Growth Inhibitory Effects Research Articles

Riboflavin-Induced DNA Damage and Anticancer Activity in Breast Cancer Cells under Visible Light: A TD-DFT and In Vitro Study.

Targeted treatments for breast cancer that minimize harm to healthy cells are highly sought after. Our study explores the potentiality of riboflavin as a targeted anticancer compound that can be activated by light irradiation. Here, we integrated time-dependent density functional theory (TD-DFT) calculations and an in vitro study under visible light. The TD-DFT calculations revealed that the electronic charge transferred from the DNA base to riboflavin, with the most significant excitation peak occurring within the visible light range. Guided by these insights, an in vitro study was conducted on the breast cancer cell lines MCF-7 and MDA-MB-231. The results revealed substantial growth inhibition in these cell lines when exposed to riboflavin under visible light, with no such impact observed in the absence of light exposure. Interestingly, riboflavin exhibited no/minimal growth-inhibitory effects on the normal cell line L929, irrespective of light conditions. Moreover, through EtBr displacement (DNA-EtBr) and the TUNEL assay, it has been illustrated that, upon exposure to visible light, riboflavin can intercalate within DNA and induce DNA damage. In conclusion, under visible light conditions, riboflavin emerges as a promising candidate with a selective and effective potent anticancer agent against breast cancer while exerting a minimal influence on regular cellular activity.

The Growth Inhibitory Effect of Resveratrol and Gallic Acid on Prostate Cancer Cell Lines through the Alteration of Oxidative Stress Balance: the Interplay between Nrf2, HO-1, and BACH1 Genes.

The association between oxidative stress and prostate cancer (PC) has been demonstrated both epidemiologically and experimentally. Balance in reactive oxygen species (ROS) levels depends on multiple factors, such as the expression of Nrf2, HO-1, and BACH1 genes. Natural polyphenols, such as resveratrol (RSV) and gallic acid (GA), affect cellular oxidative profiles. The present study investigated the possible effects of GA and RSV on the oxidative profiles of PC3 and DU145 cells, as well as Nrf2, HO-1, and BACH1 gene expression to achieve an understanding of the mechanisms involved. PC3 and DU145 cells were treated with ascending concentrations of RSV and GA for 72h. Then cell growth and mRNA expression of Nrf2, HO-1, and BACH1 genes were analyzed by real-time PCR. Various spectrophotometric analyses were performed to measure oxidative stress markers. RSV and GA significantly decreased the growth of PC3 and DU145 cells compared to the control group in a concentration-dependent manner. RSV and GA also decreased ROS production in PC3 cells, but in DU145 cells, only the latter polyphenol significantly decreased ROS content. In addition, RSV and GA had ameliorating effects on SOD, GR, GPX, and CAT activities and GSH levels in both cell lines. Also, RSV and GA induced HO- 1 and Nrf2 gene expression in both cell lines. BACH1 gene expression was induced by RSV only at lower concentrations, in contrast to GA in both cell lines. Our data suggest that RSV and GA can prevent the growth of prostate cancer cells by disrupting oxidative stress-related pathways, such as changes in Nrf2, HO-1, and BACH1 gene expression.

IκBα kinase inhibitor BAY 11-7082 promotes anti-tumor effect in RAS-driven cancers

BackgroundOncogenic mutations in the RAS gene are associated with uncontrolled cell growth, a hallmark feature contributing to tumorigenesis. While diverse therapeutic strategies have been diligently applied to treat RAS-mutant cancers, successful targeting of the RAS gene remains a persistent challenge in the field of cancer therapy. In our study, we discover a promising avenue for addressing this challenge.MethodsIn this study, we tested the viability of several cell lines carrying oncogenic NRAS, KRAS, and HRAS mutations upon treatment with IkappaBalpha (IκBα) inhibitor BAY 11-7082. We performed both cell culture-based viability assay and in vivo subcutaneous xenograft-based assay to confirm the growth inhibitory effect of BAY 11-7082. We also performed large RNA sequencing analysis to identify differentially regulated genes and pathways in the context of oncogenic NRAS, KRAS, and HRAS mutations upon treatment with BAY 11-7082.ResultsWe demonstrate that oncogenic NRAS, KRAS, and HRAS activate the expression of IκBα kinase. BAY 11-7082, an inhibitor of IκBα kinase, attenuates the growth of NRAS, KRAS, and HRAS mutant cancer cells in cell culture and in mouse model. Mechanistically, BAY 11-7082 inhibitor treatment leads to suppression of the PI3K-AKT signaling pathway and activation of apoptosis in all RAS mutant cell lines. Additionally, we find that BAY 11-7082 treatment results in the downregulation of different biological pathways depending upon the type of RAS protein that may also contribute to tumor growth inhibition.ConclusionOur study identifies BAY 11-7082 to be an efficacious inhibitor for treating RAS oncogene (HRAS, KRAS, and NRAS) mutant cancer cells. This finding provides new therapeutic opportunity for effective treatment of RAS-mutant cancers.

