Synthesis of novel 4-substituted isatin Schiff base derivatives as potential autophagy inducers and evaluation of their antitumour activity.

Induction of autophagic death in cancer cells is one of the promising strategies for the development of anti-cancer therapeutics. In the present study, we designed and synthesized a series of isatin Schiff base derivatives containing thioether structures. After discovering the highly active target compound H13 (IC50 = 4.83 µM) based on in vitro antiproliferation, we also found it had a high safety against normal cells HEK293 with CC50 of 69.01 µM, indicating a sufficient therapeutic window. In addition, to provide reference for subsequent studies, a model was successfully constructed by Sybyl software. Preliminary mechanistic studies suggested that H13-induced apoptosis may be closely related to ROS accumulation and mitochondrial dysfunction. Subsequent studies revealed that H13 inhibited cell proliferation by inducing cellular autophagy mainly through blocking signal of the PI3K/AKT/mTOR pathway. Altogether, these results suggested that H13 was potentially valuable as a lead compound.

A Novel Tryptanthrin Derivative D6 Induces Apoptosis and DNA Damage in Non-small-cell Lung Cancer Cells Through Regulating the EGFR Pathway.

BACKGROUND: Non-small-cell lung cancer is a prevalent malignancy associated with significant morbidity and mortality rates. Tryptanthrin and its derivatives have exhibited potent antitumor activity. OBJECTIVE: This study aims to investigate the inhibitory effect of a novel synthesized tryptanthrin derivative D6 on proliferation and the possible mechanism of human non-small cell lung cancer cell lines (A549) in vitro. METHODS: In this study, MTT assay, cell migration, colony formation assay, cell cycle analysis, cell apoptosis, JC- 1 staining assay, reactive oxygen species analysis, proteomics, western blotting, high content screening and absorption titrations analysis were performed. RESULTS: We found that D6 inhibited both the proliferation and migration, induced cell cycle arrest in the G2/M phase, increased levels of ROS, decreased mitochondrial membrane potential, and promoted apoptosis in A549 cells. Further mechanistic studies found that D6 reduced EGFR expression in A549 cells and inhibited the EGFR pathway by decreasing phosphorylation levels of EGFR, Stat3, AKT and Erk1/2. Moreover, DNA damage induced by D6 involved an increase in p53/MDM2 ratio and concentration-dependent accumulation of micronuclei. CONCLUSION: D6 demonstrated significant antitumor activity against A549 cells by inhibiting the EGFR signaling pathway, inducing DNA damage, and subsequently leading to oxidative stress, apoptosis, and cell cycle arrest. Our findings suggest that D6 exhibits potential as an NSCLC drug, owing to its attributes such as antiproliferative activity and ability to induce apoptosis by attenuating the EGFR-mediated signaling pathway.

Aging behavior and leaching characteristics of microfibers in landfill leachate: Important role of surface mesh structure.

Mesh-structured films formed by the post-processing of microfibers improves their permeability and dexterity, such as disposable masks. However, the aging behavior and potential risks of mesh-structured microfibers (MS-MFs) in landfill leachate remain poorly understood. Herein, the aging behavior and mechanisms of MS-MFs and ordinary polypropylene-films (PP-films) microplastics, as well as their leaching concerning dissolved organic matter (DOM) in landfill leachate were investigated. Results revealed that MS-MFs underwent more significant physicochemical changes than PP-films during the aging process in landfill leachate, due to their rich porous habitats. An important factor in the photoaging of MS-MFs was related to reactive oxygen species produced by DOM, and this process was promoted by photoelectrons under UV irradiation. Compared with PP-films, MS-MFs released more DOM and nano-plastics fragments into landfill leachate, altering the composition and molecular weight of DOM. Aged MS-MFs-DOM generated new components, and humus-like substances produced by photochemistry showed the largest increase. Correlation analysis revealed that leached DOM was positively correlated with oxygen-containing groups accumulated in aged MS-MFs. Overall, MS-MFs will bring higher environmental risks and become a new long-term source of DOM contaminants in landfill leachate. This study provides new insights into the impact of novel microfibers on landfill leachate carbon dynamics.

