Sulforaphane regulates cell proliferation and induces apoptotic cell death mediated by ROS-cell cycle arrest in pancreatic cancer cells.

Background: Pancreatic cancer (PC), sometimes referred to as pancreatic ductal adenocarcinoma (PDAC), is a major cause of global mortality from cancer. Pancreatic cancer is a very aggressive and devastating kind of cancer, characterized by limited options for therapy and low possibilities of survival. Sulforaphane (SFN), a naturally occurring sulfur-containing compound, is believed to possess anti-inflammatory, anti-obesity, and anti-cancer characteristics. Objective: However, efficient preventative and treatment measures are essential and SFN has been studied for its ability to suppress pancreatic cancer cell proliferation and induce apoptosis. Methods: Here, SFN induced cytotoxicity and apoptosis in PDAC cell lines such as MIA PaCa-2 and PANC-1 cells, as evaluated by cytotoxicity, colony formation, western blot analysis, fluorescence-activated cell sorting (FACS), reactive oxygen species (ROS) detection, caspase-3 activity assay, immunofluorescence assay, and mitochondrial membrane potential assay. Results: In MIA PaCa-2 and PANC-1 cells, SFN inhibited cell survival and proliferation in a dose-dependent manner. The activation of caspase zymogens results in cleaved PARP and cleaved caspase-3, which is associated with an accumulation in the sub G1 phase. Furthermore, SFN increased ROS level and γH2A.X expression while decreasing mitochondrial membrane potential (ΔΨm). Notably, the ROS scavenger N-Acetyl-L-cysteine (NAC) was shown to reverse SFN-induced cytotoxicity and ROS level. Subsequently, SFN-induced cell cycle arrest and apoptosis induction as a Trojan horse to eliminate pancreatic cancer cells via ROS-mediated pathways were used to inhibit pancreatic cancer cells. Conclusion: Collectively, our data demonstrates that SFN-induced cell death follows the apoptosis pathway, making it a viable target for therapeutic interventions against pancreatic cancer.

Mucosa-associated Lymphoid Tissue Misdiagnosis as Glomus Tympanicum.

Middle ear tumors are diverse, but relatively uncommon. The most frequent tumor in the middle ear is glomus tumor, followed by others such as schwannoma and cholesteatoma. We experienced a case of Mucosa-associated lymphoid tissue hyperplasia as a middle ear tumor. The mass behind tympanic membrane appeared a hypervascular tumor, mimicking a glomus tumor, but the form of multiple separate masses in middle ear and mastoid cavity was the distinguishing feature that set it apart from a glomus tumor. Additionally, another characteristic was its tendency to easily shrink under pressure. This characteristic should be considered when encounter a hypervascular looking middle ear mass. Laryngoscope, 134:1894-1896, 2024.

Clinical characteristics of local allergic rhinitis sensitized to house dust mites in Asia.

PURPOSE: Local allergic rhinitis (LAR) is characterized by a localized nasal allergic response without evidence of systemic atopy. LAR is an underdiagnosed entity and is a diagnostic and therapeutic challenge for clinicians. This study aimed to investigate the prevalence and clinical characteristics of patients with LAR to house dust mites (LAR-HDM) in Korea. METHODS: We performed a retrospective chart review of 336 adult patients with rhinitis symptoms who visited the Rhinologic Clinic at Korea University Guro Hospital from October 2019 to April 2021. Using results of the skin prick test, serologic test, and nasal provocation test, patients were classified as allergic rhinitis (AR) to HDM (AR-HDM), AR to other allergens, non-allergic rhinitis (NAR), or LAR-HDM. We excluded patients with AR to other allergens and compared the clinical characteristics of the remaining three groups. Patient demographic data were reviewed, and patients' nasal symptoms, olfactory function, serum total IgE, and severity of accompanying rhinosinusitis were evaluated. RESULTS: In total, 336 patients were examined. AR-HDM was diagnosed in 138 (41.1%) patients, AR to other allergens in 36 (10.7%) patients, NAR in 21 (42.0%) patients, and LAR-HDM in 21 (6.3%) patients. The mean age of patients with LAR-HDM was significantly higher than that of patients with AR-HDM. There were no significant differences in sex, smoking history, asthma, and family history of allergic diseases between the groups. Compared to NAR patients, there were significantly more patients with LAR-HDM who had persistent nasal symptoms. The frequency of nasal itching and sneezing was significantly higher in the LAR-HDM group than in the NAR group. The olfactory function score in the LAR-HDM group was significantly worse than that in the AR-HDM group, and the Lund-Mackay score was significantly higher in the LAR-HDM group than in the other groups. CONCLUSION: Clinical history and nasal symptoms are very similar in LAR-HDM and AR-HDM. Clinicians should take more care to differentiate them. LAR-HDM should also be considered in patients with persistent and severe nasal symptoms without systemic atopy.

