Incidence of fungal contamination in fresh ginseng samples and mycotoxigenic potential of representative fungal isolates.

BACKGROUND: Fresh ginseng is typically accompanied by soil after harvest, leading to contamination with harmful fungi during storage and distribution. In this study, we investigated the incidence of fungal contamination in fresh ginseng (5-6 years old) purchased from 22 different stores in Geumsan, Korea. RESULTS: The incidence of fungal contamination in the samples was 67.4-111.5%. Fusarium solani was the most abundant species in the head (38.5%) and fine root (19.3%) parts of the ginseng samples, whereas F. oxysporum was the most abundant in the main root (22.0%) part. We isolated Aspergillus, Fusarium and Penicillium spp. (total number of isolates: 395) from the ginseng samples, and 138 isolates were identified using phylogenetic analysis. Polymerase chain reaction-based screening of 65 mycotoxin-producing species revealed that two P. expansum isolates were positive for citrinin and/or patulin, and five F. oxysporum isolates were positive for fumonisin biosynthesis gene. One P. expansum isolate produced 738.0 mg kg-1 patulin, and the other produced 10.4 mg kg-1 citrinin and 12.0 mg kg-1 patulin on potato dextrose agar (PDA) medium. Among the 47 representative F. oxysporum isolates, 43 (91.5%) produced beauvericin (0.1-15.4 mg kg-1) and four of them (8.5%) produced enniatin B and enniatin B1 (0.1-1.8 mg kg-1) as well. However, none of these toxins was detected in fresh ginseng samples. CONCLUSION: Fusarium solani and F. oxysporum were the most abundant species in fresh ginseng samples. Most F. oxysporum (43) and P. expansum (2) strains isolated from fresh ginseng produced beauvericin and enniatins (B and B1), and patulin or citrinin, respectively, on PDA medium. This is the first report of the mycotoxigenic potential of P. expansum and F. oxysporum strains isolated from fresh ginseng. © 2024 Society of Chemical Industry.

Protective effect of mixture of Acanthopanax sessiliflorum and Chaenomeles sinensis against ultraviolet B-induced photodamage in human fibroblast and hairless mouse.

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 sessiliflorum extract (ASE) and Chaenomeles sinensis (CSE) extracts to mitigate the effects of UVB-induced photodamage in human fibroblast 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 effect, as compared to ASE and CSE. In UVB-irradiated hairless mice, oral administration of ACE effectively reduced wrinkle formation, skin roughness, and epidermal thickness while promoting the deposition of collagenous fibers. 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 findings highlight the therapeutic potential of ACE in mitigating skin photoaging. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01462-3.

Ovarian Cancer and the Microbiome: Connecting the Dots for Early Diagnosis and Therapeutic Innovations-A Review.

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.

Risk of thrombosis, hemorrhage and leukemic transformation in patients with myeloproliferative neoplasms: A nationwide longitudinal cohort study.

INTRODUCTION: There are few large-scale, population-based studies detailing the risks of thrombosis, hemorrhage, leukemic transformation in patients with myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). METHODS: We performed a nationwide longitudinal cohort study using the Korean National Health Insurance System (NHIS) database. MPN patients (n = 11,991) and their 1:4 age- and sex-matched controls (n = 47,964) were enrolled. The risk of thrombosis, hemorrhage, leukemic transformation was estimated using a Cox proportional hazards regression, and stratified analyses were performed for related factors. RESULTS: During a median of 7.8 years of follow-up, 30.1 % of MPN patients (3614/11,991) and 19.0 % of the matched controls (9141/47,964) developed arterial thrombosis, 11.6 % of MPN patients (1397/11,991) and 6.4 % of the matched controls (3099/47,964) developed venous thrombosis and 18.7 % of MPN patients (2251/11,991) and 12.1 % of the matched controls (5836/47,964) developed hemorrhage. 4.9 % of MPN patients (597/11,991) and 0.1 % of matched controls (50/47,964) developed leukemia. The overall risk of developing thrombosis, hemorrhage, leukemic transformation was higher in MPN patients (adjusted hazard ratio [aHR] 1.695, 95 % confidence interval [CI]: 1.629-1.765 for arterial thrombosis, aHR 1.963, 95 % CI: 1.838-2.096 for venous thrombosis, and aHR 1.714, 95 % CI: 1.630-1.802 for hemorrhage) than in the controls. Patients with MPNs had a 10-year cumulative incidence of leukemic transformation of 6.2 %. CONCLUSION: The patients with MPNs have a higher risk of thrombosis, hemorrhage, and leukemic transformation than matched controls. Strategies are warranted to reduce the risk of thrombosis, hemorrhage, and leukemic transformation in MPN patients.