Discovery of tryptanthrin analogues bearing F and piperazine moieties as novel phytopathogenic antibacterial and antiviral agents.

BACKGROUND: Plant bacterial infections and plant viruses seriously affect the yield and quality of crops. Based on the various activities of tryptanthrin, a series of tryptanthrin analogues bearing F and piperazine moieties were designed, synthesized, and evaluated for their biological activities against three plant bacteria and tobacco mosaic virus (TMV). RESULTS: Bioassay results indicated that compounds 6a-6l displayed excellent antibacterial activities in vitro and 6a-6c and 6g exhibited better antiviral activities against TMV than commercial ribavirin. In particular, 6b showed the most effect on Xanthomonas oryzae pv. oryzae (Xoo) with a half-maximal effective concentration (EC50 ) of 1.26 µg mL-1 , compared with the commercial pesticide bismerthiazol (BT; EC50 = 34.3 µg mL-1 ) and thiodiazole copper (TC; EC50 = 73.3 µg mL-1 ). Meanwhile, 6a also had the best antiviral activity at 500 µg mL-1 for curative, protection, and inactivation purposes, compared with ribavirin in vivo. CONCLUSION: Compound 6b could cause changes in bacterial morphology, induce the accumulation of reactive oxygen species, promote apoptosis of bacterial cells, inhibit the formation of biofilm, and block the growth of Xoo cells. Proteomic analysis revealed major differences in the bacterial secretory system pathways T2SS and T6SS, which inhibited membrane transport. Molecular docking revealed that 6a and 6g could interact with TMV coat protein preventing virus assembly. These results suggest that tryptanthrin analogues bearing F and piperazine moieties could be promising candidate agents for antibacterial and antiviral use in agricultural production. © 2023 Society of Chemical Industry.

Design, Synthesis, and Mechanism of Novel 9-Aliphatic Amine Tryptanthrin Derivatives against Phytopathogenic Bacteria.

Taking inspiration from the use of natural product-derived bactericide candidates in drug discovery, a series of novel 9-aliphatic amine tryptanthrin derivatives were designed, synthesized, and evaluated for their biological activity against three plant bacteria. The majority of these compounds exhibited excellent antibacterial activity in vitro. Compound 7c exhibited a significantly superior bacteriostatic effect against Xanthomonas axonopodis pv Citri (Xac), Xanthomonas oryzae pv Oryzae (Xoo), and Pseudomonas syringae pv Actinidiae (Psa) with final corrected EC50 values of 0.769, 1.29, and 15.5 µg/mL, respectively, compared to the commercial pesticide thiodiazole copper which had EC50 values of 58.8, 70.9, and 91.9 µg/mL. Preliminary mechanism studies have demonstrated that 7c is capable of altering bacterial morphology, inducing reactive oxygen species accumulation, promoting bacterial cell apoptosis, inhibiting normal cell growth, and affecting cell membrane permeability. Moreover, in vivo experiments have substantiated the effectiveness of 7c as a therapeutic and defensive agent against the citrus canker. The proteomic analysis has unveiled that the major disparities are located within the bacterial secretion system pathway, which hinders membrane transportation. These discoveries imply that 7c could be an auspicious prototype for developing antiphytopathogenic bacterial agents.

Discovery and Mechanism of Azatryptanthrin Derivatives as Novel Anti-Phytopathogenic Bacterial Agents for Potent Bactericide Candidates.

The natural alkaloids of tryptanthrin and their derivatives have a wide range of biological activities. In this research, four series of azatryptanthrin derivatives containing 4-aza/3-aza/2-aza/1-aza tryptanthrin were prepared by condensation cyclization reaction against plant pathogens to develop a new natural product-based bacterial pesticide. Compound 4Aza-8 displayed a remarkable growth inhibitory effect on pathogenic bacteria of Xanthomonas axonopodis pv. citri (Xac), Xanthomonas oryzae pv. Oryzae (Xoo), and Pseudomonas syringae pv. actinidiae (Psa) with the final corrected EC50 values of 0.312, 1.91, and 18.0 µg/mL, respectively, which were greatly superior than that of tryptanthrin (Tryp). Moreover, 4Aza-8 also showed effective therapeutic and protective activities in vivo on citrus canker. Further mechanism studies on Xac elucidated that compound 4Aza-8 was able to affect the growth curve of Xac and the formation of biofilm, cause severe shrinkage in bacterial morphology, increase reactive oxygen species levels, and induce apoptosis in bacterial cells. Quantitative analysis of differential protein profiles found that the major differences were mainly concentrated on the endometrial protein in the bacterial secretion system pathway, which blocked the membrane transport and affected the transfer of DNA to the host cell. In summary, these research results suggest that 4Aza-8 represents a promising anti-phytopathogenic-bacteria agent, which is worth being further investigated as a bactericide candidate.

