale is a plant widespread in East Asia, used in folk medicine to treat various disorders, such as pneumonia, colitis, stomatitis, and carbuncle. Whether the essential oil from C. boreale (ECB) and its active constituents have anti-proliferative activities in lung cancer is unknown. Therefore, we investigated the cytotoxic effects of ECB in A549 and NCI-H358 human lung cancer cells. Culture of A549 and NCI-H358 cells with ECB induced apoptotic cell death, as revealed by an increase in annexin V staining. ECB treatment reduced mitochondrial membrane potential (MMP), disrupted the balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and activated caspase-8, -9, and -3, as assessed by western blot analysis. Interestingly, pretreatment with a broad-spectrum caspase inhibitor (z-VAD-fmk) significantly attenuated ECB-induced apoptosis. Furthermore, gas chromatography−mass spectrometry (GC/MS) analysis of ECB identified six compounds. Among them, β-caryophyllene exhibited a potent anti-proliferative effect, and thus was identified as the major active compound. β- Caryophyllene induced G1 cell cycle arrest by downregulating cyclin D1, cyclin E, cyclin-dependent protein kinase (CDK) -2, -4, and -6, and RB phosphorylation, and by upregulating p21CIP1/WAF1 and p27KIP1. These results indicate that β-caryophyllene exerts cytotoxic activity in lung cancer cells through induction of cell cycle arrest.

Gukulenin A is a bis-tropolone tetraterpenoid isolated from the marine sponge Phorbas gukhulensis. In this study, we examined the anticancer activities of gukulenin A in ovarian cancer cell lines (A2780, SKOV3, OVCAR-3, and TOV-21G) and in an ovarian cancer mouse model generated by injecting A2780 cells. We found that gukulenin A suppressed tumor growth in A2780-bearing mice. Gukulenin A markedly inhibited cell viability in four ovarian cancer cell lines, including the A2780 cell line. Gukulenin A treatment increased the fraction of cells accumulated at the sub G1 phase in a dose-dependent manner and the population of annexin V-positive cells, suggesting that gukulenin A induces apoptotic cell death in ovarian cancer cells. In addition, gukulenin A triggered the activation of caspase-3, -8, and -9, and caspase inhibitors attenuated gukulenin A-induced A2780 cell death. The results suggest that gukulenin A may be a potential therapeutic agent for ovarian cancer.

In the original version of the Supplementary Information file associated with this Article, Supplementary Fig. 18 panel b was inadvertently replaced with a duplicate of panel a. The error has now been fixed and the corrected version of the Supplementary Information PDF is available to download from the HTML version of the Article.

The natural product 23-hydroxyursolic acid (23-HUA) is a derivative of ursolic acid, which is known to induce cancer cell apoptosis. However, apoptotic effects and mechanisms of 23-HUA have not been well characterized yet. Herein, we investigated the molecular mechanisms of 23-HUA-induced apoptosis in HL-60 human promyelocytic leukemia cells. 23-HUA-treated HL-60 cells showed apoptotic features including internucleosomal DNA condensation and fragmentation as well as externalization of phosphatidylserine residues. 23-HUA induced a series of mitochondrial events including disruption of mitochondrial membrane potential (ΔΨm), cytochrome c and Smac/DIABLO release and loss of balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins in HL-60 cells. In addition, 23-HUA activated caspase-8, caspase-9 and caspase-3. Pretreatment with a broad caspase inhibitor (z-VAD-fmk), a caspase-3 inhibitor (z-DEVD-fmk), and a caspase-8 inhibitor (z-IETD-fmk) significantly attenuated 23-HUA-induced DNA fragmentation. After 23-HUA-induced apoptosis, proteins expression levels of FasL, Fas and FADD constituting the death-inducing signaling complex (DISC) were upregulated in HL-60 cells. Moreover, transfection with Fas or FADD siRNA significantly blocked 23-HUA-induced DNA fragmentation and caspases activation. Taken together, these findings indicate that 23-HUA induces apoptosis in HL-60 human promyelocytic leukemia cells through formation of DISC and caspase-8 activation leading to loss of ΔΨm and caspase-3 activation.

