circ_PPAPDC1A promotes Osimertinib resistance by sponging the miR-30a-3p/ IGF1R pathway in non-small cell lung cancer (NSCLC).

BACKGROUND: Recent evidence has demonstrated that abnormal expression and regulation of circular RNA (circRNAs) are involved in the occurrence and development of a variety of tumors. The aim of this study was to investigate the effects of circ_PPAPDC1A in Osimertinib resistance in NSCLC. METHODS: Human circRNAs microarray analysis was conducted to identify differentially expressed (DE) circRNAs in Osimertinib-acquired resistance tissues of NSCLC. The effect of circ_PPAPDC1A on cell proliferation, invasion, migration, and apoptosis was assessed in both in vitro and in vivo. Dual-luciferase reporter assay, RT-qPCR, Western-blot, and rescue assay were employed to confirm the interaction between circ_PPAPDC1A/miR-30a-3p/IGF1R axis. RESULTS: The results revealed that circ_PPAPDC1A was significantly upregulated in Osimertinib acquired resistance tissues of NSCLC. circ_PPAPDC1A reduced the sensitivity of PC9 and HCC827 cells to Osimertinib and promoted cell proliferation, invasion, migration, while inhibiting apoptosis in Osimertinib-resistant PC9/OR and HCC829/OR cells, both in vitro and in vivo. Silencing circ_PPAPDC1A partially reversed Osimertinib resistance. Additionally, circ_PPAPDC1A acted as a competing endogenous RNA (ceRNA) by targeting miR-30a-3p, and Insulin-like Growth Factor 1 Receptor (IGF1R) was identified as a functional gene for miR-30a-3p in NSCLC. Furthermore, the results confirmed that circ_PPAPDC1A/miR-30a-3p/IGF1R axis plays a role in activating the PI3K/AKT/mTOR signaling pathway in NSCLC with Osimertinib resistance. CONCLUSIONS: Therefore, for the first time we identified that circ_PPAPDC1A was significantly upregulated and exerts an oncogenic role in NSCLC with Osimertinib resistance by sponging miR-30a-3p to active IGF1R/PI3K/AKT/mTOR pathway. circ_PPAPDC1A may serve as a novel diagnostic biomarker and therapeutic target for NSCLC patients with Osimertinib resistance.

Dermonecrosis caused by a spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib.

Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the etiological venom toxins in Naja nigricollis venom responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a therapeutic strategy that may effectively prevent life-changing morbidity caused by snakebite in rural Africa.

Preparation of antibacterial hydrogel from poly(aspartic hydrazide) and quaternized N-[3-(dimethylamino) propyl] methylacrylamide copolymer with antioxidant and hemostatic effects for wound repairing.

Hydrogels as wound dressing have attracted extensive attention in past decade because they can provide moist microenvironment to promote wound healing. Herein, this research designed a multifunctional hydrogel with antibacterial property and antioxidant activity fabricated from quaternary ammonium bearing light emitting quaternized TPE-P(DAA-co-DMAPMA) (QTPDD) and poly(aspartic hydrazide) (PAH). The protocatechuic aldehyde (PCA) grafted to the hydrogel through dynamic bond endowed the hydrogel with antioxidant activity and the tranexamic acid (TXA) was loaded to enhance the hemostatic performance. The hydrogel possesses preferable gelation time for injectable application, good antioxidant property and tissue adhesion, improved hemostatic performance fit for wound repairing. Furthermore, the hydrogel has excellent antimicrobial property to both E. coli and S. aureus based on quaternary ammonium structure. The hydrogel also showed good biocompatibility and the in vivo experiments proved this hydrogel can promote the wound repairing rate. This study suggests that TXA/hydrogel with quaternary ammonium structure and dynamic grafted PCA have great potential in wound healing applications.

Effect of NAMPT on the proliferation and apoptosis in odontoblast-like MDPC-23 cell.

