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Bladder cancer poses a significant challenge to chemotherapy due to its resistance to cisplatin, especially at advanced stages. Understanding the mechanisms behind cisplatin resistance is crucial for improving cancer therapy. The enzyme glutathione S-transferase omega class 1 (GSTO1) is known to be involved in cisplatin resistance in colon cancer. This study focused on its role in cisplatin resistance in bladder cancer. Our analysis of protein expression in bladder cancer cells stimulated by secretions from tumor-associated macrophages (TAMs) showed a significant increase in GSTO1. This prompted further investigation into the role of GSTO1 in bladder cancer. We found a strong correlation between GSTO1 expression and cisplatin resistance. Mechanistically, GSTO1 triggered the release of large extracellular vesicles (EVs) that promoted cisplatin efflux, thereby reducing cisplatin-DNA adduct formation and enhancing cisplatin resistance. Inhibition of EV release effectively counteracted the cisplatin resistance associated with GSTO1. In conclusion, GSTO1-mediated EV release may contribute to cisplatin resistance caused by TAMs in bladder cancer. Strategies to target GSTO1 could potentially improve the efficacy of cisplatin in treating bladder cancer., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here, we identify a disintegrin and metalloproteinase domain (ADAM)9 as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor 1 (PAI-1), which functions as a selective autophagy receptor in conjunction with light chain 3 (LC3), triggering lysosomal degradation of KRAS. Suppression of ADAM9 by a small-molecule inhibitor restricts disease progression in spontaneous models, and combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

This study aimed to evaluate the efficacy of Lactobacillus delbrueckii ssp. bulgaricus ( L. bulgaricus ) in improving body weight, obesity-related outcomes, and lipid profiles of overweight people. Thirty-six overweight participants were randomly assigned to either a probiotic or a placebo group. A placebo powder or L. bulgaricus powder (containing 1 × 10 8 colony-forming unit (CFU) of the probiotic) was administered daily for 12 weeks. Body composition was determined, and blood tests were performed before and after the intervention. L. bulgaricus supplementation under the present condition did not affect the body weight, fat percentage, or body mass index (BMI) of the participants, while it resulted in a notable decrease in blood triglyceride (TG) levels, which corresponded to a lowering of the TG proportion in the composition of large VLDL (L-XXL sized fractions) and HDL (M and L fractions) in the probiotic-treated group. These results suggest that L. bulgaricus supplementation under the current conditions may not be helpful for losing weight, but it has the potential to decrease blood TG levels by modulating TG accumulation in or transport by VLDL/HDL in obese patients. L. bulgaricus supplements may have health-promoting properties in preventing TG-related diseases in overweight people.

The present study investigated the potential anti-obesity properties of Citrus depressa Hayata (CDH) juice in HBV transgenic mice, as well as the impact of fermentation on the effectiveness of the juice. The results revealed that fermentation increased the levels of polyphenols and hesperidin in CDH juice. The animal study demonstrated that both juices were effective in mitigating the weight gain induced by a high-fat diet by correcting metabolic parameter imbalances, reducing hepatic lipid accumulation, and reversing hepatic immune suppression. Furthermore, fermented juice exhibited superior efficacy in managing body weight and inhibiting the expansion of white adipose tissue (WAT). Fermented juice significantly enhanced adiponectin production and PPARγ expression in WAT, while also reducing hypertrophy. This study offers valuable insights into the potential role of CDH juices in combating obesity associated with high fat consumption and underscores the promise of CDH juice as a functional beverage., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Objectives: This study aimed to analyze the possible causes of changes in cardiac function and investigate the feasibility of clinical assessment of gastrointestinal cancer in patients with or without acute kidney injury (AKI) assessed using a non-invasive impedance cardiography (ICG, Bioz. Cardio Dynamics, USA) to identify independent risk factors., Methods: Patients admitted to the Fourth Hospital of Hebei Medical University, China, between May 1, 2019, and February 15, 2022, were included in this study. A total of 51 patients with gastrointestinal cancer (31 men and 20 women, mean age 61.1 ± 10.9 years) with or without AKI were evaluated for ICG. A total of 19 patients underwent ultrasound cardiography (UCG) and ICG evaluations., Result: There was a significant positive correlation between cardiac output (CO), cardiac index (CI), stroke volume (SV), left cardiac work index (LCWI), and ejection fraction (EF) measured using UCG and ICG. The relationship was observed between CO ICG and CO UCG (r = 0.707, P = 0.001), CI ICG and CI UCG (r = 0.718, P = 0.001), SV ICG and SV UCG (r = 0.837, P < 0.001), and LCWI ICG and EF UCG (r = 0.540, P = 0.017). Cardiac function parameters measured using ICG were statistically different between patients with gastrointestinal cancer with or without AKI (P ≤ 0.05). Multivariate analysis revealed that AKI independently affects cardiac function in patients with gastrointestinal cancer., Conclusions: UCG and ICG methods are significantly associated with cardiac function in patients with or without AKI, and patients with gastrointestinal cancer with AKI are worse than those without AKI. AKI is an independent risk factor for cardiac function in patients with gastrointestinal cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: To evaluate the effect of the weighting of input imaging combo and ADC threshold on the performance of the U-Net and to find an optimized input imaging combo and ADC threshold in segmenting acute ischemic stroke (AIS) lesion., Methods: This study retrospectively enrolled a total of 212 patients having AIS. Four combos, including ADC-ADC-ADC (AAA), DWI-ADC-ADC (DAA), DWI-DWI-ADC (DDA), and DWI-DWI-DWI (DDD), were used as input images, respectively. Three ADC thresholds including 0.6, 0.8 and 1.8 × 10 -3 mm 2 /s were applied. Dice similarity coefficient (DSC) was used to evaluate the segmentation performance of U-Nets. Nonparametric Kruskal-Wallis test with Tukey-Kramer post-hoc tests were used for comparison. A p < .05 was considered statistically significant., Results: The DSC significantly varied among different combos of images and different ADC thresholds. Hybrid U-Nets outperformed uniform U-Nets at ADC thresholds of 0.6 × 10 -3 mm 2 /s and 0.8 × 10 -3 mm 2 /s (p < .001). The U-Net with imaging combo of DDD had segmentation performance similar to hybrid U-Nets at an ADC threshold of 1.8 × 10 -3 mm 2 /s (p = .062 to 1). The U-Net using the imaging combo of DAA at the ADC threshold of 0.6 × 10 -3 mm 2 /s achieved the highest DSC in the segmentation of AIS lesion., Conclusions: The segmentation performance of U-Net for AIS varies among the input imaging combos and ADC thresholds. The U-Net is optimized by choosing the imaging combo of DAA at an ADC threshold of 0.6 × 10 -3 mm 2 /s in segmentating AIS lesion with highest DSC., Key Points: • Segmentation performance of U-Net for AIS differs among input imaging combos. • Segmentation performance of U-Net for AIS differs among ADC thresholds. • U-Net is optimized using DAA with ADC = 0.6 × 10 -3 mm 2 /s., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Rationale: To investigate the clinical efficacy of the axillary approach in the surgical treatment of Ideberg type I and II scapular glenoid fractures., Patient Concerns and Diagnosis: Retrospective analysis of 13 cases of scapular glenoid fracture treated in the affiliated Hospital of Jining Medical College, Jiaxiang County People hospital, Zoucheng City people Hospital, Yanzhou District People Hospital, and Juancheng County people Hospital from December 2020 to January 2022. Eight males (including 1 bilateral) and 5 females, with an average age of 57.5 years (range from 33 to 75 years). According to Ideberg classification, there were 10 cases of type I a, 1 case of type I a combined with type I b, and 2 cases of type II. All patients were treated with axillary approach surgery and 7 patients with combined anterior shoulder dislocation were treated by first-stage manipulation and second-stage reoperation. Seven patients were fixed with a wire anchor, 3 patients with type I a were fixed with a "T" plate, and 5 patients were complicated with rotator cuff tear and were repaired with a wire anchor. At the last follow-up, the Constant-Murley shoulder function score, visual analog score, DASH score, and Hawkins grade were used to evaluate shoulder function, pain, and stability after treatment., Intervention: The intervention was to treat patients with Ideberg type I and II scaphoid fractures using an axillary approach., Outcomes: All 13 patients in this group were followed up thoroughly, and the follow-up time was 12 to 25 months, with an average of 18.6 months. The operation time was 65 to 135 minutes, with an average of 85.6 minutes. Intraoperative blood loss ranged from 20 to 120 mL, averaging 55.6 mL. The duration of hospitalization ranged from 7 to 22 days, with an average of 9.6 days. The surgical incisions of all patients were grade-A healing. Bone healing of glenoid fractures was observed 3 months after the operation., Lessons: The axillary approach for Ideberg type I and II scapular glenoid fractures is a feasible surgical approach with complete access through the muscle gap, minimal surgical trauma, mild postoperative pain, and satisfactory clinical results., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Globally, breast cancer is the most common cause of cancer deaths. In Taiwan, it is the most prevalent cancer among females. Since San-Huang-Xie-Xin-Tang (SHXXT) exerts not only an anti-inflammatory but an immunomodulatory effect, it may act as a potent anti-tumor agent. Herein, the study aimed to explore the influence of SHXXT and its constituents on the mortality rate among breast cancer patients in Taiwan regarding the component effect and the dose-relationship effect. By using the Taiwan National Health Insurance (NHI) Research Database (NHIRD), the study analyzed 5387 breast cancer patients taking Chinese herbal medicine (CHM) and 5387 breast cancer patients not using CHM. CHM means SHXXT and its constituents in the study. The Kaplan-Meier method was utilized to determine the mortality probabilities among patients. Whether the CHM influences the mortality rate among patients was estimated by Cox proportional hazard regression analysis. The use of CHM could lower the cancer mortality rate by 59% in breast cancer patients. The protective effect was parallel to the cumulative days of CHM use and the annual average CHM dose. In addition, the mortality rate was lower in patients who used SHXXT compared to those who only used one of its constituents. SHXXT and its constituents were all promising therapeutic weapons against breast cancer.