Synthesis and biological assessment of indole derivatives containing penta-heterocycles scaffold as novel anticancer agents towards A549 and K562 cells.

Herein, a new series of 2-chloro-N-(5-(2-oxoindolin-3-yl)-4H-pyrazol-3-yl) acetamide derivatives containing 1,3,4-thiadiazole (10a-i) and 4H-1,2,4-triazol-4-amine (11a-r) moiety was designed, synthesised as novel anticancer agents. The antiproliferative activity values indicated that compound 10 b stood as the most potent derivative with IC50 values of 12.0 nM and 10 nM against A549 and K562 cells, respectively. Mechanism investigation and docking studies of 10 b indicated that it possessed good apoptosis characteristic and dose-dependent growth arrest of A549 and K562 cells, blocked cell cycle into G2/M phase. Interestingly, 10 b suppressed the growth of A549 and K562 cells via modulation of EGFR and p53-MDM2 mediated pathway.

Discovery of Tryptanthrin and Its Derivatives and Its Activities against NSCLC In Vitro via Both Apoptosis and Autophagy Pathways.

In this study, a series of novel tryptanthrin derivatives were synthesized and their inhibitory activities against selected human cancer cell lines, namely, lung (A549), chronic myeloid leukemia (K562), prostate (PC3), and live (HepG2), were evaluated using a methyl thiazolyl tetrazolium colorimetric (MTT) assay. Among the tested compounds, compound C1 exhibited a promising inhibitory effect on the A549 cell line with an IC50 value of 0.55 ± 0.33 µM. The observation of the cell morphological result showed that treatment with C1 could significantly inhibit the migration of A549 cells through the cell migration assay. Moreover, after treatment with C1, the A549 cells exhibited a typical apoptotic morphology and obvious autophagy. In addition, the detection of apoptosis and the mitochondrial membrane potential indicated that C1 induced A549 cell apoptosis via modulating the levels of Bcl2 family members and disrupted the mitochondrial membrane potential. Compound C1 also suppressed the expression of cyclin D1 and increased the expression of p21 in the A549 cells, inducing cell cycle arrest in the G2/M phase in a dose dependent manner. The further mechanism study found that C1 markedly increased the transformation from LC3-I to LC3-II. Taken together, our results suggest that C1 is capable of inhibiting the proliferation of non-small cell lung cancer (NSCLC) cells, inducing cell apoptosis, and triggering autophagy.

