Cytotoxic Peptaibols from Trichoderma strigosum.

Five new lipopeptaibols (1-5) and eight new 19-residue peptaibols (8-15) along with two known lipopeptaibols, lipovelutibols C (6) and D (7) were isolated from Trichoderma strigosum. The planar structures of the newly discovered peptaibols (1-5, 8-15) were elucidated using 1D and 2D NMR, and UPLC-MS/MS data. The absolute configurations for new peptaibols (1-5, 8-15) were elucidated using the advanced Marfey's method and GITC (2,3,4,6-tetra-O-acetyl-ß-d-glucopyranosyl isothiocyanate) derivatization. Through analysis of CD spectra, these peptabols were found to have right-handed helical conformations. While most of the new compounds were significantly more active than the positive control, 9, 10, 12, and 15 containing Ser and Leu at positions 10 and 11, respectively, were the most cytotoxic against MDA-MB-231, SNU449, SKOV3, DU145, and HCT116 cancer cell lines, and the 19-residue peptaibols were generally more potent than lipopeptaibols.

Cytotoxic Peptaibols from Trichoderma guizhouense, a Fungus Isolated from an Urban Soil Sample.

Soil sustains human life by nourishing crops, storing food sources, and housing microbes, which may affect the nutrition and biosynthesis of secondary metabolites, some of which are used as drugs. To identify lead compounds for a new class of drugs, we collected soil-derived fungal strains from various environments, including urban areas. As various human pathogens are assumed to influence the biosynthetic pathways of metabolites in soil fungi, leading to the production of novel scaffolds, we focused our work on densely populated urban areas and tourist attractions. A soil-derived fungal extract library was screened against MDA-MB-231 cells to derive their cytotoxic activity. Notably, 10 µg/mL of the extract of Trichoderma guizhouense (DS9-1) was found to exhibit an inhibitory effect of 71%. Fractionation, isolation, and structure elucidation efforts led to the identification of nine new peptaibols, trichoguizaibols A-I (1-9), comprising 14 amino acid residues (14-AA peptaibols), and three new peptaibols, trichoguizaibols J-L (10-12), comprising 18 amino acid residues (18-AA peptaibols). The chemical structures of 1-12 were determined based on their 1D and 2D NMR spectra, HRESIMS, electronic circular dichroism data, and results of the advanced Marfey's method. The 18-AA peptaibols were found to exhibit cytotoxicity against MDA-MB-231, SK-Hep1, SKOV3, DU145, and HCT116 cells greater than that of the 14-AA peptaibols. Among these compounds, 10-12 exhibited potent sub-micromolar IC50 values. These results are expected to shed light on a new direction for developing novel scaffolds as anticancer agents.

Selection of climate variables in ant species distribution models: case study in South Korea.

The selection of explanatory variables is important in modeling prediction of changes in species distribution in response to climate change. In this study, we evaluated the importance of variable selection in species distribution models. We compared two different types of models for predicting the distribution of ant species: temperature-only and both temperature and precipitation. Ants were collected at 343 forest sites across South Korea from 2006 through 2009. We used a generalized additive model (GAM) to predict the future distribution of 16 species that showed significant responses to changes in climatic factors (temperature and/or precipitation). Four types of GAMs were constructed: temperature, temperature with interaction of precipitation, temperature and precipitation without interaction, and temperature and precipitation with interaction. Most species displayed similar results between the temperatureonly and the temperature and precipitation models. The results for predicted changes in species richness were different from the temperature-only model. This indicates higher uncertainty in the prediction of species richness, which is obtained by combining the prediction results of distribution change for each species, than in the prediction of distribution change. The turnover rate of the ant assemblages was predicted to increase with decreases in temperature and increases in elevation, which was consistent with other studies. Finally, our results showed that the prediction of the distribution or diversity of organisms responding to climate change is uncertain because of the high variability of the model outputs induced by the variables used in the models.

Lipid raft protein flotillin-1 is important for the interaction between SOS1 and H-Ras/K-Ras, leading to Ras activation.