Deep learning allows automatic segmentation of teeth on cone beam computed tomography (CBCT). However, the segmentation performance of deep learning varies among different training strategies. Our aim was to propose a 3.5D U-Net to improve the performance of the U-Net in segmenting teeth on CBCT. This study retrospectively enrolled 24 patients who received CBCT. Five U-Nets, including 2Da U-Net, 2Dc U-Net, 2Ds U-Net, 2.5Da U-Net, 3D U-Net, were trained to segment the teeth. Four additional U-Nets, including 2.5Dv U-Net, 3.5Dv5 U-Net, 3.5Dv4 U-Net, and 3.5Dv3 U-Net, were obtained using majority voting. Mathematical morphology operations including erosion and dilation (E&D) were applied to remove diminutive noise speckles. Segmentation performance was evaluated by fourfold cross validation using Dice similarity coefficient (DSC), accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV). Kruskal-Wallis test with post hoc analysis using Bonferroni correction was used for group comparison. P < 0.05 was considered statistically significant. Performance of U-Nets significantly varies among different training strategies for teeth segmentation on CBCT (P < 0.05). The 3.5Dv5 U-Net and 2.5Dv U-Net showed DSC and PPV significantly higher than any of five originally trained U-Nets (all P < 0.05). E&D significantly improved the DSC, accuracy, specificity, and PPV (all P < 0.005). The 3.5Dv5 U-Net achieved highest DSC and accuracy among all U-Nets. The segmentation performance of the U-Net can be improved by majority voting and E&D. Overall speaking, the 3.5Dv5 U-Net achieved the best segmentation performance among all U-Nets., (© 2022. The Author(s).)

Introduction: Gastric cancer (GCa) is a malignancy with few effective treatments. Ursolic acid (UA), a bioactive triterpenoid enriched in Hedyotis diffusa Willd, known to suppress GCa without identified target. CYP19A1 (cytochrome P450 family 19A1; also known as aromatase, Ar) was correlated to GCa prognosis. Relatedly, Ar silencers, which halt the expression of Ar exhibited anti-GCa effects in experimental models, are currently being investigated., Method: The docking simulation score of UA was compared with Ar inhibitors, e.g., letrozole, exemestane, in Ar protein crystallization. Hedyotis diffusa Willd ethanol extract, UA, or 5-fluracil were applied onto AGS, SC-M1, MKN45 GCa cells for cancer inhibition tests. Immunoblot for measuring gene expressions upon drug treatments, or gene knockdown/overexpression. Treatments were also applied in a MKN45 implantation tumor model. A web-based GCa cohort for Ar expression association with prognosis was performed., Result: The ethanol extracts of Hedyotis diffusa Willd, enrich with UA, exhibited cytotoxic activity against GCa cells. Molecular docking simulations with the 3D Ar structure revealed an excellent fitting score for UA. UA increase cytotoxic, and suppressed colony, in addition to its Ar silencing capacity. Moreover, UA synergistically facilitated 5-FU, (a standard GCa treatment) regimen in vitro. Consistent with those results, adding estradiol did not reverse the cancer-suppressing effects of UA, which confirmed UA acts as an Ar silencer. Furthermore, UA exhibited tumor-suppressing index (TSI) score of 90% over a 6-week treatment term when used for single dosing in xenograft tumor model. In the clinical setting, Ar expression was found to be higher in GCa tumors than normal parental tissue from the TCGA (The Cancer Genome Atlas) cohort, while high Ar expression associated with poor prognosis. Together, the results indicate UA could be used to treat GCa by silencing Ar expression in GCa. Hedyotis diffusa Willd ethanol extract could be an functional food supplements., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aurora A kinase (Aurora A) is a serine/threonine kinase regulating control of multiple events during cell-cycle progression. Playing roles in promoting proliferation and inhibiting cell death in cancer cells leads Aurora A to become a target for cancer therapy. It is overexpressed and associated with a poor prognosis in ovarian cancer. Improving cisplatin therapy outcomes remains an important issue for advanced-stage ovarian cancer treatment, and Aurora A inhibitors may improve it. In the present study, we identified natural compounds with higher docking scores than the known Aurora A ligand through structure-based virtual screening, including the natural compound fangchinoline, which has been associated with anticancer activities but not yet investigated in ovarian cancer. The binding and inhibition of Aurora A by fangchinoline were verified using cellular thermal shift and enzyme activity assays. Fangchinoline reduced viability and proliferation in ovarian cancer cell lines. Combination fangchinoline and cisplatin treatment enhanced cisplatin-DNA adduct levels, and the combination index revealed synergistic effects on cell viability. An in vivo study showed that fangchinoline significantly enhanced cisplatin therapeutic effects in OVCAR-3 ovarian cancer-bearing mice. Fangchinoline may inhibit tumor growth and enhance cisplatin therapy in ovarian cancer. This study reveals a novel Aurora A inhibitor, fangchinoline, as a potentially viable adjuvant for ovarian cancer therapy.

