[Application of multiomics mass spectrometry in the research of chemical exposome].

Environmental factors, such as environmental pollutants, behaviors, and lifestyles, are the leading causes of chronic noncommunicable diseases. Estimates indicate that approximately 50% of all deaths worldwide can be attributed to environmental factors. The exposome is defined as the totality of human environmental (i.e., all nongenetic) exposures from conception, including general external exposure (e.g., climate, education, and urban environment), specific external exposure (e.g., pollution, physical activity, and diet), and internal exposure (e.g., metabolic factors, oxidative stress, inflammation, and protein modification). As a new paradigm, this concept aims to comprehensively understand the link between human health and environmental factors. Therefore, a comprehensive measurement of the exposome, including accurate and reliable measurements of exposure to the external environment and a wide range of biological responses to the internal environment, is of great significance. The measurement of the general external exposome depends on advances in environmental sensors, personal-sensing technologies, and geographical information systems. The determination of exogenous chemicals to which individuals are exposed and endogenous chemicals that are produced or modified by external stressors relies on improvements in methodology and the development of instrumental approaches, including colorimetric, chromatographic, spectral, and mass-spectrometric methods. This article reviews the research strategies for chemical exposomes and summarizes existing exposome-measurement methods, focusing on mass spectrometry (MS)-based methods. The top-down and bottom-up approaches are commonly used in exposome studies. The bottom-up approach focuses on the identification of chemicals in the external environment (e.g., soil, water, diet, and air), whereas the top-down approach focuses on the evaluation of endogenous chemicals and biological processes in biological samples (e.g., blood, urine, and serum). Low- and high-resolution MS (LRMS and HRMS, respectively) have become the most popular methods for the direct measurement of exogenous and endogenous chemicals owing to their superior sensitivity, specificity, and dynamic range. LRMS has been widely applied in the targeted analysis of expected chemicals, whereas HRMS is a promising technique for the suspect and unknown screening of unexpected chemicals. The development of MS-based multiomics, including proteomics, metabolomics, epigenomics, and spatial omics, provides new opportunities to understand the effects of environmental exposure on human health. Metabolomics involves the sum of all low-molecular-weight metabolites in a living system. Nontargeted metabolomics can measure both endogenous and exogenous chemicals, which would directly link exposure to biological effects, internal dose, and disease pathobiology, whereas proteomics could play an important role in predicting potential adverse health outcomes and uncovering molecular mechanisms. MS imaging (MSI) is an emerging technique that provides unlabeled in-depth measurements of endogenous and exogenous molecules directly from tissue and cell sections without changing their spatial information. MSI-based spatial omics, which has been widely applied in biomarker discovery for clinical diagnosis, as well as drug and pollutant monitoring, is expected to become an effective method for exposome measurement. Integrating these response measurements from metabolomics, proteomics, spatial omics, and epigenomics will enable the generation of new hypotheses to discover the etiology of diseases caused by chemical exposure. Finally, we highlight the major challenges in achieving chemical exposome measurements.

Pentapeptide PYRAE triggers ER stress-mediated apoptosis of breast cancer cells in mice by targeting RHBDF1-BiP interaction.

Reinforced cellular responses to endoplasmic reticulum (ER) stress are caused by a variety of pathological conditions including cancers. Human rhomboid family-1 protein (RHBDF1), a multiple transmembrane protein located mainly on the ER, has been shown to promote cancer development, while the binding immunoglobulin protein (BiP) is a key regulator of cellular unfolded protein response (UPR) for the maintenance of ER protein homeostasis. In this study, we investigated the role of RHBDF1 in maintaining ER protein homeostasis in breast cancer cells. We showed that deleting or silencing RHBDF1 in breast cancer cell lines MCF-7 and MDA-MB-231 caused marked aggregation of unfolded proteins in proximity to the ER. We demonstrated that RHBDF1 directly interacted with BiP, and this interaction had a stabilizing effect on the BiP protein. Based on the primary structural motifs of RHBDF1 involved in BiP binding, we found a pentapeptide (PE5) targeted BiP and inhibited BiP ATPase activity. SPR assay revealed a binding affinity of PE5 toward BiP (Kd = 57.7 µM). PE5 (50, 100, 200 µM) dose-dependently promoted ER protein aggregation and ER stress-mediated cell apoptosis in MCF-7 and MDA-MB-231 cells. In mouse 4T1 breast cancer xenograft model, injection of PE5 (10 mg/kg, s.c., every 2 days for 2 weeks) significantly inhibited the tumor growth with markedly increased ER stress and apoptosis-related proteins in tumor tissues. Our results suggest that the ability of RHBDF1 to maintain BiP protein stability is critical to ER protein homeostasis in breast cancer cells, and that the pentapeptide PE5 may serve as a scaffold for the development of a new class of anti-BiP inhibitors.