Ras mutations have been frequently observed in human cancer. Although there is a high degree of similarity between Ras isomers, they display preferential coupling in specific cancer types. The binding of Ras to the plasma membrane is essential for its activation and biological functions. The present study elucidated Ras isoform-specific interactions with the membrane and their role in Ras-mediated biological activities. We investigated the role of a lipid raft protein flotillin-1 (Flot-1) in the activations of Ras. We found that Flot-1 was co-localized with H-Ras, but not with N-Ras, in lipid rafts of MDA-MB-231 human breast cells. The amino-terminal hydrophobic domain (1-38) of Flot-1 interacted with the hypervariable region of H-Ras. The epidermal growth factor-stimulated activation of H-Ras required Flot-1 which was not necessary for that of N-Ras in breast cancer cells. Flot-1 interacted with son of sevenless (SOS)-1, which promotes the conversion of Ras-bound GDP to GTP. Notably, Flot-1 was crucial for the interaction between SOS1 and H-Ras/K-Ras in breast and pancreatic cancer cells. Stable knockdown of Flot-1 reduced the in vivo metastasis in a mouse xenograft model with human breast carcinoma cells. A tissue microarray composed of 61 human pancreatic cancer samples showed higher levels of Flot-1 expression in pancreatic tumor tissues compared to normal tissues, and a correlation between K-Ras and Flot-1. Taken together, our findings suggest that Flot-1 may serve as a membrane platform for the interaction of SOS1 with H-Ras/K-Ras in human cancer cells, presenting Flot-1 as a potential target for Ras-driven cancers.

Efficacy and safety of enavogliflozin, a novel SGLT2 inhibitor, in Korean people with type 2 diabetes: A 24-week, multicentre, randomized, double-blind, placebo-controlled, phase III trial.

AIMS: To evaluate the efficacy and safety of a novel sodium-glucose cotransporter 2 inhibitor, enavogliflozin 0.3 mg monotherapy, in Korean people with type 2 diabetes mellitus (T2DM) inadequately controlled with diet and exercise. MATERIALS AND METHODS: This study was a randomized, double-blind, placebo-controlled trial conducted in 23 hospitals. Individuals with haemoglobin A1c (HbA1c) of 7.0%-10.0% after at least 8 weeks of diet and exercise modification were randomized to receive enavogliflozin 0.3 mg (n = 83) or placebo (n = 84) for 24 weeks. The primary outcome was a change in HbA1c at week 24 from baseline. Secondary outcomes included the proportion of participants achieving HbA1c <7.0%, change in fasting glucose, body weight and lipid levels. Adverse events were investigated throughout the study. RESULTS: At week 24, the placebo-adjusted mean change in HbA1c from baseline in the enavogliflozin group was -0.99% (95% confidence interval -1.24%, -0.74%). The proportions of patients achieving HbA1c <7.0% (71% vs. 24%) at week 24 was significantly higher in the enavogliflozin group (p < .0001). Placebo-adjusted mean changes in fasting plasma glucose (-40.1 mg/dl) and body weight (-2.5 kg) at week 24 were statistically significant (p < .0001). In addition, a significant decrease in blood pressure, low-density lipoprotein cholesterol, triglyceride, and homeostasis model assessment of insulin resistance were observed, along with a significant increase in high-density lipoprotein cholesterol. No significant increase in treatment-related adverse events was observed for enavogliflozin. CONCLUSIONS: Monotherapy with enavogliflozin 0.3 mg improved glycaemic control in people with T2DM. Enavogliflozin therapy also exerted beneficial effects on body weight, blood pressure and lipid profile.

Development of the non-occupational post-exposure prophylaxis (NPEP) knowledge scale among Chinese men who have sex with men.

BACKGROUND: Nonoccupational post-exposure prophylaxis (NPEP) is a short course of medication taken to reduce the likelihood of acquiring human immunodeficiency virus (HIV) infection upon exposure. A review of the literature demonstrates an urgent need for an empirically validated instrument that measures detailed knowledge of NPEP among the key population of men who have sex with men (MSM). METHODS: Semi-structured interviews, focus groups, and a cross-sectional survey with a sample of 419 MSM was conducted in 2018 in China to develop and psychometrically evaluate the new instrument, the NPEP Knowledge Scale. Exploratory and confirmatory factor analyses, differential item functioning analyses, and structural equation modeling were conducted using Mplus 7.4. RESULTS: The NPEP Knowledge Scale demonstrated excellent reliability and validity. Cronbach's alpha was 0.903. The range of item R2 were 0.527-0.969, p's < 0.001. Model estimated inter-item correlations ranged between 0.534 and 0.968. In addition, HIV knowledge, NPEP use, and NPEP knowledge were all significantly correlated. CONCLUSIONS: The NPEP Knowledge Scale is suitable for research, program evaluation, and clinical and community services that require using NPEP to minimize the ever-present risk of new HIV infections.