BK002 Induces miR-192-5p-Mediated Apoptosis in Castration-Resistant Prostate Cancer Cells via Modulation of PI3K/CHOP.

BK002 consists of Achyranthes japonica Nakai (AJN) and Melandrium firmum Rohrbach (MFR) that have been used as herbal medicines in China and Korea. AJN and MFR have been reported to have anti-inflammatory, anti-oxidative, and anti-cancer activities, although the synergistic targeting multiple anti-cancer mechanism in castration-resistant prostate cancer (CRPC) has not been well reported. However, the drug resistance and transition to the androgen-independent state of prostate cancer contributing to CRPC is not well studied. Here, we reported that BK002 exerted cytotoxicity and apoptosis in CRPC PC3 cell lines and prostate cancer DU145 cell lines examined by cytotoxicity, western blot, a LIVE/DEAD cell imaging assay, reactive oxygen species (ROS) detection, quantitative real-time polymerase chain reaction (RT-PCR), and transfection assays. The results from our investigation found that BK002 showed more cellular cytotoxicity than AJN and MFR alone, suggesting that BK002 exhibited potential cytotoxic properties. Consistently, BK002 increased DNA damage, and activated p-γH2A.X and depletion of survivin-activated ubiquitination of pro-PARP, caspase9, and caspase3. Notably, live cell imaging using confocal microscopy found that BK002 effectively increased DNA-binding red fluorescent intensity in PC3 and DU145 cells. Also, BK002 increased the anti-proliferative effect with activation of the C/EBP homologous protein (CHOP) and significantly attenuated PI3K/AKT expression. Notably, BK002-treated cells increased ROS generation and co-treatment of N-Acetyl-L-cysteine (NAC), an ROS inhibitor, significantly preventing ROS production and cellular cytotoxicity, suggesting that ROS production is essential for initiating apoptosis in PC3 and DU145 cells. In addition, we found that BK002 significantly enhanced miR-192-5p expression, and co-treatment with BK002 and miR-192-5p inhibitor significantly reduced miR-192-5p expression and cellular viability in PC3 and DU145 cells, indicating modulation of miR-192-5p mediated apoptosis. Finally, we found that BK002-mediated CHOP upregulation and PI3K downregulation were significantly reduced and restrained by miR-192-5p inhibitor respectively, suggesting that the anti-cancer effect of BK002 is associated with the miR-192-5p/PI3K/CHOP pathway. Therefore, our study reveals that a combination of AJN and MFR might be more effective than single treatment against apoptotic activities of both CRPC cells and prostate cancer cells.