Depression and Anxiety Symptoms and Their Associated Factors Among Chinese Residents After the Lifting of the Dynamic Zero-COVID Policy: A Cross-Sectional Study.

Purpose: China lifted its strict zero-Covid approach on December 7, 2022. This study aimed to investigate depression and anxiety symptoms and their associations among Chinese residents after the change in public policy. Methods: A cross-sectional sample of 925 Chinese residents (726 females and 199 males) was recruited using convenience and snowball sampling approach between 16 and 25 December 2022. Participants completed online questionnaires on basic information, depression, anxiety, COVID-19 related perceptions, and protective behaviors change. Results: Mild and moderate-to-severe depression symptoms were reported by 35.6% and 19.1% of participants, respectively. Nearly 40% of participants reported mild anxiety and 18.7% reported moderate-to-severe anxiety. Results from multinomial logistic regression analysis indicated that male gender, younger age, the presence of chronic disease, poorer self-rated mental health status, perceived impact, and worry were risk factors for both depression and anxiety, while higher education and protective behaviors change were protective factors. Besides, living with or caring for children (4-6 years), family members or other housemates currently with influenza-like symptoms, and perceived severity were also risk factors for depression. Conclusion: Our findings provided initial evidence that Chinese residents may face heightened depression and anxiety during the early stage after the policy was released. Furthermore, we identified some vulnerable populations in need of prioritizing mental health assistance and some potentially modifiable factors associated with depression and anxiety, which provides an important guide for developing timely and effective psychological interventions and preparing for future pandemics.

RHBDF1 deficiency suppresses melanoma glycolysis and enhances efficacy of immunotherapy by facilitating glucose-6-phosphate isomerase degradation via TRIM32.

Melanoma is a dangerous form of skin cancer, making it important to investigate new mechanisms and approaches to enhance the effectiveness of treatment. Here, we establish a positive correlation between the human rhomboid family-1 (RHBDF1) protein and melanoma malignancy. We demonstrate that the melanoma RHBDF1 decrease dramatically inhibits tumor growth and the development of lung metastases, which may be related to the impaired glycolysis. We show that RHBDF1 function is essential to the maintenance of high levels of glycolytic enzymes, especially glucose-6-phosphate isomerase (GPI). Additionally, we discover that the E3 ubiquitin ligase tripartite motif-containing 32 (TRIM32) mediates the K27/K63-linked ubiquitination of GPI and the ensuing lysosomal degradation process. We prove that the multi-transmembrane domain of RHBDF1 is in competition with GPI, preventing the latter from interacting with NCL1-HT2A-LIN41 (NHL) domain of TRIM32. We also note that the mouse RHBDF1's R747 and Y799 are crucial for competitive binding and GPI protection. Artificially silencing the Rhbdf1 gene in a mouse melanoma model results in declined lactic acid levels, elevated cytotoxic lymphocyte infiltration, and improved tumor responsiveness to immunotherapy. These results provide credence to the hypothesis that RHBDF1 plays a significant role in melanoma regulation and suggest that blocking RHBDF1 may be an efficient technique for reestablishing the tumor immune microenvironment (TIME) in melanoma and halting its progression.

Effects of multicomponent exercise on quality of life, depression and anxiety among stroke survivors: A systematic review and meta-analysis.