This study aimed to evaluate the physiological role of NAMPT associated with MDPC-23 odontoblast cell proliferation. Cell viability was measured using the (DAPI) staining, caspase activation analysis and immunoblotting were performed. Visfatin promoted MDPC-23 odontoblast cell growth in a dose-dependent manner. Furthermore, the up-regulation of Visfatin promoted odontogenic differentiation and accelerated mineralization through an increase in representative odontoblastic biomarkers in MDPC-23 cells. However, FK-866 cell growth in a dose-dependent manner induced nuclear condensation and fragmentation. FK-866-treated cells showed H&E staining and increased apoptosis compared to control cells. The expression of anti-apoptotic factors components of the mitochondria-dependent intrinsic apoptotic pathway significantly decreased following FK-866 treatment. The expression of pro-apoptotic increased upon FK-866 treatment. In addition, FK-866 activated caspase-3 and PARP to induce cell death. In addition, after treating FK-866 for 72 h, the 3/7 activity of MDPC-23 cells increased in a concentration-dependent manner, and the IHC results also confirmed that Caspase-3 increased in a concentration-dependent. Therefore, the presence or absence of NAMPT expression in dentin cells was closely related to cell proliferation and formation of extracellular substrates.

Genome-wide CRISPR screens identify the YAP/TEAD axis as a driver of persister cells in EGFR mutant lung cancer.

Most lung cancer patients with metastatic cancer eventually relapse with drug-resistant disease following treatment and EGFR mutant lung cancer is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cancer cell lines, revealed the landscape of pathways that cause resistance to the EGFR inhibitors osimertinib or gefitinib in EGFR mutant lung cancer. Among the most recurrent resistance genes were those that regulate the Hippo pathway. Following osimertinib treatment a subpopulation of cancer cells are able to survive and over time develop stable resistance. These 'persister' cells can exploit non-genetic (transcriptional) programs that enable cancer cells to survive drug treatment. Using genetic and pharmacologic tools we identified Hippo signalling as an important non-genetic mechanism of cell survival following osimertinib treatment. Further, we show that combinatorial targeting of the Hippo pathway and EGFR is highly effective in EGFR mutant lung cancer cells and patient-derived organoids, suggesting a new therapeutic strategy for EGFR mutant lung cancer patients.

Osimertinib in combination with anti-angiogenesis therapy presents a promising option for osimertinib-resistant non-small cell lung cancer.

BACKGROUND: Osimertinib has become standard care for epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer (NSCLC) patients whereas drug resistance remains inevitable. Now we recognize that the interactions between the tumor and the tumor microenvironment (TME) also account for drug resistance. Therefore, we provide a new sight into post-osimertinib management, focusing on the alteration of TME. METHODS: We conducted a retrospective study on the prognosis of different treatments after osimertinib resistance. Next, we carried out in vivo experiment to validate our findings using a humanized mouse model. Furthermore, we performed single-cell transcriptome sequencing (scRNA-seq) of tumor tissue from the above treatment groups to explore the mechanisms of TME changes. RESULTS: Totally 111 advanced NSCLC patients have been enrolled in the retrospective study. The median PFS was 9.84 months (95% CI 7.0-12.6 months) in the osimertinib plus anti-angiogenesis group, significantly longer than chemotherapy (P = 0.012) and osimertinib (P = 0.003). The median OS was 16.79 months (95% CI 14.97-18.61 months) in the osimertinib plus anti-angiogenesis group, significantly better than chemotherapy (P = 0.026), the chemotherapy plus osimertinib (P = 0.021), and the chemotherapy plus immunotherapy (P = 0.006). The efficacy of osimertinib plus anlotinib in the osimertinib-resistant engraft tumors (R-O+A) group was significantly more potent than the osimertinib (R-O) group (P<0.05) in vitro. The combinational therapy could significantly increase the infiltration of CD4+ T cells (P<0.05), CD25+CD4+ T cells (P<0.001), and PD-1+CD8+ T cells (P<0.05) compared to osimertinib. ScRNA-seq demonstrated that the number of CD8+ T and proliferation T cells increased, and TAM.mo was downregulated in the R-O+A group compared to the R-O group. Subtype study of T cells explained that the changes caused by combination treatment were mainly related to cytotoxic T cells. Subtype study of macrophages showed that proportion and functional changes in IL-1ß.mo and CCL18.mo might be responsible for rescue osimertinib resistance by combination therapy. CONCLUSIONS: In conclusion, osimertinib plus anlotinib could improve the prognosis of patients with a progressed disease on second-line osimertinib treatment, which may ascribe to increased T cell infiltration and TAM remodeling via VEGF-VEGFR blockage.