Leonurus japonicus Houttuyn induces reactive oxygen species-mediated apoptosis via regulation of miR-19a-3p/PTEN/PI3K/AKT in U937 and THP-1 cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Leonurus japonicus Houttuyn is a medicinal ingredient in more than 300 prescriptions in traditional Korean medicine. It is especially important for women's health and blood-related diseases. Recent research revealed that Leonurus japonicus Houttuyn extracts have antioxidative, anticancer, analgesic, anti-inflammatory, and neuroprotective properties. AIM OF THE STUDY: However, its underlying anti-cancerous mechanisms remain unclear. This study elucidated the anticancer mechanism of Leonurus japonicus Houttuyn in U937 and THP-1 cancer cells. MATERIALS AND METHODS: High-performance liquid chromatography (HPLC) was used for detecting main compound of Leonurus japonicus Houttuyn, rutin. EZ-Cytox cell viability assay, Western blot analysis, live and dead cell assay, 2', 7' dichlorofluorescin diacetate (DCFDA) assay, quantitative real-time PCR (qRT-PCR) analysis, and microRNA (miR) mimic transfection assay were applied to further investigate anti-cancer efficacies and underlying mechanism in U937 and THP-1 cells. RESULTS: The main compound of Leonurus japonicus Houttuyn, rutin was detected using HPLC. The cytotoxic effect of Leonurus japonicus Houttuyn was exerted in U937 and THP-1 cancer cells but not in MDBK and IEC-6 normal cells. Leonurus japonicus Houttuyn decreased mitochondria membrane potential (ΔΨm). Consistently, Leonurus japonicus Houttuyn reduced the expression of survivin and cleaved caspase-9, caspase-3, and poly (ADP-ribose) polymerase (PARP). Cell death was increased in Leonurus japonicus Houttuyn treated groups. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and CCAAT-enhancer-binding protein homologous protein (CHOP) was increased and phosphatidylinositol-3-kinase (PI3K) and Protein kinase B (AKT) were decreased by Leonurus japonicus Houttuyn. Reactive oxygen speices generation was elevated by Leonurus japonicus Houttuyn and its cytotoxicity was reversed by N-acetyl-l-cysteine (NAC) pretreatment. Moreover, onco-microRNA (miR), miR-19a-3p was suppressed by Leonurus japonicus Houttuyn and transfection of miR-19a-3p mimic reversed the regulated PTEN, p-AKT, CHOP expression, attenuating Leonurus japonicus Houttuyn induced apoptosis. CONCLUSIONS: These findings indicated that Leonurus japonicus Houttuyn has anti-cancer effects by regulation of PTEN/PI3K/AKT signal pathway and ROS-related ER stress-induced apoptosis via regulation of miR-19a-3p. Leonurus japonicus Houttuyn may be an effective candidate for triggering PTEN-dependent apoptosis of cancer cells related to acute myeloid leukemia.

Natural Products for Pancreatic Cancer Treatment: From Traditional Medicine to Modern Drug Discovery.

Pancreatic cancer, the seventh most lethal cancer around the world, is considered complicated cancer due to poor prognosis and difficulty in treatment. Despite all the conventional treatments, including surgical therapy and chemotherapy, the mortality rate is still high. Therefore, the possibility of using natural products for pancreatic cancer is increasing. In this study, 68 natural products that have anti-pancreatic cancer effects reported within five years were reviewed. The mechanisms of anti-cancer effects were divided into four types: apoptosis, anti-metastasis, anti-angiogenesis, and anti-resistance. Most of the studies were conducted for natural products that induce apoptosis in pancreatic cancer. Among them, plant extracts such as Eucalyptus microcorys account for the major portion. Some natural products, including Moringa, Coix seed, etc., showed multi-functional properties. Natural products could be beneficial candidates for treating pancreatic cancer.

Recent Advances in Nanotechnology with Nano-Phytochemicals: Molecular Mechanisms and Clinical Implications in Cancer Progression.

Biocompatible nanoparticles (NPs) containing polymers, lipids (liposomes and micelles), dendrimers, ferritin, carbon nanotubes, quantum dots, ceramic, magnetic materials, and gold/silver have contributed to imaging diagnosis and targeted cancer therapy. However, only some NP drugs, including Doxil® (liposome-encapsulated doxorubicin), Abraxane® (albumin-bound paclitaxel), and Oncaspar® (PEG-Asparaginase), have emerged on the pharmaceutical market to date. By contrast, several phytochemicals that were found to be effective in cultured cancer cells and animal studies have not shown significant efficacy in humans due to poor bioavailability and absorption, rapid clearance, resistance, and toxicity. Research to overcome these drawbacks by using phytochemical NPs remains in the early stages of clinical translation. Thus, in the current review, we discuss the progress in nanotechnology, research milestones, the molecular mechanisms of phytochemicals encapsulated in NPs, and clinical implications. Several challenges that must be overcome and future research perspectives are also described.