BACKGROUND: Current guidelines stress the importance of exercise, especially multicomponent exercise to older adults with chronic conditions. AIM: To critically synthesise evidence that evaluates the effects of multicomponent exercise on quality of life, depression and anxiety after stroke. DESIGN: Systematic review and meta-analysis followed the PRISMA 2020 statement. METHODS: A systematic search of PubMed, Embase, Web of Science, Cochrane Library, CINAHL and PsycINFO from inception to 12 June 2023 was performed. Risk of bias was assessed using the Revised Cochrane risk-of-bias tool for randomised trials (RoB 2). Meta-analyses were conducted using Review Manager 5.4 and narrative syntheses were adopted whenever meta-analysis was inappropriate. The overall certainty of the evidence was rated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. RESULTS: Of 15,351 records identified, nine were eligible and data were available for seven randomised controlled trials, three of which were identified as having a high risk of bias, one as low risk, and five as having some concerns. Subgroup pooled analyses indicated that multicomponent exercise engaged in longer exercise sessions (>60 min) was effective in improving quality of life immediately post-intervention and through 3-6 months post-intervention. However, multicomponent exercise did not significantly affect depression and anxiety. CONCLUSIONS: Multicomponent exercise with longer duration of exercise sessions has promising effects on both short- to medium-term quality of life among stroke survivors. PATIENT OR PUBLIC CONTRIBUTION: This does not apply to our work as it is a review paper. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers could consider encouraging the patients to participate in multicomponent exercise sessions for more than 60 min. It is important to note that stroke survivors should be supervised by trained personnel at the beginning of the training. REGISTRATION: The protocol was registered on PROSPERO.

[Research advances in histone modification-regulated plant stress memory and defense priming.] / ç»„è›‹ç™½ä¿®é¥°è°ƒæŽ§æ¤ç‰©å¯¹èƒè¿«çš„è®°å¿†ä¸Žè­¦å¤‡æŠ—æ€§çš„ç ”ç©¶è¿›å±•.

Plants, grown in the immobile soils, have evolved various strategies in response to environmental stresses, including the "stress memory" and "defense priming" mechanisms. The environmental stresses cannot immediately change the DNA base sequence in plants in the short-term. Therefore, epigenetic inheritance is a key mechanism for stress memory and defense priming. In particular, histone modification is considered to be the most important mechanism, which offers the possibility of stress memory. We summarized research advances in plant histone modifications involved in stress memory and defense priming under biotic and abiotic stresses, and proposed pro-blems in the field and the focus and directions in the future research. In-depth understanding of the relationship between histone modification and environmental stresses would facilitate the quick adaptation of plants to harsh environments, and provide theoretical and technical guidance for plant phenotype shaping, organ regeneration, and crop genetic improvement.

Dyadic effects of rumination and self-disclosure on posttraumatic growth in newly diagnosed gynecological cancer couples: an actor-partner interdependence modeling approach.

OBJECTIVE: To examine the dyadic effects of rumination and self-disclosure on posttraumatic growth among newly diagnosed gynecological cancer couples. METHODS: This cross-sectional study recruited 400 newly diagnosed gynecological cancer couples from a tertiary general hospital from July to December 2020. Questionnaires were administered to collect information on demographic and cancer-related characteristics, rumination, self-disclosure, and posttraumatic growth. The actor-partner interdependence model was used to explore the dyadic effects of rumination and self-disclosure on posttraumatic growth. RESULTS: Gynecological cancer survivors reported more posttraumatic growth than their spouses. The patients' deliberate rumination and self-disclosure and spouses' self-disclosure had actor and partner effects on their own and their spouses' posttraumatic growth. Besides, the patients' intrusive rumination and spouses' deliberate rumination had actor effects on their own posttraumatic growth. CONCLUSIONS: Spouses' posttraumatic growth was influenced by their own and their wives' deliberate rumination and self-disclosure, while survivors' posttraumatic growth was affected by their own deliberate rumination, intrusive rumination, self-disclosure, and their spouses' self-disclosure. Promoting deliberate rumination and self-disclosure could facilitate the couples' posttraumatic growth. Besides, reducing intrusive rumination may be useful for the survivors and indirectly contribute to spouses' posttraumatic growth. This study indicates that couple-centered interventions may be crucial and more effective in facilitating posttraumatic growth among newly diagnosed gynecological cancer couples.