Paeonol alleviates postmenopause-induced neuropsychiatric symptoms through the modulation of GPR30 in ovariectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: The Moutan cortex (MC), the root bark of Paeonia suffruticosa Anderws (Paeoniaceae), has been historically employed in traditional herbal medicine for addressing women's ailments by replenishing kidney Yin. AIM OF THE STUDY: We aimed to explore if paeonol, an active constituent of MC, could ameliorate neuropsychiatric symptoms, such as anxiety, depression, and cognitive impairments, associated with post-menopausal syndrome (PMS) in an ovariectomized (OVX) mouse model. MATERIALS AND METHODS: The experimental design comprised 6 groups, including a sham group, OVX group, paeonol administration groups (3, 10 or 30 mg/kg, p.o.), and an estradiol (E2)-treated positive control group. Behavioral tests including the open field, novel object recognition, Y-maze, elevated plus-maze, splash, and forced swimming tests were conducted. In addition, we investigated the effets of paeonol on the phosphorylated levels of phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), as well as on the expression levels of G protein-coupled receptor (GPR30) and brain-derived neurotrophic factor (BDNF) in the prefrontal cortex and hippocampus. RESULTS: Paeonol treatment (10 and 30 mg/kg, p.o.) effectively reversed the cognitive decline in OVX mice, measured by the novel object recognition and Y-maze tests, similar to that in the positive control group. Additionally, it alleviated anxiety- and depressive-like behaviors, as evaluated by the elevated plus-maze test, splash test, and forced swimming test. Paeonol restored GPR30 expression levels in the prefrontal cortex and hippocampus, mirroring the effects of E2 administration. Furthermore, it reversed the reduced expression levels of the PI3K-Akt-mTOR signaling pathway in the prefrontal cortex and hippocampus and increased BDNF expression in the hippocampus of OVX mice. CONCLUSION: This research suggests that paeonol would be beneficial for alleviating PMS-associated cognitive impairment, anxiety and depression.

Regulation of colonic neuropeptide Y expression by the gut microbiome in patients with ulcerative colitis and its association with anxiety- and depression-like behavior in mice.

Patients 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.

D-Pinitol attenuates postmenopausal symptoms in ovariectomized mice.