We previously reported that 5-[4-(4-fluorophenoxy) phenyl] methylene-3-{4-[3-(4-methylpiperazin-1-yl)propoxy]phenyl}-2-thioxo-4-thiazolidinone dihydrochloride (KSK05104) has potent, selective and metabolically stable IKKβ inhibitory activities. However, the apoptosis-inducing of KSK05104 and its underlying mechanism have not yet been elucidated in human colon cancer cells. We show that KSK05104 triggered apoptosis, as indicated by externalization of Annexin V-targeted phosphatidylserine residues in HT-29 and HCT-116 cells. KSK05104 induced the activation of caspase-8, -9, and -3, and the cleavage of poly (ADP ribose) polymerase-1 (PARP-1). KSK05104-induced apoptosis was significantly suppressed by pretreatment with z-VAD-fmk (a broad caspase inhibitor). KSK05104 also induced release of cytochrome c (Cyt c), apoptosis inducing factor (AIF), and endonuclease G (Endo G) by damaging mitochondria, resulting in caspase-dependent and -independent apoptotic cell death. KSK05104 triggered endoplasmic reticulum (ER) stress and changed the intracellular calcium level ([Ca2+]i). Interestingly, treatment with KSK05104 activated not only ER stress marker proteins including inositol-requiring enzyme 1-alpha (IRE-1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK), but also μ-calpain, and caspase-12 in a time-dependent manner. KSK05104-induced apoptosis substantially decreased in the presence of BAPTA/AM (an intracellular calcium chelator). Taken together, these results suggest that mitochondrial dysfunction and ER stress contribute to KSK05104-induced apoptosis in human colon cancer cells.

Two tetrahydrofurofurano lignans (1 and 2), four phenylpropanoids (3–6), and two alkamides (7 and 8) were isolated from the EtOAc-soluble fraction of the roots of Asarum sieboldii. The chemical structures of the isolates were identified by analysis of spectroscopic data measurements, and by a comparison of their data with published values. The isolates (1, 2, 4–8) were evaluated for their cytotoxicity against human ovarian cancer cells (A2780 and SKOV3) and immortalized ovarian surface epithelial cells (IOSE80PC) using a MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide) assay. Of the isolates, (−)-asarinin (1) exhibited the most potent cytotoxicity to both A2780 and SKOV3 cells. A propidium iodide/annexin V-fluorescein isothiocyanate (V-FITC) double staining assay showed that (−)-asarinin (1) induces apoptotic cell death in ovarian cancer cells. In addition, (−)-asarinin (1) increased the activation of caspase-3, caspase-8, and caspase-9 in ovarian cancer cells. Pretreatment with caspase inhibitors attenuated the cell death induced by (−)-asarinin (1). In conclusion, our findings show that (−)-asarinin (1) from the roots of A. sieboldii may induce caspase-dependent apoptotic cell death in human cancer cells.

The present investigation of the chemical constituents of the stem barks of Ailanthus altissima has resulted in the isolation of six canthinone-type alkaloids, including a new compound, (R)-5-(1-hydroxyethyl)-canthine-6-one (1), and five known compounds (2–6). Moreover, four phenyl propanoids (7–10), two lignans (11 and 12), two triterpenoids (13 and 14) and a fatty acid (15) having previously known chemical structures were isolated during the same course of this study. The structure of the new compound was elucidated by physical (m.p., [α]D) and spectroscopic data (1H-NMR, 13C-NMR, 2D NMR, and HR-DART-MS) interpretation and its absolute configuration was determined by electronic circular dichroism (ECD) data and quantum chemical calculations. The inflammatory activities of the isolates were screened on lipopolysaccharide (LPS)-induced nitric oxide (NO), a proinflammatory mediator, in RAW 264.7 cells. Among these isolated compounds, six compounds exhibited significant inhibition of NO production, with IC50 values in the range of 5.92 ± 0.9 to 15.09 ± 1.8 μM.

Skin photoaging, characterized by collagen degradation and upregulation of matrix metalloproteinases (MMPs), is a major concern caused by UVB irradiation. In this study, we investigated the potential of Acanthopanax sessiliforum extract (ASE) and Chaenomeles sinensis (CSE) extracts to mitigate the efects of UVB-induced photodamage in human fbroblast and hairless mice. Water extracts of AS (ASE) and CS (CSE) were found to inhibit the expression of MMP-1/-3 in vitro. Furthermore, the extract of mixture of AS and CS (ACE) showed more potent inhibitor efect, as compared to ASE and CSE. In UVB-irradiated hairless mice, oral administration of ACE efectively reduced wrinkle formation, skin roughness, and epidermal thickness while promoting the deposition of collagenous fbers. These results indicate that ACE has the potential to protect against skin photoaging by restoring the impaired skin via downregulation of MMP-1/-3 expression and secretion. Our fndings highlight the therapeutic potential of ACE in mitigating skin photoaging. [ABSTRACT FROM AUTHOR]