Design, Synthesis, and Biological Evaluation of Novel EGFR PROTACs Targeting C797S Mutation.

The epidermal growth factor receptor (EGFR) tertiary C797S mutation is an important cause of resistance to Osimertinib, which seriously hinders the clinical application of Osimertinib. Developing proteolysis-targeting chimeras (PROTACs) targeting EGFR mutants can offer a promising strategy to overcome drug resistance. In this study, some novel PROTACs targeting C797S mutation were designed and synthesized based on a new EGFR inhibitor and displayed a potent degradation effect in H1975-TM cells harboring EGFRL858R/T790M/C797S. The representative compound C6 exhibited a DC50 of 10.2 nM against EGFRL858R/T790M/C797S and an IC50 of 10.3 nM against H1975-TM. Furthermore, C6 also showed potent degradation activity against various main EGFR mutants, including EGFRDel19/T790M/C797S. Mechanistic studies revealed that the protein degradation was achieved through the ubiquitin-proteasome system. Finally, C6 inhibited tumor growth in the H1975-TM xenograft tumor model effectively and safely. This study identifies a novel and potent EGFR PROTAC to overcome Osimertinib resistance mediated by C797S mutation.

DNA topoisomerase II inhibition potentiates osimertinib's therapeutic efficacy in EGFR-mutant non-small cell lung cancer models.

Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a third-generation EGFR inhibitor for the treatment of EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC), is urgently needed. This study reports that DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide, synergistically decreased cell survival, with enhanced induction of DNA damage and apoptosis in osimertinib-resistant cells; suppressed the growth of osimertinib-resistant tumors; and delayed the emergence of osimertinib-acquired resistance. Mechanistically, osimertinib decreased Topo IIα levels in EGFRm NSCLC cells by facilitating FBXW7-mediated proteasomal degradation, resulting in induction of DNA damage; these effects were lost in osimertinib-resistant cell lines that possess elevated levels of Topo IIα. Increased Topo IIα levels were also detected in the majority of tissue samples from patients with NSCLC after relapse from EGFR tyrosine kinase inhibitor treatment. Enforced expression of an ectopic TOP2A gene in sensitive EGFRm NSCLC cells conferred resistance to osimertinib, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their susceptibility to osimertinib-induced DNA damage and apoptosis. Together, these results reveal an essential role of Topo IIα inhibition in mediating the therapeutic efficacy of osimertinib against EGFRm NSCLC, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib.

Peficitinib alleviated acute lung injury by blocking glycolysis through JAK3/STAT3 pathway.

Peficitinib is a selective Janus kinase (JAK3) inhibitor recently developed and approved for the treatment of rheumatoid arthritis in Japan. Glycolysis in macrophages could induce NOD-like receptor (NLR) family and pyrin domain-containing protein 3 (NLRP3) inflammasome activation, thus resulting in pyroptosis and acute lung injury (ALI). The aim of our study was to investigate whether Peficitinib could alleviate lipopolysaccharide (LPS)-induced ALI by inhibiting NLRP3 inflammasome activation. Wild type C57BL/6J mice were intraperitoneally injected with Peficitinib (5 or 10 mg·kg-1·day-1) for 7 consecutive days before LPS injection. The results showed that Peficitinib pretreatment significantly relieved LPS-induced pulmonary edema, inflammation, and apoptosis. NLRP3 inflammasome and glycolysis in murine lung tissues challenged with LPS were also blocked by Peficitinib. Furthermore, we found that the activation of JAK3/signal transducer and activator of transcription 3 (STAT3) was also suppressed by Peficitinib in mice with ALI. However, in Jak3 knockout mice, Peficitinib did not show obvious protective effects after LPS injection. In vitro experiments further showed that Jak3 overexpression completely abolished Peficitinib-elicited inhibitory effects on pyroptosis and glycolysis in LPS-induced RAW264.7 macrophages. Finally, we unveiled that LPS-induced activation of JAK3/STAT3 was mediated by toll-like receptor 4 (TLR4) in RAW264.7 macrophages. Collectively, our study proved that Peficitinib could protect against ALI by blocking JAK3-mediated glycolysis and pyroptosis in macrophages, which may serve as a promising candidate against ALI in the future.