An Afferent Neuropeptide System Transmits Mechanosensory Signals Triggering Sensitization and Arousal in C. elegans.

Sensitization is a simple form of behavioral plasticity by which an initial stimulus, often signaling danger, leads to increased responsiveness to subsequent stimuli. Cross-modal sensitization is an important feature of arousal in many organisms, yet its molecular and neural mechanisms are incompletely understood. Here we show that in C. elegans, aversive mechanical stimuli lead to both enhanced locomotor activity and sensitization of aversive chemosensory pathways. Both locomotor arousal and cross-modal sensitization depend on the release of FLP-20 neuropeptides from primary mechanosensory neurons and on their receptor FRPR-3. Surprisingly, the critical site of action of FRPR-3 for both sensory and locomotor arousal is RID, a single neuroendocrine cell specialized for the release of neuropeptides that responds to mechanical stimuli in a FLP-20-dependent manner. Thus, FLP-20 peptides function as an afferent arousal signal that conveys mechanosensory information to central neurons that modulate arousal and other behavioral states.

Effects of artificial light at night on human health: A literature review of observational and experimental studies applied to exposure assessment.

It has frequently been reported that exposure to artificial light at night (ALAN) may cause negative health effects, such as breast cancer, circadian phase disruption and sleep disorders. Here, we reviewed the literature assessing the effects of human exposure to ALAN in order to list the health effects of various aspects of ALAN. Several electronic databases were searched for articles, published through August 2014, related to assessing the effects of exposure to ALAN on human health; these also included the details of experiments on such exposure. A total of 85 articles were included in the review. Several observational studies showed that outdoor ALAN levels are a risk factor for breast cancer and reported that indoor light intensity and individual lighting habits were relevant to this risk. Exposure to artificial bright light during the nighttime suppresses melatonin secretion, increases sleep onset latency (SOL) and increases alertness. Circadian misalignment caused by chronic ALAN exposure may have negative effects on the psychological, cardiovascular and/or metabolic functions. ALAN also causes circadian phase disruption, which increases with longer duration of exposure and with exposure later in the evening. It has also been reported that shorter wavelengths of light preferentially disturb melatonin secretion and cause circadian phase shifts, even if the light is not bright. This literature review may be helpful to understand the health effects of ALAN exposure and suggests that it is necessary to consider various characteristics of artificial light, beyond mere intensity.

Polycyclic aromatic hydrocarbons exposure in residents living near a cement factory with kilns.

PURPOSE: This study was performed to investigate polycyclic aromatic hydrocarbons (PAHs) exposure in the area around a cement factory with kilns using waste, including refuse plastic fuel. METHODS: Atmospheric total suspended particulates (TSPs) for each of an exposed area and a non-exposed area were collected. Similarly, urine samples were collected from 330 subjects in the exposed area and 126 subjects in the non-exposed area. Gas chromatography with mass spectrometry was used to analyze PAHs in the collected TSP samples and the PAH metabolites, urinary 2-naphthol (2-NAP) and 1-hydroxypyrene (1-OHP), of the residents. The concentrations of urinary 2-NAP and 1-OHP were adjusted by creatinine concentrations. RESULTS: The atmospheric concentrations of PAHs, including naphthalene and pyrene, were higher in the exposed area than those in the non-exposed area. The geometric means (GMs) of the urinary 2-NAP concentrations in the exposed and non-exposed groups without work experience were 4.06 and 1.55 µg/g creatinine, respectively. The GMs of the urinary 1-OHP concentrations were 0.26 and 0.14 µg/g creatinine, respectively. The results showed that the concentrations of PAH metabolites were significantly higher in the exposed group than those in the non-exposed group (p < 0.001). Multiple linear regression analysis with the log-transformed urinary 2-NAP and 1-OHP concentrations and other variables indicated a strong correlation of residence in the exposed area and smoking with an increase in the urinary 2-NAP and 1-OHP concentrations. CONCLUSIONS: In addition to the known risk factors, this study indicated that living near a cement factory with kilns is also a risk factor for PAH exposure.

pH-responsive assembly of gold nanoparticles and "spatiotemporally concerted" drug release for synergistic cancer therapy.