AIMS: Menopause is a natural process in women that can lead to post-menopausal syndrome with symptoms such as hot flushes, weight gain, anxiety, cognitive decline, and depression. Hormonal replacement therapy is commonly prescribed. However, it has serious adverse effects. Herbal medicinal products and isoflavones are used as alternatives. D-Pinitol found in Pinaceae and Fabaceae families has anti-inflammatory and antioxidant effects. However, it has not received as much attention as isoflavones. In this study, we investigated whether D-pinitol could alleviate post-menopausal symptoms using an ovariectomized (OVX) mouse model. MAIN METHODS: Female ICR mice were divided into six groups: sham (vehicle), OVX (vehicle), OVX + D-pinitol (10, 30, 100 mg/kg, p.o.), and OVX + estradiol (0.5 mg/kg, s.c.). Treatment with vehicle, D-pinitol, and estradiol began at seven weeks post ovariectomy. We employed several behavioral tests, hot-flush test, and Western blot analysis. KEY FINDINGS: We found that D-pinitol treatment (30, 100 mg/kg, p.o.) reversed cognitive dysfunction in OVX mice (novel object recognition and Y-maze test). Additionally, D-pinitol alleviated anxiety-like behaviors (elevated plus-maze) and reversed depressive-like behaviors (splash test, tail suspension test). It also normalized increased basal tail skin temperature in OVX mice. Moreover, D-pinitol administration reversed decreased expression of ERß and synaptophysin and phosphorylation of ERK and PI3K-Akt-GSK-3ß induced by OVX in the hippocampus and prefrontal cortex. SIGNIFICANCE: These findings indicate that D-pinitol might be a promising candidate for treating post-menopausal symptoms by increasing ERß and synaptophysin expression levels and activation of ERK or PI3K-Akt-GSK-3ß signaling pathway, at least in part.

Unveiling the Neural Environment in Cancer: Exploring the Role of Neural Circuit Players and Potential Therapeutic 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.

Sedum middendorffianum Maxim Induces Apoptosis and Inhibits the Invasion of Human Ovarian Cancer Cells via Oxidative Stress Regulation.

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.

Effects of Artemisia annua L. on postmenopausal syndrome in ovariectomized mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia annua L. (Asteraceae) has been used as an antipyretic and anti-parasitic drug in traditional medicine for more than 2000 years. It has also been prescribed to treat symptoms caused by deficiency of Yin, which might be observed in menopausal state from the point of view of traditional medicine. AIM OF THE STUDY: We hypothesized that A. annua might be useful for treating menopausal disorders with less adverse effects than hormone replacement therapy. Thus, the aim of the present study was to investigate effects of A. annua on postmenopausal symptoms of ovariectomized (OVX) mice. MATERIALS AND METHODS: OVX mice were employed as a model for postmenopausal disorders. Mice were treated with a water extract of A. annua (EAA; 30, 100 or 300 mg/kg, p.o.) or 17ß-estradiol (E2; 0.5 mg/kg, s.c.) for 8 weeks. Open field test (OFT), novel object recognition task (NOR), Y-maze test, elevated plus maze test (EPM), splash test and tail suspension test (TST) were conducted to determine whether EAA could ameliorate postmenopausal symptoms. Phosphorylated levels of extracellular signal-regulated kinase (ERK), protein kinase B (Akt), and glycogen synthase kinase-3ß (GSK-3ß), ß-catenin and expression level of synaptophysin in the cortex and hippocampus were evaluated by Western blot analysis. RESULTS: EAA treatment significantly increased the discrimination index in NOR, decreased the time in closed arm than in open arm in EPM, increased grooming time in splash test, and decreased immobility time in TST, as did E2 treatment. In addition, decreased phosphorylation levels of ERK, Akt, GSK-3ß, and ß-catenin and expression levels of synaptophysin in the cortex and hippocampus after OVX were reversed by administration of EAA and E2. CONCLUSION: These results suggest that A. annua can ameliorate postmenopausal symptoms such as cognitive dysfunction, anxiety, anhedonia, and depression by activating ERK, Akt, and GSK-3ß/ß-catenin signaling pathway and hippocampal synaptic plasticity, and that A. annua would be a novel treatment for postmenopausal symptoms.

Treatment pattern of chronic lymphocytic leukemia/small lymphocytic lymphoma in Korea: a multicenter retrospective study (KCSG LY20-06).