AXIN1/MYC Axis Mediated the Osimertinib Resistance in EGFR Mutant Non-Small Cell Lung Cancer Cells.

Osimertinib, a promising and approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is a standard strategy for EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, developed resistance is unavoidable, which reduces its long-term effectiveness. In this study, RNA sequencing was performed to analyze differentially expressed genes (DEGs). The PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA) were used to identify the key genes for clinical prognosis and gene correlation respectively. Protein expression was determined by western blot analysis. Cell viability assay and Ki67 staining were used to evaluate the effect of osimertinib on tumor cells. Finally, we screened out two hub genes, myelocytomatosis oncogene (Myc) and axis inhibition protein 1 (Axin1), upregulated in three osimertinib-resistant cell lines through RNA sequencing and bioinformatics analysis. Next, cell experiment confirmed that expression of C-MYC and AXIN1 were elevated in different EGFR mutant NSCLC cell lines with acquired resistance to osimertinib, compared with their corresponding parental cell lines. Furthermore, we demonstrated that AXIN1 upregulated the expression of C-MYC and mediated the acquired resistance of EGFR mutant NSCLC cells to osimertinib in vitro. In conclusion, AXIN1 affected the sensitivity of EGFR mutant NSCLC to osimertinib via regulating C-MYC expression in vitro. Targeting AXIN1/MYC signaling may be a potential new strategy for overcoming acquired resistance to osimertinib.

Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Osimertinib resistance prognostic gene signature: STRIP2 is associated with immune infiltration and tumor progression in lung adenocarcinoma.

OBJECTIVE: Although the use of osimertinib can significantly improve the survival time of lung adenocarcinoma (LUAD) patients with epithelial growth factor receptor mutation, eventually drug resistance will limit the survival benefit of most patients. This study aimed to develop a novel prognostic predictive signature based on genes associated with osimertinib resistance. METHODS: The differentially expressed genes (DEGs) associated with osimertinib resistance in LUAD were screened from Gene Expression Omnibus datasets and The Cancer Genome Atlas datasets. Multivariate cox regression was used to establish a prognostic signature, and then a nomogram was developed to predict the survival probability of LUAD patients. We used ROC curve and DCA curve to evaluate its clinical prediction accuracy and net benefit. In addition, the differentially expressed genes significantly associated with prognosis were selected for immune infiltration analysis and drug sensitivity analysis, and their roles in the progression of lung adenocarcinoma were verified by in vitro experiments. RESULTS: Our evaluation results indicated that the new nomogram had higher clinical prediction accuracy and net benefit value than the TN nomogram. Further analysis showed that patients with low STRIP2 expression had a higher level of immune response, and may be more likely to benefit from immune checkpoint inhibitors and conventional antitumor drugs. This may help to select more precise and appropriate therapy for LUAD patients with osimertinib resistance. Furthermore, in vitro experiments showed that STRIP2 promoted the LUAD cells proliferation, migration and invasion. This further demonstrates the importance of this gene signature for prognostic prediction. CONCLUSION: We developed a reliable prognostic model based on DEGs associated with osimertinib resistance and screened for biomarker that can predict the immune response in LUAD patients, which may help in the selection of treatment regimens after osimertinib resistance.

Design, synthesis, antiviral evaluation, and In silico studies of acrylamides targeting nsP2 from Chikungunya virus.