Background and Aim: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters cells through the binding of the viral spike protein with human angiotensin-converting enzyme 2 (ACE2), resulting in the development of coronavirus disease 2019 (COVID-19). To date, few antiviral drugs are available that can effectively block viral infection. This study aimed to identify potential natural products from Taiwan Database of Extracts and Compounds (TDEC) that may prevent the binding of viral spike proteins with human ACE2 proteins., Methods: The structure-based virtual screening was performed using the AutoDock Vina program within PyRX software, the binding affinities of compounds were verified using isothermal titration calorimetry (ITC), the inhibitions of SARS-CoV-2 viral infection efficacy were examined by lentivirus particles pseudotyped (Vpp) infection assay, and the cell viability was tested by 293T cell in MTT assay., Results and Conclusion: We identified 39 natural products targeting the viral receptor-binding domain (RBD) of the SARS-CoV-2 spike protein in silico . In ITC binding assay, dioscin, celastrol, saikosaponin C, epimedin C, torvoside K, and amentoflavone showed dissociation constant ( K d ) = 0.468 μM, 1.712 μM, 6.650 μM, 2.86 μM, 3.761 μM and 4.27 μM, respectively. In Vpp infection assay, the compounds have significantly and consistently inhibition with the 50-90% inhibition of viral infection efficacy. In cell viability, torvoside K, epimedin, amentoflavone, and saikosaponin C showed IC 50  > 100 μM; dioscin and celastrol showed IC 50  = 1.5625 μM and 0.9866 μM, respectively. These natural products may bind to the viral spike protein, preventing SARS-CoV-2 from entering cells., Section 1: Natural Products., Taxonomy Classification by Evise: SARS-CoV-2, Structure-Based Virtual Screening, Isothermal Titration Calorimetry and Lentivirus Particles Pseudotyped (Vpp) Infection Assay, in silico and in vitro study ., Competing Interests: Author Shu-Ting Chan was employed by the company TCI CO., Ltd., Taiwan. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2021 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC.)

Aurora kinase A (AURKA) carries out an essential role in proliferation and involves in cisplatin resistance in various cancer cells. Overexpression of AURKA is associated with the poor prognosis of cancer patients. Thus, AURKA has been considered as a target for cancer therapy. Developing AURKA inhibitors became an important issue in cancer therapy. A natural compound emodin mainly extracted from rhubarbs possesses anti-cancer properties. However, the effect of emodin on AURKA has never been investigated. In the present study, molecular docking analysis indicated that emodin interacts with AURKA protein active site. We also found nine emodin analogues from Key Organic database by using ChemBioFinder software. Among that, one analogue 8L-902 showed a similar anti-cancer effect as emodin. The bindings of emodin and 8L-902 on AURKA protein were confirmed by cellular thermal shift assay. Furthermore, emodin inhibited the AURKA kinase activity in vitro and enhanced the cisplatin-DNA adduct level in a resistant ovarian cancer cell line. It seems that emodin may have the potential to inhibit cancer cell growth and enhance cisplatin therapy in cancer with resistance. Collectively, our finding reveals a novel AURKA inhibitor, emodin, which may be vulnerable to ovarian cancer therapy in the future., (© 2021 John Wiley & Sons A/S.)

An innovative wireless device for bioimpedance analysis was developed for post-dual-site free vascularized lymph node transfer (VLNT) evaluation. Seven patients received dual-site free VLNT for unilateral upper or lower limb lymphedema. A total of 10 healthy college students were enrolled in the healthy control group. The device was applied to the affected and unaffected limbs to assess segmental alterations in bioimpedance. The affected proximal limb showed a significant increase in bioimpedance at postoperative sixth month (3.3 [2.8, 3.6], p = 0.001) with 10 kHz currents for better penetration, although the difference was not significant (3.3 [3.3, 3.8]) at 1 kHz. The bioimpedance of the affected distal limb significantly increased after dual-site free VLNT surgery, whether passing with the 1 kHz (1.6 [0.7, 3.4], p = 0.030, postoperative first month; 2.8 [1.0, 4.2], p = 0.027, postoperative third month; and 1.3 [1.3, 3.4], p = 0.009, postoperative sixth month) or 10 kHz current ((1.4 [0.5, 2.7], p = 0.049, postoperative first month; 3.2 [0.9, 6.3], p = 0.003, postoperative third month; and 3.6 [2.5, 4.1], p < 0.001, postoperative sixth month). Bioimpedance alterations on the affected distal limb were significantly correlated with follow-up time ( rho = 0.456, p = 0.029 detected at 10 kHz). This bioimpedance wireless device could quantitatively monitor the interstitial fluid alterations, which is suitable for postoperative real-time surveillance.

Methadone maintenance treatment (MMT) remains the cornerstone for the management of opiate abuse. However, MMT can be associated with complex factors, including complications during the tolerance phase, the inability of some patients to maintain treatment effects during the tapering or abstinence phases, and the development of methadone dependence. Previous studies have revealed a sex disparity in MMT efficacy, showing that women undergoing MMT experiencing an increase in psychological symptoms compared with men and suggesting a link between disparate responses and the effects of estrogen signaling on methadone metabolism. More specifically, estradiol levels are positively associated with MMT dosing, and the expression of a single-nucleotide polymorphism (SNP) associated with estrogen receptor (ER) regulation is also associated with MMT dosing. In addition to performing mechanistic dissections of estrogen signaling in the presence of methadone, past studies have also proposed the targeting of estrogen signaling during MMT. The present report provides an overview of the relevant literature regarding sex effects, including differences in sex hormones and their potential impacts on MMT regimens. Moreover, this article provides a pharmacological perspective on the targeting of estrogen signals through the use of selective ER modulators (SERMs) during MMT. Preliminary preclinical experiments were also performed to evaluate the potential effects of targeting estrogen signaling with tamoxifen on methadone metabolism., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Huang, Chiang, Chang, Su, Yang, Cheng, Lane, Ho and Ma.)

With the continuing rise of lipidomic studies, there is an urgent need for a useful and comprehensive tool to facilitate lipidomic data analysis. The most important features making lipids different from general metabolites are their various characteristics, including their lipid classes, double bonds, chain lengths, etc. Based on these characteristics, lipid species can be classified into different categories and, more interestingly, exert specific biological functions in a group. In an effort to simplify lipidomic analysis workflows and enhance the exploration of lipid characteristics, we have developed a highly flexible and user-friendly web server called LipidSig. It consists of five sections, namely, Profiling, Differential Expression, Correlation, Network and Machine Learning, and evaluates lipid effects on cellular or disease phenotypes. One of the specialties of LipidSig is the conversion between lipid species and characteristics according to a user-defined characteristics table. This function allows for efficient data mining for both individual lipids and subgroups of characteristics. To expand the server's practical utility, we also provide analyses focusing on fatty acid properties and multiple characteristics. In summary, LipidSig is expected to help users identify significant lipid-related features and to advance the field of lipid biology. The LipidSig webserver is freely available at http://chenglab.cmu.edu.tw/lipidsig., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

A highly diastereoselective method for the synthesis of novel spiro -tetrahydroquinoline derivatives is reported here, using a one-pot reaction method. All compounds were characterized by 1 H-nuclear magnetic resonance (NMR) and mass spectroscopy, and their stereo configurations were confirmed by X-ray analysis. These activities of these derivatives were then tested in human keratocyte cells. The responses of cells to treatment with selected compounds were studied using scratch analysis, and the compounds were tested in a mouse excision wound model. Three of the derivatives demonstrated significant wound-healing activities.