BACKGROUND/AIMS: Little attention is paid to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in Korea due to the rarity of the disease. With its rising incidence, we aimed to evaluate recent changes in treatment patterns and survival outcomes of patients with CLL/SLL. METHODS: A total of 141 patients diagnosed with CLL/SLL between January 2010 and March 2020 who received systemic therapy were analyzed in this multicenter retrospective study. RESULTS: The median patient age was 66 years at diagnosis, and 68.1% were male. The median interval from diagnosis to initial treatment was 0.9 months (range: 0-77.6 months), and the most common treatment indication was progressive marrow failure (50.4%). Regarding first-line therapy, 46.8% received fludarabine, cyclophosphamide, plus rituximab (FCR), followed by chlorambucil (19.9%), and obinutuzumab plus chlorambucil (GC) (12.1%). The median progression-free survival (PFS) was 49.3 months (95% confidence interval [CI], 32.7-61.4), and median overall survival was not reached (95% CI, 98.4 mo- not reached). Multivariable analysis revealed younger age (≤ 65 yr) (hazard ratio [HR], 0.46; p < 0.001) and first-line therapy with FCR (HR, 0.64; p = 0.019) were independently associated with improved PFS. TP53 aberrations were observed in 7.0% (4/57) of evaluable patients. Following reimbursement, GC became the most common therapy among patients over 65 years and second in the overall population after 2017. CONCLUSION: Age and reimbursement mainly influenced treatment strategies. Greater effort to apply risk stratifications into practice and clinical trials for novel agents could help improve treatment outcomes in Korean patients.

Macrophages Promote Ovarian Cancer-Mesothelial Cell Adhesion by Upregulation of ITGA2 and VEGFC in Mesothelial Cells.

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.

Upregulation of SPI1 in Ectopic Endometrium Contributes to an Invasive Phenotype.

BACKGROUD AND AIM: Endometriosis is one of the most common gynecological diseases associated with chronic pelvic pain, infertility, and cancer. However, its molecular pathogenesis remains unclear. This study aimed to identify key genes involved in the pathogenesis of endometriosis. METHODS: Bioinformatic analyses were perfomed to identify key differentially expressed genes (DEGs), transcription factors (TFs), and functionally enriched pathways. Effect of SPI1 on migration, invasion, expression of ADH1B, MYH11, and PLN were analyzed in human endometriotic cells. RESULTS: By screening three transcriptome datasets from the GEO for overlapping DEGs between eutopic and ectopic endometria in patients with endometriosis, we found that the expression of ADH1B, MYH11, and PLN was markedly upregulated in the ectopic endometrium. Knockdown of ADH1B, MYH11, and PLN significantly inhibited the migration and invasion of human endometriotic 12Z cells. Additionally, gene set enrichment analysis revealed that epithelial-mesenchymal transition gene signature was positively correlated with ADH1B, MYH11, and PLN expression. Notably, the TF SPI1 was found to regulate the expression of these three genes in the endometriotic tissues and 12TZ cells. Moreover, SPI1 expression was associated with the invasion of endometriotic cells and was increased in the ectopic endometrium of patients with endometriosis. CONCLUSION: These data suggest that SPI1 plays a key role in the progression of endometriosis by regulating ADH1B, MYH11, and PLN expression and may therefore serve as a potential prognostic and therapeutic factor for endometriosis.

Cytotoxic Properties of C17 Polyacetylenes from the Fresh Roots of Panax ginseng on Human Epithelial Ovarian Cancer Cells.

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.

CCL2 overexpression is associated with paclitaxel resistance in ovarian cancer cells via autocrine signaling and macrophage recruitment.