The Togaviridae family comprises several New- and Old-World Alphaviruses that have been responsible for thousands of human illnesses, including the RNA arbovirus Chikungunya virus (CHIKV). Firstly, it was reported in Tanzania in 1952 but rapidly it spread to several countries from Europe, Asia, and the Americas. Since then, CHIKV has been circulating in diverse countries around the world, leading to increased morbidity rates. Currently, there are no FDA-approved drugs or licensed vaccines to specifically treat CHIKV infections. Thus, there is a lack of alternatives to fight against this viral disease, making it an unmet need. Structurally, CHIKV is composed of five structural proteins (E3, E2, E1, C, and 6k) and four non-structural proteins (nsP1-4), in which nsP2 represents an attractive antiviral target for designing novel inhibitors since it has an essential role in the virus replication and transcription. Herein, we used a rational drug design strategy to select some acrylamide derivatives to be synthesized and evaluated against CHIKV nsP2 and also screened on CHIKV-infected cells. Thus, two regions of modifications were considered for these types of inhibitors, based on a previous study of our group, generating 1560 possible inhibitors. Then, the 24 most promising ones were synthesized and screened by using a FRET-based enzymatic assay protocol targeting CHIKV nsP2, identifying LQM330, 333, 336, and 338 as the most potent inhibitors, with Ki values of 48.6 ± 2.8, 92.3 ± 1.4, 2.3 ± 1.5, and 181.8 ± 2.5 µM, respectively. Still, their Km and Vmax kinetic parameters were also determined, along with their competitive binding modes of CHIKV nsP2 inhibition. Then, ITC analyses revealed KD values of 127, 159, 198, and 218 µM for LQM330, 333, 336, and 338, respectively. Also, their ΔH, ΔS, and ΔG physicochemical parameters were determined. MD simulations demonstrated that these inhibitors present a stable binding mode with nsP2, interacting with important residues of this protease, according to docking analyzes. Moreover, MM/PBSA calculations displayed that van der Waals interactions are mainly responsible for stabilizing the inhibitor-nsP2 complex, and their binding energies corroborated with their Ki values, having -198.7 ± 15.68, -124.8 ± 17.27, -247.4 ± 23.78, and -100.6 ± 19.21 kcal/mol for LQM330, 333, 336, and 338, respectively. Since Sindbis (SINV) nsP2 is similar to CHIKV nsP2, these best inhibitors were screened against SINV-infected cells, and it was verified that LQM330 presented the best result, with an EC50 value of 0.95 ± 0.09 µM. Even at 50 µM concentration, LQM338 was found to be cytotoxic on Vero cells after 48 h. Then, LQM330, 333, and 336 were evaluated against CHIKV-infected cells in antiviral assays, in which LQM330 was found to be the most promising antiviral candidate in this study, exhibiting an EC50 value of 5.2 ± 0.52 µM and SI of 31.78. The intracellular flow cytometry demonstrated that LQM330 is able to reduce the CHIKV cytopathogenic effect on cells, and also reduce the percentage of CHIKV-positive cells from 66.1% ± 7.05 to 35.8% ± 5.78 at 50 µM concentration. Finally, qPCR studies demonstrated that LQM330 was capable of reducing the number of viral RNA copies/µL, suggesting that CHIKV nsP2 is targeted by this inhibitor as its mechanism of action.

Oxidative stress and cellular toxicity induced by dihydropyrazine: a comparative study with other Maillard reaction products.

Glycation products are generated during the Maillard reaction, a non-enzymatic reaction between reducing sugars and the amino groups of proteins, which accumulate in the body with aging and cause many diseases. Herein, we have focused on dihydropyrazines (DHPs), which are glycation products formed by the dimerization of D-glucosamine or 5-aminolevulinic acid, and have reported that DHPs can produce several kinds of radicals and induce cytotoxicity via oxidative stress. To advance our understanding of DHP-mediated cytotoxicity, we selected a DHP, 3-hydro-2,2,5,6-tetramethylpyrazine (DHP-3), and two major Maillard reaction products, Nε-(carboxymethyl)-L-lysine (CML) and acrylamide, and performed comparative experiments focusing on their cytotoxicity and their ability to induce oxidative stress. The order of increasing cytotoxicity was DHP-3, acrylamide, and CML, and the LC50 value could be calculated only for DHP-3 (0.53 mM), indicating that DHP-3 is more toxic than the other Maillard reaction products. However, their toxicities were significantly lower than those of common toxic chemicals. Further, the results of their cytotoxicity assay were consistent with the results of intracellular reactive oxygen species production and activation of oxidative stress response signaling. These results indicate that the acute toxicity of Maillard reaction products is closely related to their ability to induce oxidative stress, and that DHP-3 is a particularly strong inducer of oxidative stress and thus exhibits high cytotoxicity among Maillard reaction products. In addition, we have shown that a comprehensive analysis comparing multiple Maillard reaction products is effective for elucidating their complex and diverse toxicities.