The aerial portions of Cynara scolymus commonly have been eaten as vegetables or functional foods by the people lived in Mediterranean region. In preliminary antioxidant screening, the rhizome portions (CSR) of this species showed better potential than leaves ones. However, neither phytochemical nor pharmacology studies of CSR have been reported to date. The purpose of this research was to identify the active components from CSR through bioassay-guided fractionation. The antioxidant properties of secondary metabolites 1 - 9 were evaluated in this investigation. Compounds 4 - 6 , 8 , and 9 showed antioxidant activities based on DPPH free radical scavenging activity with IC 50 values of 22.91-147.21 μM. Besides, compound 8 significantly and dose-dependently reduced H 2 O 2 -induced ROS levels in keratinocyte HaCaT cells without cytotoxicity toward HaCaT. Overall, our studies demonstrated the rhizome of C. scolymus could be used as a new natural antioxidant like the edible aerial portions and phenolic compounds are the active components.

Diterpenoids jolkinolide A and B, were first isolated from Euphorbia fischeriana. In our previous research, 19-(Benzyloxy)-19-oxojolkinolide B (19-BJB), a derivative of jolkinolides, was synthesized as a novel ent -abietane diterpene diepoxide. In this study, 19-BJB showed strong in vitro activity against bladder cancer cell lines. DNA damage which was observed through the interaction of 19-BJB with nucleotide chains and affected DNA repair resulted in the activation of checkpoint kinase 1 (Chk1) and checkpoint kinase 2 (Chk2) in bladder cancer cell lines. In vivo testing in nude mice also proved that 19-BJB revealed a potential inhibitory effect on tumor growth. Additionally, the 3D-QSAR models of jolkinolides were established. Briefly, we proved that 19-BJB could potentially be used as a drug to inhibit the growth of bladder tumor., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Surgical wounds are common injuries of skin and tissues and usually become a clinical problem. Until now, various synthetic and natural peptides have been widely explored as potential drug candidates for wound healing. Inhibition of the TNF-α signaling pathway and promotion of angiogenesis are suggested to be involved in their effects. Angiogenesis at the wound site is one of the essential requisites for rapid healing. In the present study, a novel peptide extract derived from the natural source Lates calcarifer , commonly known as sea bass or barramundi, was evaluated for its wound healing property. The specific acidic and enzymatic approaches were employed for producing sea bass extract containing small size peptides (molecular weight ranging from 1 kD to 5 kD). The cytotoxicity of the extract was examined in HaCaT and NIH3T3. After this, the effects of enzyme digested peptide extracts of sea bass on wound healing in mice were investigated. The peptide extracts (660 and 1320 mg/kg/day) and control protein (1320 mg/kg/day) was orally given to the wounded mice, respectively, for 12 days. The surgical method was improved by implanting a silicone ring at the wound site. The ring avoided the contracting effect in murine wounds, making it more closely related to a clinical condition. The results showed promising improvement at the wound site in mice. Sea bass peptide extracts accelerated the wound healing process and enhanced the microvessel formation at the wound site. The remarkable effects of this novel sea bass peptide extract in healing traumatic injuries revealed a new option for developing wound management.

Background/aim: Estrogen receptor α (ERα) antagonist is the most common treatment for ERα-positive breast cancer. However, compensatory signaling contributes to resistance to ERα antagonists. Thus, to explore the potential agents for targeting compensatory signaling, we screened multiple target inhibitors for breast cancer treatment., Materials and Methods: We attempted to build a structure-based virtual screening model that can find potential compounds and assay the anticancer ability of these drugs by overall cell survival assay. The downstream compensatory phosphorylated signaling was measured by immunoblotting., Results: Hamamelitannin and glucocheirolin were hits for ERα, phosphoinositide 3-kinase (PI3K), and KRAS proto-oncogene, GTPase (KRAS), which were active against estrogen and epidermal growth factor-triggered proliferation. Additionally, we select aminopterin as a hit for ERα, PI3K, KRAS, and SRC proto-oncogene, non-receptor tyrosine kinase (SRC) with inhibitory activities toward AKT serine/threonine kinase 1 (AKT) and mitogen-activated protein kinase kinase (MEK) signaling., Conclusion: Our structure-based virtual screening model selected hamamelitannin, glucocheirolin, aminopterin, and pemetrexed as compounds that may act as potential inhibitors for improving endocrine therapies for breast cancer., (Copyright© 2021, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Urothelial carcinoma (UC) is one of the highest incidence cancers that rank the fourth commonly diagnosed tumors worldwide. The unresectable lesions that are resistant to therapeutic interventions is the major cause leading to death. Previous studies had shown that the resistance and metastatic consequence may arise from cancer stem-like cells population. The phytochemical flavonoids have promised bioactivity and potent anti-carcinogenic effects, and trap great attentions for cancer chemoprevention and/or adjuvant chemotherapy. However, the mechanisms of flavonoids on cancer stemness is still obscured. In this study, we analyzed the biofunctional effects of as-prepared flavonoid derivative-WYC0209 on T24, BFTC905 and BFTC909 human UC cell lines. Our results demonstrated that WYC0209 significantly induced anti-cell viability on UC cells through decreased Akt/NFkB signaling. Moreover, WYC0209 enhanced the cell apoptosis through activated the caspase-3 activity and inactivated Bcl-xL expression. Interestingly, WYC0209 dramatically inhibited the cancer stem cells (CSCs) traits, including attenuation of side population and tumorsphere formation in which were through declined EMT-CSCs markers including MDR1, ABCG2 and BMI-1. We further validated the effects of WYC0209 on several CSC surface markers including CD133, CD44, SOX-2 and Nanog. Our results showed that WYC0209 markedly inhibited CD133 expressions in both transcriptional and translational levels. High expression levels of CD133 was also demonstrated in human upper tract UC specimens. In summary, our study showed that WYC0209 may potentially as an adjuvant agent to against CD133-driven UC CSCs and provide a beneficial strategy to against UC cancer therapeutics resistant., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Recurrence and metastasis remain the major cause of cancer mortality. Even for early-stage lung cancer, adjuvant chemotherapy yields merely slight increase to patient survival. EF-hand domain-containing protein D2 (EFHD2) has recently been implicated in recurrence of patients with stage I lung adenocarcinoma. In this study, we investigated the correlation between EFHD2 and chemoresistance in non-small cell lung cancer (NSCLC). High expression of EFHD2 was significantly associated with poor overall survival of NSCLC patients with chemotherapy in in silica analysis. Ectopic EFHD2 overexpression increased cisplatin resistance, whereas EFHD2 knockdown improved chemoresponse. Mechanistically, EFHD2 induced the production of NADPH oxidase 4 (NOX4) and in turn the increase of intracellular reactive oxygen species (ROS), consequently activating membrane expression of the ATP-binding cassette subfamily C member 1 (ABCC1) for drug efflux. Non-steroidal anti-inflammatory drug (NSAID) ibuprofen suppressed EFHD2 expression by leading to the proteasomal and lysosomal degradation of EFHD2 through a cyclooxygenase (COX)-independent mechanism. Combining ibuprofen with cisplatin enhanced antitumor responsiveness in a murine xenograft model in comparison with the individual treatment. In conclusion, we demonstrate that EFHD2 promotes chemoresistance through the NOX4-ROS-ABCC1 axis and therefore developing EFHD2-targeting strategies may offer a new avenue to improve adjuvant chemotherapy of lung cancer., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