A challenge in using plasmonic nanostructure-drug conjugates for thermo-chemo combination cancer therapy lies in the huge size discrepancy; the size difference can critically differentiate their biodistributions and hamper the synergistic effect. Properly tuning the plasmonic wavelength for photothermal therapy typically results in the nanostructure size reaching ∼100 nm. We report a new combination cancer therapy platform that consists of relatively small 10 nm pH-responsive spherical gold nanoparticles and conjugated doxorubicins. They are designed to form aggregates in mild acidic environment such as in a tumor. The aggregates serve as a photothermal agent that can selectively exploit external light by their collective plasmon modes. Simultaneously, the conjugated doxorubicins are released. The spatiotemporal concertion is confirmed at the subcellular, cellular, and organ levels. Both agents colocalize in the cell nuclei. The conjugates accumulate in cancer cells by the rapid phagocytic actions and effective blockage of exocytosis by the increased aggregate size. They also effectively accumulate in tumors up to 17 times over the control because of the enhanced permeation and retention. The conjugates exhibit a synergistic effect enhanced by nearly an order of magnitude in cellular level. The synergistic effect is demonstrated by the remarkable reductions in both the therapeutically effective drug dosage and the photothermal laser threshold. Using an animal model, effective tumor growth suppression is demonstrated. The conjugates induce apoptosis to tumors without any noticeable damage to other organs. The synergistic effect in vivo is confirmed by qRT-PCR analysis over the thermal stress and drug-induced growth arrest.

Association of arsenic levels in soil and water with urinary arsenic concentration of residents in the vicinity of closed metal mines.

Arsenic (As) pollution in the surroundings of metal mines has been observed, and may induce serious health problems, in particular cancer. Health hazard attributed to As in contaminated soil and water in the vicinity of closed or abandoned metal mines may be high. Little is known about how environmental exposure to As has affected the health of resident near closed metal mines. The objectives of this study were to compare the urinary level of As for those living near closed metal mines (the exposed group) with that of non-exposed group; and to investigate the correlation between As levels in soil (SoilAs) and water (WaterAs) and the urinary levels (UrineAs) of residents in the exposed group. Data for SoilAs and WaterAs were obtained from the national environmental survey performed between 2003 and 2005 by the Ministry of Environment in Korea. To measure UrineAs, 2674 and 237 subjects were selected from 67 closed metal mines (exposed areas) and two rural areas (non-exposed areas), respectively. Five milliliters of urine samples were taken, and graphite furnace atomic absorption spectrometry was used to analyze UrineAs. Of all the exposed areas, high SoilAs and WaterAs areas that exceed the Korean standards of As in soil (6 mg/kg-soil) and stream or groundwater (0.05 mg/l-water) were classified to evaluate the health risks in high polluted areas. Also, high UrineAs group was defined as 20 µg/g creatinine or more. Student's t-test was performed to compare the UrineAs level between the exposed and non-exposed groups. The odds ratio (OR) was calculated by a logistic analysis to evaluate the risk for high UrineAs level from high SoilAs and WaterAs areas. The mean of urinary As were 8.90 ± 8.34 µg/g-creatinine for the exposed group and 7.68 ± 4.98 µg/g creatinine for the non-exposed group, respectively; and the significant difference of urinary As level was observed between both groups (p<0.05). Moreover, the means for urinary As of people in areas with high As level in soil and water were significantly higher than that for the control areas (p<0.001), and these differences were more pronounced for the As level in water. The odds of subjects with high UrineAs were positively and significantly associated with living in the areas with high As level in soil (OR=1.62; 95% C.I.=1.13-2.31). These associations were much stronger for the areas with high WaterAs (OR=3.79; 95% C.I.=2.32-6.19). These results indicate that the high level of As in environment may increase the risk of having high urinary As level of people in the exposed areas.