Protective effect of Aronia melanocarpa juice against acrylamide-induced cellular toxicity.

Acrylamide (AA) a widely used industrial chemical is also formed during food processing by the Maillard reaction, which makes its exposure to humans almost unavoidable. In this study, we used Schizosaccharomyces pombe as a model organism to investigate AA toxicity (10 or 20 mM concentration) in eukaryotes. In S. pombe, AA delays cell growth causes oxidative stress by enhancement of ROS production and triggers excitement of the antioxidant defence system resulting in the division arrest. Aronia fruit contains a variety of health-promoting substances with considerable antioxidant potential. Therefore, Aronia juice supplementation was tested to evaluate its protective effect against AA-derived perturbations of the organism. Cell treatment with several Aronia juice concentrations ranging from 0 to 2% revealed the best protective effect of 1 or 2% Aronia juice solutions. Both chosen Aronia juice concentrations alleviated AA toxicity through the improvement of the antioxidant cell capacity and metabolic activity by their strong ROS scavenging property. Efficiency of Aronia juice cell protection is dose dependent as the 2% solution led to significantly higher cellular defence compared with 1%. Due to the high similarity of biological processes of S. pombe with higher eukaryotes, the protective effect of Aronia juice against AA toxicity might also apply to higher organisms.

Repeated administration of acrylamide for 28 days suppresses adult neurogenesis of the olfactory bulb in young-adult rats.

Acrylamide (AA) is a neurotoxicant that inhibits synaptic function in distal axons. We previously found that AA decreased neural cell lineages during late-stage differentiation of adult hippocampal neurogenesis and downregulated genes related to neurotrophic factor, neuronal migration, neurite outgrowth, and synapse formation in the hippocampal dentate gyrus in rats. To investigate whether olfactory bulb (OB)-subventricular zone (SVZ) neurogenesis is similarly affected by AA exposure, AA was administered to 7-week-old male rats via oral gavage at doses of 0, 5, 10, and 20 mg/kg for 28 days. Immunohistochemical analysis revealed that AA decreased the numbers of doublecortin-positive (+) cells and polysialic acid-neural cell adhesion molecule+ cells in the OB. On the other hand, the numbers of doublecortin+ cells and polysialic acid-neural cell adhesion molecule+ cells in the SVZ did not change with AA exposure, suggesting that AA impaired neuroblasts migrating in the rostral migratory stream and OB. Gene expression analysis in the OB revealed that AA downregulated Bdnf and Ncam2, which are related to neuronal differentiation and migration. These results suggest that AA decreased neuroblasts in the OB by suppressing neuronal migration. Thus, AA decreased neuronal cell lineages during late-stage differentiation of adult neurogenesis in the OB-SVZ, similar to the effect on adult hippocampal neurogenesis.

Biological evaluation of polycyclic chalcone based acrylamides in human MCF-7 and HeLa cancer cell lines.

Breast and cervical cancer account for the majority of cancer-narrated fatalities among women worldwide, necessitating the development of novel, effective therapeutic ways to combat the disease. In this study, we synthesized 6-methoxy naphthalene and anthracene-based acrylamide chalcone (NBA and ABA) and evaluated its activity for cell multiplication inhibition against two cancer cell lines from humans such as MCF-7 (Human Breast) and HeLa (Cervical) by MTT assay. Physiochemical characterization, such as FT-IR and NMR analyses, validated the synthesized NBA and ABA. Both NBA and ABA have shown antiproliferative action against two cancer cell lines, each with IC50 values of 38.46 and 48.25 µg/mL for HeLa cells and 38.02 and 36.35 µg/mL for MCF-7 cell lines. The results suggest that these acrylamide chalcones for cancer therapy at the lowest concentration. NBA and ABA could prevent cervical and breast cancer in-vitro, and their anti-cancer activity was closely related to methoxy-substituted naphthalene, anthracene ring, α, ß-unsaturated carbonyl and amide group. According to docking data, the NBA and ABA have dock scores ranging from -8.7 to -11.44 kcal/mol. The highest dock score for compound ABA was -11.58 kcal/mol and compound NBA was -10.77 kcal/mol with Braf (5VAM) binding site.