This study aims to explore lipidic mechanism towards low-density lipoprotein receptor (LDLR)-mediated platinum chemotherapy resistance. By using the lipid profiling technology, LDLR knockdown was found to increase lysosomal lipids and decrease membranous lipid levels in EOC cells. LDLR knockdown also down-regulated ether-linked phosphatidylethanolamine (PE-O, lysosomes or peroxisomes) and up-regulated lysophosphatidylcholine [LPC, lipid droplet (LD)]. This implies that the manner of using Lands cycle (conversion of lysophospholipids) for LDs might affect cisplatin sensitivity. The bioinformatics analyses illustrated that LDLR-related lipid entry into LD, rather than an endogenous lipid resource (eg Kennedy pathway), controls the EOC prognosis of platinum chemotherapy patients. Moreover, LDLR knockdown increased the number of platinum-DNA adducts and reduced the LD platinum amount. By using a manufactured LPC-liposome-cisplatin (LLC) drug, the number of platinum-DNA adducts increased significantly in LLC-treated insensitive cells. Moreover, the cisplatin content in LDs increased upon LLC treatment. Furthermore, lipid profiles of 22 carcinoma cells with differential cisplatin sensitivity (9 sensitive vs 13 insensitive) were acquired. These profiles revealed low storage lipid levels in insensitive cells. This result recommends that LD lipidome might be a common pathway in multiple cancers for platinum sensitivity in EOC. Finally, LLC suppressed both cisplatin-insensitive human carcinoma cell training and testing sets. Thus, LDLR-platinum insensitivity can be due to a defective Lands cycle that hinders LPC production in LDs. Using lipidome assessment with the newly formulated LLC can be a promising cancer chemotherapy method., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The aim of this study was to evaluate the imaging quality and diagnostic performance of fast spin echo diffusion-weighted imaging with periodically rotated overlapping parallel lines with enhanced reconstruction (FSE-PROP-DWI) in distinguishing parotid pleomorphic adenoma (PMA) from Warthin tumor (WT). This retrospective study enrolled 44 parotid gland tumors from 34 patients, including 15 PMAs and 29 WTs with waived written informed consent. All participants underwent 1.5 T diffusion-weighted imaging including FSE-PROP-DWI and single-shot echo-planar diffusion-weighted imaging (SS-EP-DWI). After imaging resizing and registration among T2WI, FSE-PROP-DWI and SS-EP-DWI, imaging distortion was quantitatively analyzed by using the Dice coefficient. Signal-to-noise ratio and contrast-to-noise ratio were qualitatively evaluated. The mean apparent diffusion coefficient (ADC) of parotid gland tumors was calculated. Wilcoxon signed-rank test was used for paired comparison between FSE-PROP-DWI versus SS-EP-DWI. Mann-Whitney U test was used for independent group comparison between PMAs versus WTs. Diagnostic performance was evaluated by receiver operating characteristics curve analysis. P < 0.05 was considered statistically significant. The Dice coefficient was statistically significantly higher on FSE-PROP-DWI than SS-EP-DWI for both tumors (P < 0.005). Mean ADC was statistically significantly higher in PMAs than WTs on both FSE-PROP-DWI and SS-EP-DWI (P < 0.005). FSE-PROP-DWI and SS-EP-DWI successfully distinguished PMAs from WTs with an AUC of 0.880 and 0.945, respectively (P < 0.05). Sensitivity, specificity, positive predictive value, negative predictive value and accuracy in diagnosing PMAs were 100%, 69.0%, 62.5%, 100% and 79.5% for FSE-PROP-DWI, and 100%, 82.8%, 75%, 100% and 88.6% for SS-EP-DWI, respectively. FSE-PROP-DWI is useful to distinguish parotid PMAs from WTs with less distortion of tumors but lower AUC than SS-EP-DWI., (© 2020 John Wiley & Sons, Ltd.)

Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptor-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularities, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients' disease prognosis. In vitro and in vivo add-in/silencing LDLR was introduced to determine cisplatin sensitivity and cancer growth. Results revealed that knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR→LPC (Lyso-phosphatidylcholine)→FAM83B (phospholipase-related)→FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR→LPC→FAM83B→FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs. Significance: this study describes the role of LDLR in the development of insensitivity to platinum-based chemotherapy in epithelial ovarian cancer. The lipidome (e.g., LPC) and transcriptome (e.g., FAM38B) interactions revealed using trans-omics approaches an LDLR→LPC→FAM83B→FGFRs regulatory axis in cancer cells, in an animal model, and in patients.

CYP19A1/aromatase (Ar) is a prognostic biomarker of gastric cancer (GCa). Ar is a critical enzyme for converting androstenedione to oestradiol in the steroidogenesis cascade. For decades, Ar has been targeted with Ar inhibitors (ARIs) in gynaecologic malignancies; however, it is unexplored in GCa. A single-cohort tissue microarray examination was conducted to study the association between Ar expression and disease outcome in Asian patients with GCa. The results revealed that Ar was a prognostic promoter. Bioinformatics analyses conducted on a Caucasian-based cDNA microarray databank showed Ar to be positively associated with GCa prognosis for multiple clinical modalities, including surgery, 5-Fluorouracil (5-FU) for adjuvant chemotherapy, or HER2 positivity. These findings imply that targeting Ar expression exhibits a potential for fulfilling unmet medical needs. Hence, Ar-targeting compounds were tested, and the results showed that exemestane exhibited superior cancer-suppressing efficacy to other ARIs. In addition, exemestane down-regulated Ar expression. Ablating Ar abundance with short hairpin (sh)Ar could also suppress GCa cell growth, and adding 5-FU could facilitate this effect. Notably, adding oestradiol could not prevent exemestane or shAr effects, implicating a nonenzymatic mechanism of Ar in cancer growth. Regarding translational research, treatment with exemestane alone exhibited tumour suppression efficacy in a dose-dependent manner. Combining subminimal doses of 5-FU and exemestane exerted an excellent tumour suppression effect without influencing bodyweight. This study validated the therapeutic potentials of exemestane in GCa. Combination of metronomic 5-FU and exemestane for GCa therapy is recommended., (© 2019 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Currently, the use of magnetic resonance imaging (MRI) in patients with esophageal carcinoma is limited. However, the quality of MRI for esophageal carcinoma continues to improve and the importance of MRI in patients with esophageal carcinoma has been gradually recognized. Compared with endoscopic ultrasound and computed tomography applied in T and N staging, MRI has now achieved excellent results after the imaging technique has been optimized. We review the literature on MRI and discuss the future of MRI in esophageal carcinoma. While the role of MRI in staging, tumor volume target delineation and evaluation for preoperative chemoradiotherapy, prognosis and recurrence is still evolving. The application of MRI in esophageal carcinoma has a bright future and potential to improve precision of T and N staging as well as treatment delivery., (© 2019 John Wiley & Sons Australia, Ltd.)