Covariate inclusion in factor mixture modeling: Evaluating one-step and three-step approaches under model misspecification and overfitting.

Factor mixture modeling (FMM) has been increasingly used in behavioral and social sciences to examine unobserved population heterogeneity. Covariates (e.g., gender, race) are often included in FMM to help understand the formation and characterization of latent subgroups or classes. This Monte Carlo simulation study evaluated the performance of one-step and three-step approaches to covariate inclusion across three scenarios, i.e., correct specification (study 1), model misspecification (study 2), and model overfitting (study 3), in terms of direct covariate effects on factors. Results showed that the performance of these two approaches was comparable when class separation was large and the specification of covariate effect was correct. However, one-step FMM had better class enumeration than the three-step approach when class separation was poor, and was more robust to the misspecification or overfitting concerning direct covariate effects. Recommendations regarding covariate inclusion approaches are provided herein depending on class separation and sample size. Large sample size (1000 or more) and the use of sample size-adjusted BIC (saBIC) in class enumeration are recommended.

Examining potential effects of non-occupational post-exposure prophylaxis (nPEP) on sexual behaviors of Chinese men who have sex with men: a cross-sectional study.

BACKGROUND: In China, non-occupational post-exposure prophylaxis (nPEP) is not a conventional service yet and nPEP related studies are very few. Recently, China's 13th Five Year Action Plan for HIV/AIDS Containment and Prevention examines the feasibility of including nPEP as one of the national strategies for HIV prevention. However, there is a concern that nPEP use might exacerbate high-risk sexual activities. In order to facilitate a research-based policy making of routinizing nPEP services, the current study examined potential effects of nPEP use on condom use and number of sexual partners among Chinese men who have sex with men (MSM) . METHODS: A cross-sectional survey was conducted in two cities of China in November and December 2018. Descriptive analyses of participants' sociodemographic and behavioral characteristics were conducted using SPSS 24.0. Mplus 7.4 was used to conduct confirmatory factor analysis and structural equation modeling. RESULTS: The sample included 419 Chinese MSM with a mean age of 28.04 (SD = 9.71). Participants reported more positive anticipation of their own behaviors than other MSM's behaviors regarding condom use and number of sexual partners if nPEP were to be routinized in China. About 60% of participants reported discrepancies between anticipated individual and population behaviors as a potential result of routinization of nPEP services. Anticipated individual behavioral change was positively related to age and duration of residence in the current city, and negatively related to education. Anticipated population behavioral change was positively related to age. Anticipated behavioral discrepancy was positively related to being ethnic minority and never married. CONCLUSIONS: These findings identify a high-risk subgroup of MSM, who reported they would use condoms less and/or have more sexual partners when nPEP becomes available. This subgroup of MSM might benefit from targeted health interventions. Moreover, there is a clear discrepancy between anticipated individual and population behavioral changes regarding future routinization of nPEP services, suggesting incorporating nPEP services as a means of community development for MSM.

An oncogenic activity of PDGF-C and its splice variant in human breast cancer.

Despite strong evidence for the involvement of PDGF signaling in breast cancer, little is known about the PDGF ligand responsible for PDGFR activation during breast cancer progression. Here, we found PDGF-C to be highly expressed in breast carcinoma cell lines. Immunohistochemical analysis of invasive breast cancer revealed an association between increased PDGF-C expression and lymph node metastases, Ki-67 proliferation index, and poor disease-free survival. We also identified a PDGF-C splice variant encoding truncated PDGF-C (t-PDGF-C) isoform lacking the signal peptide and the N-terminal CUB domain. While t-PDGF C homodimer is retained intracellularly, it can be secreted as a heterodimer with full-length PDGF-C (FL-PDGF-C). PDGF-C downregulation reduced anchorage-independent growth and matrigel invasion of MDA-MB-231 cells. Conversely, ectopic expression of t-PDGF-C enhanced phenotypic transformation and invasion in BT-549 cells expressing endogenous FL-PDGF-C. The present study provides new insights into the functional significance of PDGF-C and its splice variant in human breast cancer.