Social Support, Sense of Coherence, and Self-Management among Hemodialysis Patients.

Self-management is essential for patients who require regular hemodialysis treatment. This study aimed to explore the relationships between social support, sense of coherence (SOC), and self-management in hemodialysis patients and to examine whether SOC plays a mediating role. In a cross-sectional study, 402 hemodialysis patients from four tertiary hospitals were recruited. Data were analyzed using structural equation modeling. Social support, SOC, and self-management were significantly correlated with each other. The proposed model provided a good fit to the data. Social support had a direct effect on self-management and SOC, partially mediated the effect of social support on self-management (ß = 0.248, p = 0.001). Social support and SOC explained 69% of the variance in self-management. Our findings indicate that health care providers can enhance social support with an emphasis on strengthening SOC strategies to better improve self-management in hemodialysis patients.

RHBDF2 gene functions are correlated to facilitated renal clear cell carcinoma progression.

BACKGROUND: The rhomboids are a family of multi-transmembrane proteins, many of which have been implicated in facilitating tumor progression. Little is yet known, however, about rhomboid-associated biomarkers in cancers. An analysis of such biomarkers could yield important insights into the role of the rhomboids in cancer pathology. METHODS: In this study, we carried out the univariate Cox regression analysis and compared gene expression patterns of several rhomboid genes in 30 types of cancers by using The Cancer Genome Atlas (TCGA) database and the methods delineated in Gene Expression Profiling Interactive Analysis (GEPIA). We then used datasets GSE47032, GSE126964, GSE68417 and 75 paired pathological specimens to verify the influences of the rhomboid genes in cancer progression. Moreover, we carried out Weighted Gene Correlation Network Analysis (WGCNA) to investigate gene-related functions and we exploited potential correlations between rhomboid genes expression and immune cell infiltration in cancer tissues. Furthermore, we constructed gene-knockdown cancer cell lines to investigate rhomboid gene functions. RESULTS: We find that kidney renal clear cell carcinoma (KIRC) disease progression is affected by fluctuations in the expression of a number of the rhomboid family of genes and, more specifically, high levels of RHBDF2 gene expression are a good indicator of poor prognosis of the disease, as patients with high RHBDF2 expression levels exhibit less favorable survival rates compared to those with low RHBDF2 levels. Silencing of the RHBDF2 gene in KIRC cell lines leads to significantly diminished cell proliferation and migration; this is in good agreement with the identification of an enhanced presence of a number of cell growth and migration promoting signaling molecules in KIRC tumors. We found that, although high level of RHBDF2 correlated with increased infiltration of lymphocytes in cancer tissues, artificially overexpressed RHBDF2 led to an inhibition of the activity of the infiltrated immune cells through sustaining PD-L1 protein level. Furthermore, we show that RHBDF2 related cell migration and PD-L1 regulation were potentially mediated by EGFR signaling pathway. CONCLUSIONS: RHBDF2 gene functions are correlated to facilitated renal clear cell carcinoma progression and may serve as a critical prognostic biomarker for the disease.

Correlates of posttraumatic growth among spouses of newly diagnosed gynecological cancer survivors: A cross-sectional study.