Background: Phytochemical naphtho[1,2-b] furan-4,5‑dione (NFD) presenting in Avicennia marina exert anti-cancer effects, but little is known regarding about DNA damage-mediated apoptosis in non-small-cell lung carcinoma (NSCLC)., Purpose: To examine whether NFD-induced apoptosis of NSCLC cells is correlated with the induction of DNA damage, and to investigate its underlying mechanism., Study Design: The anti-proliferative effects of NFD were assessed by MTS Assay Kit FACS assay, and in vivo nude mice xenograft assay. The DNA damage related proteins, the Bcl-2 family and pro-apoptotic factors were examined by immunofluorescence assay, q-PCR, and western blotting. The activity of NF-κB p65 in nuclear extracts was detected using a colorimetric DNA-binding ELISA assay. The inhibitory activity of topoisomerase II (TOPO II) was evaluated by molecular docking and TOPO II catalytic assay., Results: NFD exerted selective cytotoxicity against NSCLC H1299, H1437 and A549 cells rather than normal lung-embryonated cells MRC-5. Remarkably, we found that NFD activated the hull marker and modulator of DNA damage repairs such as γ-H2AX, ATM, ATR, CHK1, and CHK2 probably caused by the accumulation of intracellular reactive oxygen species (ROS) and inhibition of TOPO II activity. Furthermore, the suppression of transcription factor NF-κB by NFD resulted in significantly decreased levels of pro-survival proteins including Bcl-2 family Bcl-2, Bcl-xL and Mcl-1 and the endogenous inhibitors of apoptosis XIAP and survivin in H1299 cells. Moreover, the nude mice xenograft assay further validated the suppression of H1299 growth by NFD, which is the first report for evaluating the anti-cancer effect of NFD in vivo., Conclusion: These findings provide a novel mechanism indicating the inhibition of TOPO II activity and NF-κB signaling by NFD, leading to DNA damage and apoptosis of NSCLC tumor cells., (Copyright © 2018. Published by Elsevier GmbH.)

Six new diterpenes, leojaponins G-L (1-6) along with 19 known compounds (7-25) were isolated from Leonurus japonicus. Their structures were elucidated by NMR, MS, IR, UV, and ECD spectroscopic data. Anti-melanogenesis assay indicated that 7 could safely and dose-dependently decrease melanin production in B16F10 melanoma cell with an IC 50 value of 59.1 μM, but moderately inhibit tyrosinase activity. Without cytotoxicities at 20 μM, compounds 11, 14, 15, and 17-21 showed significant melanogenesis stimulation activities at the percentages of 7.7-48.2. Antioxidants 19 and 24 could notably inhibit ROS production in a dose-dependent manner with percentages of 24.7-42.2 and 27.9-40.2, respectively among the concentrations of 0.16 to 100 μM. Our results demonstrated L. japonicus and its constituents could be potential botanical resources of cosmeceutical development for treatment and prevention of skin disorders., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Sphingosine-1-phosphate (S1P) is a bioactive lipid that exerts various pathophysiological functions through binding to its receptor family (S1PRs). Since first report of the breast cancer (BCA) promoting function by S1P production (through the function of sphingosine kinases) and S1P/S1PR signaling, their antagonists have never been successfully progress to clinics after three decades. Taking advantage of bioinformatics linking to gene expression to disease prognosis, we examined the impact of associated genes in BCA patients. We found high gene expressions involved in S1P anabolism suppressed disease progression of patients who are basal cell type BCA or receiving adjuvant therapy. In addition, S1PRs expression also suppressed disease progress of multiple categories of BCA patient progression. This result is contradictory to tumor promoter role of S1P/S1PRs which revealed in the literature. Further examination by directly adding S1P in BCA cells found a cell growth suppression function, which act via the expression of S1PR1. In conclusion, our study is the first evidence claiming a survival benefit function of S1P/S1PR signaling in BCA patients, which might explain the obstacle of relative antagonist apply in clinics., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Heteronemin, a marine sesterterpenoid-type natural product, possesses diverse bioactivities, especially antitumor effect. Accumulating evidence shows that heteronemin may act as a potent anticancer agent in clinical therapy. To fully understand the antitumor mechanism of heteronemin, we further explored the precise molecular targets in prostate cancer cells. Initially, heteronemin exhibited potent cytotoxic effect against LNcap and PC3 prostate cancer cells with IC 50 1.4 and 2.7 &mu;M after 24 h, respectively. In the xenograft animal model, the tumor size was significantly suppressed to about 51.9% in the heteronemin-treated group in comparison with the control group with no significant difference in the mice body weights. In addition, the results of a cell-free system assay indicated that heteronemin could act as topoisomerase II (topo II) catalytic inhibitor through the elimination of essential enzymatic activity of topoisomerase II&alpha; expression. We found that the use of heteronemin-triggered apoptosis by 20.1⁻68.3%, caused disruption of mitochondrial membrane potential (MMP) by 66.9⁻99.1% and promoted calcium release by 1.8-, 2.0-, and 2.1-fold compared with the control group in a dose-dependent manner, as demonstrated by annexin-V/PI, rhodamine 123 and Fluo-3 staining assays, respectively. Moreover, our findings indicated that the pretreatment of LNcap cells with an inhibitor of protein tyrosine phosphatase (PTPi) diminished growth inhibition, oxidative and Endoplasmic Reticulum (ER) stress, as well as activation of Chop/Hsp70 induced by heteronemin, suggesting PTP activation plays a crucial rule in the cytotoxic activity of heteronemin. Using molecular docking analysis, heteronemin exhibited more binding affinity to the N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. Finally, heteronemin promoted autophagy and apoptosis through the inhibition of Hsp 90 and topo II as well as PTP activation in prostate cancer cells. Taken together, these multiple targets present heteronemin as an interesting candidate for its future development as an antiprostatic agent.

Burning incense to worship deities is a popular religious ritual in large parts of Asia, and is a popular custom affecting more than 1.5 billion adherents. Due to incomplete combustion, burning incense has been well recognized to generate airborne hazards to human health. However, the correlation between burning incense and lung cancer in epidemiological studies remains controversy. Therefore, we speculated that some unknown materials in incense smoke are involved in the initiation or progression of lung cancer. Based on this hypothesis, we identified a major compound auramine O (AuO) from the water-soluble fraction of incense burned condensate using mass spectrometry. AuO is commonly used in incense manufacture as a colorant. Due to thermostable, AuO released from burned incenses becomes an unexpected air pollutant. AuO is classified as a Group 2B chemical by the International Agency of Research on Cancer (IARC), however, the damage of AuO to the respiratory system remains elusive. Our study revealed that AuO has no apparent effect on malignant transformation; but, it dramatically promotes lung cancer malignancy. AuO accumulates in the nucleus and induces the autophagy activity in lung tumor cells. AuO significantly enhances migration and invasive abilities and the in vitro and in vivo stemness features of lung tumor cells through activating the expression of aldehyde dehydrogenase family 1 member A1 (ALDH1A1), and ALDH1A1 knockdown attenuates AuO-induced autophagy activity and blocks AuO-induced lung tumor malignancy. In conclusion, we found that AuO, an ingredient of incense smoke, significantly increases the metastatic abilities and stemness characters of lung tumor cells through the activation of ALDH1A1, which is known to be associated with poor outcome and progression of lung cancer. For public health, reducing or avoiding the use of AuO in incense is recommended., (© 2017 The Authors Environmental Toxicology Published by Wiley Periodicals, Inc.)

The stability of a pressure driven flow in a duct heated from below and subjected to a vertical magnetic field (Hunt-Rayleigh-Bénard flow) is studied. We use the Chebyshev collocation approach to solve the eigenvalue problem for the small-amplitude perturbations. It is demonstrated that the magnetic field can stabilize the flow, while the temperature field can disturb the flow. There exists a threshold for the Hartmann number below which the growth rate changes with the Prandtl number non-monotonously (first increases and then decreases) with a critical Prandtl number for the maximum growth rate. By comparing the [Formula: see text] neutral curves at different Rayleigh numbers, we find that the critical Reynolds number decreases with the increase in the Rayleigh number, which has an obvious influence on the long-wave instability and a little influence on the short-wave instability. The dominant mode of the long-wave instability changes from the boundary layer instability to the inflectional instability with the increase in the growth rate, which forms a new flow map. We also compare the [Formula: see text] curves and find that the critical Rayleigh number decreases with the increase in the Reynolds number. The obtained results gain an insight into the flow stability affected by the temperature field and the magnetic field.