A novel role for flotillin-1 in H-Ras-regulated breast cancer aggressiveness.

Elevated expression and aberrant activation of Ras have been implicated in breast cancer aggressiveness. H-Ras, but not N-Ras, induces breast cell invasion. A crucial link between lipid rafts and H-Ras function has been suggested. This study sought to identify the lipid raft protein(s) responsible for H-Ras-induced tumorigenicity and invasiveness of breast cancer. We conducted a comparative proteomic analysis of lipid raft proteins from invasive MCF10A human breast epithelial cells engineered to express active H-Ras and non-invasive cells expressing active N-Ras. Here, we identified a lipid raft protein flotillin-1 as an important regulator of H-Ras activation and breast cell invasion. Flotillin-1 was required for epidermal growth factor-induced activation of H-Ras, but not that of N-Ras, in MDA-MB-231 triple-negative breast cancer (TNBC) cells. Flotillin-1 knockdown inhibited the invasiveness of MDA-MB-231 and Hs578T TNBC cells in vitro and in vivo. In xenograft mouse tumor models of these TNBC cell lines, we showed that flotillin-1 played a critical role in tumor growth. Using human breast cancer samples, we provided clinical evidence for the metastatic potential of flotillin-1. Membrane staining of flotillin-1 was positively correlated with metastatic spread (p = 0.013) and inversely correlated with patient disease-free survival rates (p = 0.005). Expression of flotillin-1 was associated with H-Ras in breast cancer, especially in TNBC (p < 0.001). Our findings provide insight into the molecular basis of Ras isoform-specific interplay with flotillin-1, leading to tumorigenicity and aggressiveness of breast cancer.

Chemical inhibition of prometastatic lysyl-tRNA synthetase-laminin receptor interaction.

Lysyl-tRNA synthetase (KRS), a protein synthesis enzyme in the cytosol, relocates to the plasma membrane after a laminin signal and stabilizes a 67-kDa laminin receptor (67LR) that is implicated in cancer metastasis; however, its potential as an antimetastatic therapeutic target has not been explored. We found that the small compound BC-K-YH16899, which binds KRS, impinged on the interaction of KRS with 67LR and suppressed metastasis in three different mouse models. The compound inhibited the KRS-67LR interaction in two ways. First, it directly blocked the association between KRS and 67LR. Second, it suppressed the dynamic movement of the N-terminal extension of KRS and reduced membrane localization of KRS. However, it did not affect the catalytic activity of KRS. Our results suggest that specific modulation of a cancer-related KRS-67LR interaction may offer a way to control metastasis while avoiding the toxicities associated with inhibition of the normal functions of KRS.

Characteristics of thyroid nodules causing globus symptoms.

A globus sensation is one of the most common complaints in otolaryngologic clinics, and laryngopharyngeal reflux is the most common cause. However, thyroid nodules also can cause globus symptoms. The purpose of this study was to identify the characteristics of thyroid nodules that cause globus. We selected patients prospectively with a single thyroid nodule on ultrasonograms. Patients with other causes of globus symptoms were excluded using questionnaires, fiber optic laryngoscopic examinations, and a psychiatric screening tool. In total, 175 patients were enrolled. Patients were divided into two groups according to globus symptoms. Ultrasonographic characteristics and clinicopathological parameters were compared between the groups. Among various clinicopathologic and ultrasonographic parameters, size and horizontal location of the thyroid nodule showed significant differences between the groups. Nodules larger than 3 cm and those located anterior to the trachea had a tendency to cause globus symptoms. Regarding horizontal location, nodules that all parts were located anterior to the trachea showed a higher tendency to cause globus symptoms than nodules that only some parts were located anterior to the trachea. In conclusion, thyroid nodules with specific size and location can cause globus symptoms, and this finding can be indicated in patient counseling. Also, conservative treatments or thyroidectomy may be helpful in relieving patients' globus symptoms.