PURPOSE: Despite increasing research on posttraumatic growth (PTG) of spouses of cancer patients, and the positive effects of spouses' PTG on both spouses and patients, there is little information on PTG and its correlates among husbands of gynecological cancer survivors, especially those of newly diagnosed survivors. We aimed to assess PTG among spouses of newly diagnosed gynecological cancer survivors and to examine its correlates. METHODS: In a cross-sectional study, a total of 400 spouses of newly diagnosed gynecological cancer survivors were recruited and completed questionnaires with information on general characteristics, rumination, self-disclosure, locus of control, and PTG. Univariate analysis and multiple linear regression analysis were performed. RESULTS: The mean score of PTG among the spouses was 57.77 (SD = 12.03). There were significant differences in PTG among spouses with different education levels, marriage duration, number of children, per capita monthly income, other traumatic events within 6 months, and time since diagnosis groups. Pearson's correlation analysis revealed that deliberate rumination, self-disclosure, and locus of control were significantly associated with PTG. The multiple regression model revealed that 53.6% of the variance in PTG was explained by marriage duration, time since diagnosis, self-disclosure, deliberate rumination, and internality locus of control. CONCLUSIONS: This study was one of the early attempts in evaluating PTG among spouses of newly diagnosed gynecological cancer survivors and identified several significant, potentially modifiable factors (self-disclosure, deliberate rumination, and internality locus of control) associated with PTG, providing an important guide for the development of effective psychosocial interventions for this population.

Comprehensive Review of Phytochemical Constituents, Pharmacological Properties, and Clinical Applications of Prunus mume.

Prunus mume is one of the most ancient medicinal herbs and health foods commonly used in Asian countries. It is widely used as a constituent of many medicinal preparations and as a food ingredient for its beneficial health effects. In this review, we retrieved reports from PubMed, embase, Scopus, and SciFinder databases, to collect extensive scientific evidence on the phytochemical constituents, pharmacological properties, and clinical applications of Prunus mume. The literature review revealed that approximately 192 compounds have been isolated from different parts of the plant, and their molecular structures have been identified. The pharmacological properties of the plant, including anti-diabetic, liver-protective, antitumor, antimicrobial, antioxidant, and anti-inflammatory activities, as well as their underlying mechanisms, have been clarified by in vitro and in vivo studies. Clinical studies, although very limited, have been highlighted in this review to provide a reference for further exploration on therapeutic applications of the plant.

Correlates of Symptom Burden of Hemodialysis Patients.

This cross-sectional study assessed the overall symptom burden, including the prevalence, frequency, severity, and distress of symptoms among hemodialysis patients, and explored the relationship between demographic characteristics, clinical variables, self-management, sense of coherence, social support, and symptom burden in these patients. Herein, a regression analysis was performed to determine associations with symptom burden. The mean score of symptom burden among the participants (n = 382) was 74.12, with an average number of 12 symptoms. The analysis revealed that self-management, sense of coherence, and social support were negatively associated with the overall symptom burden. The multiple regression model showed that 48.6% of the variance in symptom burden was explained by meaningfulness, emotional management, daily urine output, subjective support, gender, and manageability. These findings contribute to the knowledge of symptom burden among hemodialysis patients and some new predictors (self-management, sense of coherence, and social support) of their symptom burden.

The KNRL nuclear receptor controls hydrolase-mediated vitellin breakdown during embryogenesis in the brown planthopper, Nilaparvata lugens.

Vitellin (Vn) homeostasis is central to the fecundity of oviparous insects. Most studies have focused on the synthesis and transportation of Vn as a building block for developing eggs during vitellogenesis; however, less is known about how the utilization of this nutrient reserve affects embryonic development. Here, we show that the single ortholog of the knirps and knirps-like nuclear receptors, KNRL, negatively regulates Vn breakdown by suppressing the expression of hydrolase genes in the brown planthopper, Nilaparvata lugens. KNRL was highly expressed in the ovary of adult females, and knockdown of KNRL by RNA interference resulted in the acceleration of Vn breakdown and the inhibition of embryonic development. Transcriptome sequencing analysis revealed that numerous hydrolase genes, including cathepsins and trypsins were up-regulated after KNRL knockdown. At least eight of the nine significantly enriched Gene Ontology terms for the up-regulated genes were in proteolysis-related categories. The expression levels of five selected trypsin genes and the enzymatic activities of trypsin in the embryos were significantly increased after KNRL knockdown. Moreover, trypsin injection prolonged egg duration, delayed embryonic development, accelerated Vn breakdown and severely reduced egg hatchability, a pattern similar to that observed in KNRL-silenced N. lugens. These observations suggest that KNRL controls Vn breakdown in embryos via the transcriptional inhibition of hydrolases. Generally, this study provides a foundation for understanding how embryo nutrient reserves are mobilized during embryogenesis and identifies several genes and pathways that may prove valuable targets for pest control.