Six new and 16 known lanostanoids were isolated from the sclerotia of Poria cocos. The structures of the new isolates were elucidated to be 16α-hydroxy-3-oxo-24-methyllanosta-5,7,9(11),24(31)-tetraen-21-oic acid (1), 3β,16α,29-trihydroxy-24-methyllanosta-7,9(11),24(31)-trien-21-oic acid (2), 3β,16α,30-trihydroxy-24-methyllanosta-7,9(11),24(31)-trien-21-oic acid (3), 3β-acetoxy-16α,24β-dihydroxylanosta-7,9(11),25-trien-21-oic acid (4), 3β,16α-dihydroxy-7-oxo-24-methyllanosta-8,24(31)-dien-21-oic acid (5), and 3α,16α-dihydroxy-7-oxo-24-methyllanosta-8,24(31)-dien-21-oic acid (6), based on extensive spectroscopic analyses. The absolute configuration of 4 was determined using Mosher's method. The antiproliferative activity of the isolated compounds (except 3 and 4) was evaluated against four leukemic cell lines (Molt 4, CCRF-CEM, HL 60, and K562). Dehydropachymic acid (9), dehydroeburicoic acid (12), pachymic acid (14), and lanosta-7,9(11),24-trien-21-oic acid (20) exhibited an antiproliferative effect on the CCRF-CEM cancer cell line with IC 50 values of 2.7, 6.3, 4.9, and 13.1 μM, respectively. Both dehydropachymic acid (9) and dehydroeburicoic acid (12) showed antiproliferative effects against Molt 4 (IC 50 13.8 and 14.3 μM) and HL 60 (IC 50 7.3 and 6.0 μM) leukemic cell lines. Primary computational analysis using a chemical global positioning system for natural products (ChemGPS-NP) on the active lanostanoids from P. cocos suggested that targets other than topoisomerases may be involved in the antiproliferative activity.

Two new scalarane sesterterpenoids, 12β-(3'β-hydroxybutanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (1) and 12β-(3'β-hydroxypentanoyloxy)-20,24-dimethyl-24-oxo-scalara-16-en-25-al (2), along with one known tetraprenyltoluquinol-related metabolite (3), were isolated from the sponge Carteriospongia sp. In leukemia Molt 4 cells, 1 at 0.0625 μg/mL (125 nM) triggered mitochondrial membrane potential (MMP) disruption and apoptosis showing more potent effect than 2 and 3. The isolates inhibited topoisomerase IIα expression. The apoptotic-inducing effect of 3 was supported by the in vivo experiment through suppressing the volume of xenograft tumor growth (47.58%) compared with the control. Compound 1 apoptotic mechanism of action in Molt 4 cells was further elucidated through inducing ROS generation, calcium release and ER stress. Using the molecular docking analysis, 1 exhibited more binding affinity to N-terminal ATP-binding pocket of Hsp90 protein than 17-AAG, a standard Hsp90 inhibitor. The expression of Hsp90 client proteins, Akt, p70 S6k , NFκB, Raf-1, p-GSK3β, and XIAP, MDM 2 and Rb2, and CDK4 and Cyclin D3, HIF 1 and HSF1 were suppressed by the use of 1. However, the expression of Hsp70, acetylated tubulin, and activated caspase 3 were induced after 1 treatment. Our results suggested that the proapoptotic effect of the isolates is mediated through the inhibition of Hsp90 and topoisomerase activities.

Objective To explore the efficiency of sunitinib in Chinese pancreatic neuroendocrine tumors (pNET) patients. Methods Advanced pNET patients who had accepted sunitinib treatment in the oncology department of PUMC Hospital from January 2009 to June 2015 after disease progression were enrolled in this study. Data collection included clinicopathological characteristics,medical therapies and outcomes. Results Eighteen pNET patients were collected. The overall response rate (ORR) was 27.7% and the disease control rate (DCR) was 83.3%. Nine patients received sunitinib as the first-line therapy and 9 as the second/post-second line. The median progression-free survival (mPFs)(12 month vs. 12 month;HR:0.92,95%CI:0.31-2.75,P=0.88),ORR (22.2% vs.33.3%;Χ(2)=0.055,P=0.98),and DCR (88.9% vs.77.8%;Χ(2)=0.4,P=0.98)showed no significant difference between first-line therapy and post-second line therapy. The mPFS of Ki-67≥10% and Ki-67<10% group patients was not significantly different (8 months vs. 13 months;HR:1.13,95% CI:0.34-3.77,P=0.845). The commonly reported adverse events included bone marrow suppression,diarrhea,roteinuria,hypertension,and rash. Conclusions First-line or second/post-second line sunitinib treatment has certain antitumor activity in Chinese patients with advanced pNET. The efficiency and commonly reported adverse events of Sunitinib are consistent with the known Western data.

DNA damage responses contribute to cisplatin resistance; however, therapeutic strategies to overcome cisplatin resistance have not yet been established. Here, we demonstrate that inhibition of ATR-Chk1 pathway with the potent inhibitor WYC0209 sensitizes bladder cancer cells to cisplatin. In the clinical microarray profile, high ATR expression is associated with poor prognosis in bladder cancer patients who receive chemotherapy. We show that pharmacological and genetic suppressing of ATR sensitized cells to cisplatin. Treatment with WYC0209 or siATR increased levels of cisplatin-DNA adducts, concomitant with decreased levels of p-glycoprotein expression. Additionally, Combinations of cisplatin and WYC0209 show synergistic activity against bladder cancer. Ultimately, WYC0209 enhanced the anti-tumor effects of cisplatin and suppressed p-glycoprotein expression in bladder cancer xenografts. These results indicate that inhibiting ATR-Chk1 activation with WYC0209 suppresses p-glycoprotein expression and increases cisplatin activity in bladder cancer. Our findings collectively suggest that ATR-Chk1 is a target for improving the efficacy of cisplatin in bladder cancer.

Psoroptidae mites are a type of small mites with a wide range of hosts. The proliferation of Psoroptidae mites could cause symptoms such as severe itching, atopic dermatitis, and hair loss in infected animals. If severely infected, death can also occur. The morphological classification and identification of Psoroptidae mites is problematic due to the overlapping geographical distribution. In addition, there is no divergence threshold for molecular classification and identification. To solve this problem, gDNA was extracted from individual Psoroptes and Otodectes mites (China) for amplification of rDNA ITS2 and mtDNA COI. After that, the sequences obtained were aligned and analyzed with those retrieved from GenBank. Based on rDNA ITS2 sequences, Psoroptidae was divided into three genera, namely, Psoroptes, Chorioptes, and Otodectes, which was in accordance with morphological classification. The intraspecies, interspecies, and intergenera could be differentiated effectively, with thresholds ≤ 5.20, 6.18-14.86, and ≥15.72 %, respectively. However, based on mtDNA COI sequences, Psoroptidae was divided into four genera with Caparinia added, as Caparinia sp did not cluster with the other three genera. The intra- and interspecies could be differentiated effectively, but interspecies and intergenera could not. The intra- and interspecies identification thresholds were ≤ 2.12 and ≥10.93 %. Further analysis showed that host but not geographical isolation was found in Psoroptes and Chorioptes, whereas Otodectes mites parasitizing dogs and cats were the same species; neither host nor geographical isolation was observed. In conclusion, rDNA ITS2 is better than mtDNA COI for DNA barcoding in Psoroptidae.