Liujunzi Decoction ameliorated cisplatin-induced anorexia by inhibiting the JAK-STAT signaling pathway and coordinating anorexigenic and orexigenic neuropeptides in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese formula, Liujunzi Decoction (LJZD) originated from the Yi Xue Zheng Zhuan, and has a promising effect in treating chemotherapy-induced anorexia (CIA). AIM OF THE STUDY: The present study aims to investigate whether LJZD acts on interleukin-6 (IL-6)/leptin mediated janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway that regulates hypothalamus anorexigenic and orexigenic peptides to ameliorate CIA, and also elucidates the potential mechanism by metabolomic analysis. MATERIALS AND METHODS: Network pharmacology analyses were conducted to screen out potential targets and pathways. The CIA rat model was established via an intraperitoneal injection of cisplatin. The histological changes of gastric antrum, liver and ileum were observed by HE staining. The serum levels of leptin, ghrelin, IL-6 and growth differentiation factor 15 (GDF15) were measured by ELISA. The JAK1/2 and STAT levels in gastric antrum and hypothalamus were detected by Western blot. The transcriptions of gastric antrum and hypothalamus IL-6R mRNA, and hypothalamus cocaine- and amphetamine-regulated transcript (CART), pro-opiomelanocortin (POMC), thyrotropin-releasing hormone (TRH), upregulated orexigenic peptides neuropeptide Y (NPY), and agouti-related protein (AGRP) mRNA were assessed by RT-qPCR. The blood samples of control, model and high dose LJZD groups were analyzed by metabolomic. RESULTS: Network pharmacology highlighted the IL-6/leptin mediated JAK-STAT signaling pathway, which regulated downstream anorexigenic and orexigenic peptides in hypothalamus. LJZD ameliorated CIA via stimulating food intake and water consumption in rats. Cisplatin-induced gastric antrum, liver, ileum injuries were ameliorated, serum leptin level reduction was elevated, and ghrelin, IL-6, GDF15 level increases were decreased after LJZD treatments. In gastric antrum and hypothalamus, LJZD inhibited cisplatin-induced activation of JAK-STAT signaling pathway, downregulated the transcriptions of downstream anorexigenic peptides CART, POMC, TRH, and upregulated orexigenic peptides NPY, AGRP in hypothalamus. Importantly, the effect of LJZD in treating CIA might partly relate to the improvements of 23 abnormal metabolites. CONCLUSION: This study implies that inhibiting JAK-STAT signaling pathway, regulating the expressions of anorexigenic and orexigenic peptides, and mediating various metabolic pathways might be potential mechanisms of LJZD's effect against CIA.

Forsythiae Fructus aqueous extract attenuates cisplatin-induced kaolin consumption (pica) by inhibiting NLRP3 inflammasome activation in rats.

The present study was conducted to evaluate the effect of Forsythiae Fructus aqueous extract (FAE) against cisplatin-induced emesis and to explore the antiemetic mechanism of FAE by focusing on NLRP3 inflammasome activation in a rat pica model. Our results showed that FAE significantly ameliorated cisplatin-induced acute and delayed pica in rats. Moreover, FAE improved the gastrointestinal histopathological injury and reduced the levels of serum ROS, IL-1ß, and IL-18 in cisplatin-treated rats. In addition, the expressions of NLRP3, ASC, caspase-1, and IL-1ß and the colocalization of the NLRP3 with ASC or caspase-1 in rat gastric antrum and ileum were also suppressed by FAE. Taken together, our findings indicate that FAE has a therapeutic effect against CINV, which may be related to its inhibition of the activation of NLRP3 inflammasome.

Effectiveness of patient-targeted interventions to inform decision making and improve uptake of colorectal cancer genetic evaluation for at-risk individuals: A systematic review.

BACKGROUND: Inherited colorectal cancer syndromes increase the risk of contracting colorectal and other cancers. International guidelines recommend the identification of individuals with hereditary colorectal cancer and the supervision of asymptomatic individuals with a family history. However, detection of hereditary colorectal cancer is suboptimal. The prevalence of genetic counselling and testing for individuals with high genetic risk is low. OBJECTIVE: To identify, characterize and summarize patient-targeted interventions on improving the uptake of colorectal cancer genetic evaluation for at-risk individuals and enhancing their informed decision making. DESIGN: Systematic review. DATA SOURCES: Six electronic databases (PubMed, CINAHL, Web of Science, Embase, PsycINFO, and Cochrane library) were searched to identify eligible clinical trials from each database's inception to March 25, 2020. The reference lists of the included studies and reviews were checked for additional articles. REVIEW METHODS: Studies were screened and independently appraised by two reviewers using the standardized critical appraisal checklist for randomized controlled trials and quasi-experimental studies from the Joanna Briggs Institute. The results were tabulated and reported in descriptive format. RESULTS: Based on the inclusion criteria, 8 articles satisfied the inclusion criteria and were included. The studies examined patient-targeted intervention strategies related to risk assessment, education, and decision aids. Outcomes included (1) informed decisions regarding microsatellite instability testing, (2) informed decisions concerning genetic testing, (3) genetic counselling and testing. Most of the included studies revealed that interventions had positive effects on the uptake of colorectal cancer genetic evaluation for at-risk individuals and their informed decision making. CONCLUSIONS: There were few studies included in this review, and the results were inconsistent. Based on this review, the conclusion cannot be made that interventions for risk assessment, education, and decision aids have positive effects on the uptake of colorectal cancer genetic evaluation for at-risk individuals and their informed decision making. However, to our knowledge, this is the first systematic review to summarize the effectiveness of patient-targeted interventions to inform decision making and improve uptake of colorectal cancer genetic evaluation for at-risk individuals. This review provides important evidence for related topics. Future studies with rigorous designs are recommended. Nurses have a crucial role in personalized health care. The involvement of nurses in collaboration with all the stakeholders in the development, implementation and evaluation of cancer genetic screening programs to improve genetic referral of individual at risk.