Anti-inflammatory Activity of Mollugin on DSS-induced Colitis in Mice.

We aimed to explore the anti-inflammatory activity of mollugin extracted from Rubia cordifolia L, a traditional Chinese medicine, on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) in mice. Thirty C57BL/6 mice were divided into a control group (n=6), a model group (n=6), and three experimental groups (40, 20, 10 mg/kg of mollugin, n=6 each). DSS solution (3%) was given to mice in the model group and experimental groups from day 4 to day 10 to induce the mouse UC model. Mice in the experimental groups were intragastrically administrated mollugin from day 1 to day 10. Animals were orally given distilled water in the control group for the whole experiment time and in the model group from day 1 to day 3. The changes in colon pathology were detected by hematoxylin and eosin (HE) staining. Interleukin-1ß (IL-1ß) in the serum, and tumor necrosis factor-α (TNF-α) and interferon-γ (IFN) in the tissues were measured by enzyme linked immunosorbent assay. Expression levels of Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 in the colon tissues were detected by immunohistochemistry. Results showed that mollugin could significantly reduce weight loss and the disease activity index in the DSS-induced UC mouse model. HE examinations demonstrated that mollugin treatment effectively improved the histological damage (P<0.05). The overproduction of IL-1ß and TNF-α was remarkably inhibited by mollugin treatment at doses of 20 and 40 mg/kg (P<0.05). Additionally, the levels of TLR4 in colon tissues were significantly reduced in mollugin-treated groups compared with the DSS group. Our findings demonstrated that mollugin ameliorates DSS-induced UC by inhibiting the production of pro-inflammatory chemocytokines.

Rhodium-catalyzed multiple C-H activation/highly meta-selective C-H amination between amidines and alkynes.

A tandem process of multiple C-H activation and intermolecular highly meta-selective C-H amination between amidines and alkynes has been developed. Mechanistic studies demonstrate that the reaction is proposed to proceed through two different Rh(i)-Rh(iii) catalytic cycles, wherein Rhodium-complex I and Rhodacycle intermediate II were isolated for the first time.

Activiation of the nitric oxide cycle by citrulline and arginine restores susceptibility of resistant brown planthoppers to the insecticide imidacloprid.

Pest management, which is critical for global crop productivity, is hampered by rapidly evolving insecticide resistance in insect pests. The ability to manage the development of insecticide resistance is thus vital. Nitric oxide (NO) is a ubiquitous signaling molecule with important functions in a variety of biological processes. Here we show that imidacloprid-resistant brown planthoppers (BPH) are deficient in citrulline and arginine, both of which are involved in NO production, but exogenous citrulline and arginine render resistant BPH vulnerable to imidacloprid. BPH insecticide resistance results from low NO production; exogenous arginine and citrulline augment the NO signaling in BPH, leading to downregulation of CYP6AY1 and CYP6ER1, the cytochrome P450 s that contribute to imidacloprid detoxification, thereby restoring susceptibility. Two amino acids that can be used to restore susceptibility in insecticide-resistant insects are identified, establishing a novel metabolome-based approach for killing insecticide-resistant pests and providing a useful template for managing insecticide resistance.

Improved drug delivery and anti-tumor efficacy of combinatorial liposomal formulation of genistein and plumbagin by targeting Glut1 and Akt3 proteins in mice bearing prostate tumor.