A marine polycyclic quinone-type metabolite, halenaquinone (HQ), was found to inhibit the proliferation of Molt 4, K562, MDA-MB-231 and DLD-1 cancer cell lines, with IC50 of 0.48, 0.18, 8.0 and 6.76 μg/mL, respectively. It exhibited the most potent activity against leukemia Molt 4 cells. Accumulating evidence showed that HQ may act as a potent protein kinase inhibitor in cancer therapy. To fully understand the mechanism of HQ, we further explored the precise molecular targets in leukemia Molt 4 cells. We found that the use of HQ increased apoptosis by 26.23%-70.27% and caused disruption of mitochondrial membrane potential (MMP) by 17.15%-53.25% in a dose-dependent manner, as demonstrated by Annexin-V/PI and JC-1 staining assays, respectively. Moreover, our findings indicated that the pretreatment of Molt 4 cells with N-acetyl-l-cysteine (NAC), a reactive oxygen species (ROS) scavenger, diminished MMP disruption and apoptosis induced by HQ, suggesting that ROS overproduction plays a crucial rule in the cytotoxic activity of HQ. The results of a cell-free system assay indicated that HQ could act as an HDAC and topoisomerase catalytic inhibitor through the inhibition of pan-HDAC and topoisomerase IIα expression, respectively. On the protein level, the expression of the anti-apoptotic proteins p-Akt, NFκB, HDAC and Bcl-2, as well as hexokinase II was inhibited by the use of HQ. On the other hand, the expression of the pro-apoptotic protein Bax, PARP cleavage, caspase activation and cytochrome c release were increased after HQ treatment. Taken together, our results suggested that the antileukemic effect of HQ is ROS-mediated mitochondrial apoptosis combined with the inhibitory effect on HDAC and topoisomerase activities.

Eight new spirostanol saponins, macaosides A-H (1-8), and 10 new furostanol saponins, macaosides I-R (9-18), together with six known spirostanol compounds (19-24) were isolated from Solanum macaonense. The structures of the new compounds were determined from their spectroscopic data, and the compounds were tested for in vitro antineutrophilic inflammatory activity. It was found that both immediate inflammation responses including superoxide anion generation and elastase release were significantly inhibited by treatment with compounds 20, 21, and 24 (superoxide anion generation: IC50 7.0, 7.6, 4.0 μM; elastase release: IC50 3.7, 4.4, 1.0 μM, respectively). However, compounds 1 and 4 exhibited effects on the inhibition of elastase release only, with IC50 values of 3.2 and 4.2 μM, respectively, while 19 was active against superoxide anion generation only, with an IC50 value of 6.1 μM. Accordingly, spirostanols may be promising lead compounds for further neutrophilic inflammatory disease studies.

The aim of this study was to investigate the curative effect of Zeng Ye decoction on primary Sjögren's syndrome (pSS) and further explore its underlying mechanism involving aquaporin (AQP)‑1 and AQP‑5. The pSS model was established based on the immune induction method, and the saliva flow, submandibular gland index, morphological structures of salivary glands, and AQP‑1 and AQP‑5 protein expression levels in the salivary glands were determined. The saliva flow and the submandibular gland index were significantly reduced in the model group (P<0.01, compared with those in the control group), and significantly increased following interferon (IFN), Zeng Ye decoction extraction (ZYE) and Zeng Ye decoction (ZY) treatment (P<0.01, compared with those of the model group). Submandibular gland atrophy, fibrous tissue hyperplasia and multiple focal lymphocytic infiltration were observed in the model group and were attenuated when subjected to IFN, ZYE and ZY treatment. The AQP‑1 and AQP‑5 expression levels increased following IFN, ZYE and ZY treatment (P<0.01, compared with those of the model group), particularly in the ZYE‑35 group. This result indicated that ZYE had a significant protective effect on pSS via upregulation of the expression levels of AQP‑1 and/or AQP‑5. However, the AQP‑1 expression levels increased and the AQP‑5 expression levels decreased in the model groups compared with those in the control group, which indicated different regulatory pathways of the salivary gland damage on the basis of AQP‑1 and AQP‑5. This study provided a significant reference for the prevention and treatment of pSS.

As an essential branch of context awareness, activity awareness, especially daily activity monitoring and fall detection, is important to healthcare for the elderly and patients with chronic diseases. In this paper, a framework for activity awareness using surface electromyography and accelerometer (ACC) signals is proposed. First, histogram negative entropy was employed to determine the start- and end-points of static and dynamic active segments. Then, the angle of each ACC axis was calculated to indicate body postures, which assisted with sorting dynamic activities into two categories: dynamic gait activities and dynamic transition ones, by judging whether the pre- and post-postures are both standing. Next, the dynamic gait activities were identified by the double-stream hidden Markov models. Besides, the dynamic transition activities were distinguished into normal transition activities and falls by resultant ACC amplitude. Finally, a continuous daily activity monitoring and fall detection scheme was performed with the recognition accuracy over 98%, demonstrating the excellent fall detection performance and the great feasibility of the proposed method in daily activities awareness.

Arabidopsis thaliana pER8:GUS, a low-cost, highly efficient, and convenient transgenic plant system, was used to assay the estrogen-like activity of 30 traditional Chinese medicines. The MeOH extract of Caesalpinia sappan exhibited significant bioactivity in this assay, and subsequent bioactivity-guided fractionation of the extract led to the isolation of one new compound, (S)-3,7-dihydroxychroman-4-one (1), and 10 known compounds. Both the plant pER8:GUS and in vitro estrogen response element reporter assays were used to evaluate the estrogenic activity of the isolated compounds, and these two systems produced comparable results. Compounds 6, 8, and 11 showed significant estrogenic activity comparable to genistein. These active compounds were determined to be nontoxic new sources of phytoestrogens. In addition, compounds 2 and 3 inhibited ERE transcription induced by 17β-estradiol. A docking model revealed that compounds 6, 8, and 11 showed high affinity to the estrogen receptor. The pER8:GUS reporter system was demonstrated to be a useful and effective technique in phytoestrogen discovery.

Defects in apoptotic pathways confer resistance to tubulin-binding agents via downregulation of caspases or overexpression of antiapoptotic factors, urging the need for novel agents acting on an alternative pathway. The purpose of this study was to investigate whether induction of ROS can induce caspase-independent cell death in breast cancer cells and thereby enhance the activity of paclitaxel. Here, we report that gelomulide K acts as a caspase-independent cell death-inducing agent that synergizes with paclitaxel in breast cancer cells and has low toxicity in normal cells. Treatment with gelomulide K induced PARP-1 hyperactivation, AIF nuclear translocation, and cytoprotective autophagy. These effects were associated with increased ROS production and a decrease in cellular GSH levels in cancer cells. Furthermore, pretreatment with NAC, a precursor of intracellular GSH, effectively abrogated gelomulide K-induced caspase-independent cell death and autophagy, suggesting that ROS-mediated downstream signaling is essential to the anticancer effects of gelomulide K. Additionally, in a xenograft model, gelomulide K induced PARP-1 activation and reduced tumor growth. In terms of structure-activity relationships, analysis not only showed a correlation between ROS levels and drug activity but also highlighted the importance of the 8,14-epoxy group. Taken together, our results show that enhancement of paclitaxel activity can be achieved with gelomulide K and that the structurally relevant pharmacophore provides important insight into the development of new caspase-independent cell death-inducing agents., (Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.)