Arsenic mobilization affected by extracellular polymeric substances (EPS) of the dissimilatory iron reducing bacteria isolated from high arsenic groundwater.

The factors that control arsenic (As) mobilization by dissimilatory iron reduction (DIR) are complicated. The association between As mobilization and extracellular polymeric substance (EPS) of dissimilatory iron reducing bacteria (DIRB) remained unclear. In this study, three DIRB were isolated from high arsenic groundwater to understand the effects of EPS on As mobilization. In the laboratory settings, strain Klebsiella oxytoca IR-ZA released As into aqueous phase from As-bearing ferrihydrite, while strain Shewanella putrefaciens IAR-S1 and S. xiamenensis IR-S2 re-sequestrated As by forming secondary minerals during ferrihydrite reduction. Characterization of EPS contents with Fourier Transform Infrared Spectroscopy and high-performance liquid chromatography suggested that mannan and succinic acid were the main different EPS contents of the DIRB. The biomineralization processes were tightly regulated by EPS compositions. Mannan secreted by IAR-S1 and IR-S2 promoted while succinic acid secreted by IR-ZA suppressed the biomineralization and As immobilization. Energy-dispersive X-ray Spectroscopy mapping indicated that As in the secondary minerals was wrapped with EPS. X-ray diffraction and room temperature Mössbauer spectroscopy showed these secondary minerals were vivianite and magnetite, respectively. The amount of As mobilized into aqueous phase was strongly affected by available anions (H2PO4- and HCO3-). Our results indicated that the EPS of DIRB significantly influenced As mobilization.

Synthesis of amide derivatives containing capsaicin and their antioxidant and antibacterial activities.

The capsaicin in hot peppers is an important biological active substance that is widely used in food and medicine. In this work, six capsaicin derivatives such as N-(4-Hydroxy-3-acetophenone benzyl)acrylamide (A), 2-hydroxy-3-(octyloxy)phenyl-5-acrylamidemethylbenzene phenyl methanone (B), N-(2,5-dihydroxybenzene)acetamide (C), N-(5-acetamidemethyl benzene-2,4-dihydroxybenzene)acetamide (D), 4-acetamideme thylbenzene-2-benzylphenol (E), and N-(2-methyl-4-hydroxy-5-methylthiobenzene)acetamide (F) were synthesized via the Friedel-Crafts (F-C) alkylation reaction and were characterized using IR, 1 H NMR, and HRMS. The antioxidant activity of compounds was evaluated using the reducing power and DPPH radical (DPPH·) scavenging assays, and Vitamin C (Vc) was used as a control. The antibacterial activity was tested using minimum inhibition concentration (MIC) and antibacterial rate assays, and Escherichia coli and Staphylococcus aureus were used as the tested strain. The results showed that all six capsaicin derivatives had certain antioxidant and antibacterial activities, and the activities increased with increasing mass concentration. The best properties were obtained for compounds C and F; the antioxidant activity of compound C was similar to Vc and the MIC of compound F was 0.0313 mg/ml, its antibacterial rate was greater than 99% at 3 mg/ml. PRACTICAL APPLICATIONS: As a vegetable, peppers can be eaten fresh or processed to other forms such as pepper powder or pepper jam, and it is very popular because of its long history, unique flavor, and special functions. Our current study shows that capsaicin derivatives have good antioxidant and antibacterial activities, and therefore, the present study of capsaicin derivatives with good activity provides a good foundation for future applications in natural food additives and medicine.