Despite the plethora of significant research progress made to develop novel strategies for the treatment of prostate cancer, this disease remains one of the major global health challenges among men. However, using a co-treatment approach utilizing two or more anticancer drugs has shown tremendous success in the treatment of many cancer types. Nanoliposomes are well known to encapsulate multiple drugs and deliver them at the desired site. In this work, we report the synthesis of nanoliposomes (∼100 nm) encapsulating two drugs, plumbagin, and genistein, to synergistically inhibit the growth of prostate cancer cells. The combination of plumbagin and genistein drugs was found inhibiting xenograft prostate tumor growth by ∼80 % without any appreciable toxicity. Mechanistically, the combination of plumbagin and genistein containing nanoliposomes leads to the inhibition of PI3K/AKT3 signaling pathway as well as the decreased population of Glut-1 transporters to impart the retardation in tumor growth. Decrease in proliferative cells and blood vessels are early biological processes that laid the foundation of the observed anti-tumor effect. Thus, a novel, and non-toxic liposomal formulation, containing plumbagin and genistein drugs, is reported, which can deliver anticancer agents to prostate tumors and inhibit the growth.

Palladium-catalyzed decarbonylative annulation of phthalimides with arynes: direct construction of phenanthridinones.

A novel palladium-catalyzed decarbonylative annulation for the synthesis of phenanthridinones from phthalimides and arynes has been developed. This catalytic system tolerates a broad range of functional groups. Mechanistic experiments demonstrate that the Pd(ii) complex B is the key intermediate, which has been confirmed by X-ray crystallography for the first time.

Diterpenoids with herbicidal and antifungal activities from hulls of rice (Oryza sativa).

Diterpenoids are the main secondary metabolites of plants and with a range of biological activities. In the present study, 7 compounds were isolated from the hulls of rice (Oryza sativa L.). Among them, 3 diterpenoids are new namely, 3,20-epoxy-3α-hydroxy- 8,11,13-abietatrie-7-one (1), 4,6-epoxy-3ß-hydroxy-9ß-pimara-7,15-diene (2) and 2-((E)-3- (4-hydroxy-3-methoxyphenyl) allylidene) momilactone A (3). While, 4 terpenoids are known, namely momilactone A (4), momilactone B (5), ent-7-oxo-kaur-15-en-18-oic acid (6) and orizaterpenoid (7). The structures of these diterpenoids were elucidated using 1D and 2D NMR in combination with ESI-MS and HR-EI-MS. Furthermore, all isolated compounds displayed antifungal activities against four crop pathogenic fungi Magnaporthe grisea, Rhizoctonia solani, Blumeria graminearum and Fusarium oxysporum, and phytotoxicity against paddy weed Echinochloa crusgalli. The results suggested that rice could produce plenty of secondary metabolites to defense against weeds and pathogens.

Safety, tolerability, and pharmacokinetics of simotinib, a novel specific EGFR tyrosine kinase inhibitor, in patients with advanced non-small cell lung cancer: results of a phase Ib trial.

Purpose: The aim of this phase Ib study (clinicaltrials.gov: NCT01772732) was to assess safety, tolerability, and pharmacokinetics (PKs) of simotinib (a novel EGFR tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer (NSCLC) and EGFR gene mutation. Patients and methods: 41 patients with EGFR gene mutations were enrolled and received simotinib orally administered twice daily with dose escalating from 100 to 650 mg in 28 days cycle. Safety and tolerability were assessed through the study. Blood samples were collected for PK analysis on Days 1, 8, 9, 10, 15, 22 and 29. Tumor response was assessed at baseline, on Day 29 and every 8 weeks thereafter. Results: Simotinib was well tolerated, with no dose-limiting toxicities. Maximum tolerated dose (MTD) was not found. 95.1% of patients experienced at least one adverse event (AE), and most of them were mild or moderate. Rash (41.5%) and diarrhea (56.1%) were the most frequently reported AEs. Simotinib was rapidly absorbed and eliminated with average T max ranging from 1 to 4 hrs and T 1/2 ranging between 6.2 and 13.0 hrs after multiple-dose administration. No dose-response relationship between dose and exposure was observed after multiple-dose administration. 39.3% of the enrolled patients achieved a partial response and 46.3% had stable disease. Median progression-free survival and overall survival were 9.9 (CI% 4.7; 12.1) months and 14.6 (95%CI 12.3; 22.5) months, respectively. Conclusion: Simotinib was well tolerated, with manageable AEs at doses of up to 650 mg and MTD was not reached. Further studies to explore higher doses are ongoing.