Reactive oxygen species induce the association of SHP-1 with c-Src and the oxidation of both to enhance osteoclast survival.

Loss of ovarian function causes oxidative stress as well as bone loss. We hypothesized that reactive oxygen species (ROS) induced by the failure of ovarian function are responsible for the bone loss by increasing the number of osteoclasts (OC). We found that ROS enhanced OC survival via Src homology 2 domain-containing phosphatase-1 (SHP-1), c-Src, Akt, and ERK. ROS induced the association of SHP-1 with c-Src as well as the oxidation of c-Src and SHP-1. This resulted in inactivation of SHP-1 and activation of c-Src via phosphorylation of Tyr(416). Knockdown of c-Src or SHP-1 abolished the effect of ROS on OC survival. Moreover, downregulation of SHP-1 upregulated activation of c-Src, Akt, and ERK in the absence of any stimulus, suggesting that inactivation of SHP-1 is required for OC survival. We demonstrated that the association and oxidation of c-Src and SHP-1 by ROS are key steps in enhancing OC survival, which are responsible for increased bone loss when ovarian function ceases.

Host-specific growth responses of Larix kaempferi and Quercus acutissima to Asian gypsy moth defoliation in central Korea.

As the risk of gypsy moth outbreaks that have detrimental effects on forest ecosystem in the Northern Hemisphere increase due to climate change, a quantitative evaluation of the impact of gypsy moth defoliation is needed to support the adaptive forest management. To evaluate the host-specific impact of gypsy moth defoliation, radial growth and annual carbon accumulation were compared for one severely defoliated (Larix kaempferi (Lamb.) Carrière) and one moderate defoliated (Quercus acutissima Carruth.) host, in defoliated and non-defoliated site using tree-ring analysis. Finally, the resilience indices of radial growth variables were calculated to assess the ability of sampled trees to withstand defoliation. Gypsy moth defoliation mainly decreased latewood width and caused reduction in annual carbon absorption more than 40% for both tree species. However, L. kaempferi, showed the reduced growth until the year following defoliation, while Q. acutissima, showed no lagged growth depression and rapid growth recover. The findings show how each species reacts differently to gypsy moth defoliation and highlight the need of managing forests in a way that takes resilient tree species into account.

ANXA2 (annexin A2) is crucial to ATG7-mediated autophagy, leading to tumor aggressiveness in triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is associated with a poor prognosis and metastatic growth. TNBC cells frequently undergo macroautophagy/autophagy, contributing to tumor progression and chemotherapeutic resistance. ANXA2 (annexin A2), a potential therapeutic target for TNBC, has been reported to stimulate autophagy. In this study, we investigated the role of ANXA2 in autophagic processes in TNBC cells. TNBC patients exhibited high levels of ANXA2, which correlated with poor outcomes. ANXA2 increased LC3B-II levels following bafilomycin A1 treatment and enhanced autophagic flux in TNBC cells. Notably, ANXA2 upregulated the phosphorylation of HSF1 (heat shock transcription factor 1), resulting in the transcriptional activation of ATG7 (autophagy related 7). The mechanistic target of rapamycin kinase complex 2 (MTORC2) played an important role in ANXA2-mediated ATG7 transcription by HSF1. MTORC2 did not affect the mRNA level of ANXA2, but it was involved in the protein stability of ANXA2. HSPA (heat shock protein family A (Hsp70)) was a potential interacting protein with ANXA2, which may protect ANXA2 from lysosomal proteolysis. ANXA2 knockdown significantly increased sensitivity to doxorubicin, the first-line chemotherapeutic regimen for TNBC treatment, suggesting that the inhibition of autophagy by ANXA2 knockdown may overcome doxorubicin resistance. In a TNBC xenograft mouse model, we demonstrated that ANXA2 knockdown combined with doxorubicin administration significantly inhibited tumor growth compared to doxorubicin treatment alone, offering a promising avenue to enhance the effectiveness of chemotherapy. In summary, our study elucidated the molecular mechanism by which ANXA2 modulates autophagy, suggesting a potential therapeutic approach for TNBC treatment.Abbreviation: ATG: autophagy related; ChIP: chromatin-immunoprecipitation; HBSS: Hanks' balanced salt solution; HSF1: heat shock transcription factor 1; MTOR: mechanistic target of rapamycin kinase; TNBC: triple-negative breast cancer; TFEB: transcription factor EB; TFE3: transcription factor binding to IGHM enhancer 3.