Tumor cells can secret various cytokines and chemokines, which affect the tumor cells themselves and the neighboring cells. Here, we observed that human ovarian cancer (OC) cells developed resistance to paclitaxel treatment following culture with the conditioned medium (CM) derived from paclitaxel-resistant OC (OCTR) cells. A cytokine array revealed that both OCTR cells secreted large amounts of CC chemokine ligand 2 (CCL2). CCL2 and its receptor, CCR2, were overexpressed in OCTR cells. CCL2 expression was associated with worse progression-free survival in patients with ovarian cancer. The inhibition of the CCL2/CCR2 axis suppressed the chemoresistance induced by OCTR-CM. The enhanced expression and production of CCL2 in OC cells were mediated via the NF-κB pathway, and stimulated the activation of the PI3K/Akt pathway, which resulted in the development of paclitaxel resistance in OC cells. Additionally, the OCTR cells significantly increased the migration of macrophages, which was also associated with the overproduction of CCL2 in chemoresistant cancer cells. The macrophages stimulated by OCTR cells expressed high levels of markers of M2 phenotype, and their CM significantly decreased the paclitaxel responsiveness of OC cells. The administration of a CCR2 inhibitor to a murine model significantly improved the paclitaxel sensitivity. These data suggested that apart from inducing chemoresistance in OC cells by acting as an autocrine factor, CCL2 also functions as a chemokine that induces the chemotaxis of macrophages, which may contribute to chemoresistance. Therefore, targeting the CCL2/CCR2 signaling axis may improve the therapeutic response of patients with ovarian cancer to paclitaxel.

Long-term follow-up results of cytarabine-containing chemotherapy for acute promyelocytic leukemia.

BACKGROUND/AIMS: We evaluated the feasibility and long-term efficacy of the combination of cytarabine, idarubicin, and all-trans retinoic acid (ATRA) for treating patients with newly diagnosed acute promyelocytic leukemia (APL). METHODS: We included 87 patients with newly diagnosed acute myeloid leukemia and a t(15;17) or promyelocytic leukemia/retinoic acid receptor alpha (PML-RARα) mutation. Patients received 12 mg/m2/day idarubicin intravenously for 3 days and 100 mg/m2/day cytarabine for 7 days, plus 45 mg/m2/day ATRA. Clinical outcomes included complete remission (CR), relapse-free survival (RFS), overall survival (OS), and the secondary malignancy incidence during a 20-year follow-up. RESULTS: The CR, 10-year RFS, and 10-year OS rates were 89.7%, 94.1%, and 73.8%, respectively, for all patients. The 10-year OS rate was 100% for patients that achieved CR. Subjects were classified according to the white blood cell (WBC) count in peripheral blood at diagnosis (low-risk, WBC < 10,000/mm3; high-risk, WBC ≥ 10,000/mm3). The low-risk group had significantly higher RFS and OS rates than the high-risk group, but the outcomes were not superior to the current standard treatment (arsenic trioxide plus ATRA). Toxicities were similar to those observed with anthracycline plus ATRA, and higher than those observed with arsenic trioxide plus ATRA. The secondary malignancy incidence after APL treatment was 2.7%, among the 75 patients that achieved CR, and 5.0% among the 40 patients that survived more than 5 years after the APL diagnosis. CONCLUSION: Adding cytarabine to anthracycline plus ATRA was not inferior to anthracycline plus ATRA alone, but it was not comparable to arsenic trioxide plus ATRA. The probability of secondary malignancy was low.

Pennogenin-3-O-α-L-Rhamnopyranosyl-(1→2)-[α-L-Rhamnopyranosyl-(1→3)]-ß-D-Glucopyranoside (Spiroconazol A) Isolated from Dioscorea bulbifera L. var. sativa Induces Autophagic Cell Death by p38 MAPK Activation in NSCLC Cells.

In our previous study, we reported the isolation of pennogenin-3-O-α-L-rhamnopyranosyl-(1→2)-[α-L-rhamnopyranosyl-(1→3)]-ß-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.

Chemical Constituents of the Flowers of Pueraria lobata and Their Cytotoxic Properties.

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-ß-d-glucopyranoside (1), 2-hydroxy-5-methoxy-naringenin (4), and 2-hydroxy-5-methoxy-naringenin 7-O-ß-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).

Citromycin Isolated from the Antarctic Marine-Derived Fungi, Sporothrix sp., Inhibits Ovarian Cancer Cell Invasion via Suppression of ERK Signaling.

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.