Effects of a tailored health promotion program to reduce cardiovascular disease risk factors among middle-aged and advanced-age bus drivers.

A tailored health promotion program was developed and applied to reduce cardiovascular disease risk factors among middle-aged and advanced-age bus drivers. The participants were 248 bus drivers from 2 transportation companies, in whom the authors surveyed health behaviors (physical activity, diet, smoking habit, and alcohol consumption), health status (body mass index, systolic blood pressure, triglycerides, total cholesterol, high-density lipoprotein, and low-density lipoprotein), and job stress. The tailored health promotion program consisted of exercise, diet, temperance, and smoking cessation education; the program was developed to reduce cardiovascular disease risk factors and was administered for 6 months. After the program, health behaviors, such as physical activity, dietary habits, smoking habits, and alcohol consumption, and health status indicators, such as blood pressure, had significantly improved (P < .05). The authors did not find an association between job stress and health behavior and status. This suggests that a tailored health promotion program for middle-aged and advanced-age bus drivers was effective.

[The effects of wearing protective devices among residents and volunteers participating in the cleanup of the Hebei Spirit oil spill].

OBJECTIVES: To assess the protective effects of wearing protective devices among the residents and volunteers who participated in the cleanup of the Hebei Spirit oil spill. METHODS: A total of 288 residents and 724 volunteers were surveyed about symptoms, whether they were wearing protective devices and potential confounding variables. The questionnaires were administered from the second to the sixth week following the accident. Spot urine samples were collected and analyzed for metabolites of 4 volatile organic compounds (VOCs), 2 polycyclic aromatic hydrocarbons (PAHs), and 6 heavy metals. The association between the wearing of protective devices and various symptoms was assessed using a multiple logistic regression adjusted for confounding variables. A multiple generalized linear regression model adjusted for the covariates was used to test for a difference in least-square mean concentration of urinary biomarkers between residents who wore protective devices and those who did not. RESULTS: Thirty nine to 98% of the residents and 62-98% of volunteers wore protective devices. Levels of fatigue and fever were higher among residents not wearing masks than among those who did wear masks (odds ratio 4.5; 95% confidence interval 1.23-19.86). Urinary mercury levels were found to be significantly higher among residents not wearing work clothes or boots (p<0.05). CONCLUSIONS: Because the survey was not performed during the initial high-exposure period, no significant difference was found in metabolite levels between people who wore protective devices and those who did not, except for mercury, whose biological half-life is more than 6 weeks.

Confirming single nucleotide polymorphisms from expressed sequence tag datasets derived from three cattle cDNA libraries.

Using the Phred/Phrap/Polyphred/Consed pipeline established in the National Livestock Research Institute of Korea, we predicted candidate coding single nucleotide polymorphisms (cSNPs) from 7,600 expressed sequence tags (ESTs) derived from three cDNA libraries (liver, M. longissimus dorsi, and intermuscular fat) of Hanwoo (Korean native cattle) steers. From the 7,600 ESTs, 829 contigs comprising more than two EST reads were assembled using the Phrap assembler. Based on the contig analysis, 201 candidate cSNPs were identified in 129 contigs, in which transitions (69%) outnumbered transversions (31%). To verify whether the predicted cSNPs are real, 17 SNPs involved in lipid and energy metabolism were selected from the ESTs. Twelve of these were confirmed to be real while five were identified as artifacts, possibly due to expressed sequence tag sequence error. Further analysis of the 12 verified cSNPs was performed using the program BLASTX. Five were identified as nonsynonymous cSNPs, five were synonymous cSNPs, and two SNPs were located in 3'-UTRs. Our data indicated that a relatively high SNP prediction rate (71%) from a large EST database could produce abundant cSNPs rapidly, which can be used as valuable genetic markers in cattle.