Sphingosine 1-phosphate regulates matrix metalloproteinase-9 expression and breast cell invasion through S1P3-Gαq coupling.

Recent evidence suggests that inflammation is involved in malignant progression of breast cancer. Sphingosine 1-phosphate (S1P), acting on the G-protein-coupled receptors, is known as a potent inflammatory mediator. In this study, the effect of the inflammatory lipid S1P on the regulation of invasive/migratory phenotypes of MCF10A human breast epithelial cells was investigated to elucidate a causal relationship between inflammation and the control of invasiveness of breast cells. We show that S1P causes induction of matrix metalloproteinase-9 (MMP-9) in vitro and in vivo, and thus enhances invasion and migration. We also show that fos plays a crucial role in the transcriptional activation of MMP-9 by S1P. In addition, activation of extracellular-signal-regulated kinases 1 and 2 (ERK1/2), p38 and alpha serine/threonine-protein kinase (Akt) are involved in the process of S1P-mediated induction of MMP-9 expression and invasion. Activation of the S1P receptor S1P3 and G(αq) are required for S1P-induced invasive/migratory responses, suggesting that the enhancement of S1P-mediated invasiveness is triggered by the specific coupling of S1P3 to the heterotrimeric G(αq) subunit. Activation of phospholipase C-ß4 and intracellular Ca²âº release are required for S1P-induced MMP-9 upregulation. Taken together, this study demonstrated that S1P regulates MMP-9 induction and invasiveness through coupling of S1P3 and G(αq) in MCF10A cells, thus providing a molecular basis for the crucial role of S1P in promoting breast cell invasion.

Occurrence of disinfection by-products in tap water distribution systems and their associated health risk.

The concentrations of trihalomethanes (THMs), including chloroform, bromodichloromethane, dibromochloromethane, and bromoform, and haloacetic acids (HAAs; monochloroacetic acid, monobromoacetic acid, dibromoacetic acid, dichloroacetic acid, and trichloroacetic acid) were measured in tap waters passing through water distribution systems of six water treatment plants in Seoul, Korea, and their associated health risks from exposure to THMs through ingestion, dermal contact, and inhalation were estimated using a probabilistic approach. The concentration ranges for total THMs and HAA5 were 3.9-53.5 and

C-Reactive Protein Signaling Pathways in Tumor Progression.

Many cancers arise from sites of chronic inflammation, which creates an inflammatory microenvironment surrounding the tumor. Inflammatory substances secreted by cells in the inflammatory environment can induce the proliferation and survival of cancer cells, thereby promoting cancer metastasis and angiogenesis. Therefore, it is important to identify the role of inflammatory factors in cancer progression. This review summarizes the signaling pathways and roles of C-reactive protein (CRP) in various cancer types, including breast, liver, renal, and pancreatic cancer, and the tumor microenvironment. Mounting evidence suggests the role of CRP in breast cancer, particularly in triple-negative breast cancer (TNBC), which is typically associated with a worse prognosis. Increased CRP in the inflammatory environment contributes to enhanced invasiveness and tumor formation in TNBC cells. CRP promotes endothelial cell formation and angiogenesis and contributes to the initiation and progression of atherosclerosis. In pancreatic and kidney cancers, CRP contributes to tumor progression. In liver cancer, CRP regulates inflammatory responses and lipid metabolism. CRP modulates the activity of various signaling molecules in macrophages and monocytes present in the tumor microenvironment, contributing to tumor development, the immune response, and inflammation. In the present review, we overviewed the role of CRP signaling pathways and the association between inflammation and cancer in various types of cancer. Identifying the interactions between CRP signaling pathways and other inflammatory mediators in cancer progression is crucial for understanding the complex relationship between inflammation and cancer.