Penicianstinoids F-K, six undescribed meroterpenoids from the marine algicolous fungus Penicillium sp. RR-DL-1-7

Six previously undescribed meroterpenoids, penicianstinoids F-K (1–6), together with four known analogues, dehydroaustinol (7), dehydroaustin (8), penicianstinoid A (9), and furanoaustinol (10), were isolated from the cultures of the algicolous fungus Penicillium sp. RR-DL-1-7, derived from the red alga Rhodomela confervoides. Their structures and relative configuration were established by detailed spectroscopic analysis of NMR and HR-MS experiments, and the absolute configurations were assigned by X-ray diffraction and ECD spectral analysis. None of the isolates showed obvious growth inhibitory effects against five plankton and four bacteria species tested.

Mechanisms of Cancerprotective Effects of Phytosterols. Literature Review

Cancer is recognized as the second leading cause of mortality in the Russian Federation. Prolonging the life of oncology patients involves treatment with toxic drugs, causing multiple side effects. Today, scientists around the world are striving to find non-toxic drugs. The present study explores phytosterols. Phytosterols refer to a class of steroids widely distributed in plants as an essential component of plant cell membranes. They include stigmasterol, beta-sitosterol, and campesterol. Stigmasterol has been found to increase the expression of proapoptotic genes (Bax, p53) and decrease the expression of the antiapoptotic gene Bcl-2 in HepG2 liver cancer cells. Stigmasterol is able to induce cell arrest in G0-G1 phase (stationary phase), resulting in fewer cells in the G2/M phase (division phase). It induces apoptosis and protective autophagy in gastric cancer cells while inhibiting the Akt/mTOR signaling pathway. β-sitosterol exhibits growth inhibitory and cytotoxic effects against a number of established cancer cell lines in vitro and in vivo, and remains free from acute/subacute toxic effects. β-sitosterol is widely used to treat chronic prostate diseases. In 2020, spendings on dietary supplements rich in beta-sitosterol accounted for $24 827 065 in the USA. Campesterol induces cell apoptosis via the mitochondrial pathway. It appears cytotoxic to U937 hepatocellular cancer cells. Campesterol induces cell apoptosis and activates proapoptotic signaling in ovarian cancer cell lines of a person. The present literature review demonstrates that specific substances in this group, beta-sitosterol, stigmasterol, and campesterol, provide pronounced antitumor effects.

Antimycobacterial and Anticancer Properties of Myrtus communis Leaf Extract

Background: Plant-derived products or extracts are widely used in folk/traditional medicine to treat several infections, ailments, or disorders. A well-known medicinal herb, Myrtus communis is an evergreen fragrant plant native to the Mediterranean region that has been used for ages in traditional medicine around the world. Materials and methods: The microplate alamarBlue assay and the well diffusion method were used to evaluate the zone of inhibition and MIC, respectively. The double-disc diffusion method was used to investigate the synergy between antibiotics and the extract. The crystal violet method was used to investigate biofilm development. The SulphoRhodamine-B assay and DNA flow cytometry were used to investigate the proliferation and subsequent distribution of cells among different phases of the cell cycle. The apoptotic and necrotic phases of the cancer cells were examined using flow cytometry in conjunction with Annexin V-FITC/PI labeling. Using the IBM SPSS statistical program, a one-way ANOVA with Tukey’s post hoc test was employed for statistical analysis. Results: The ethanolic leaf extract of M. communis showed a strong growth inhibition effect (zone of inhibition: 20.3 ± 1.1–26.3 ± 2.5 mm, MIC: 4.88–312.5 µg/mL, and MBC: 39.07–1250 μg/mL) against several rapidly growing and slow-growing mycobacterial strains in a dose-dependent manner. Damage to the cell wall of bacterial cells was determined to be the cause of the antimycobacterial action. The extract inhibited biofilm formation (MBIC of 9.7 µg/mL) and eradicated already-formed mature and ultra-mature biofilms of M. smegmatis, with MBEC values of 78 µg/mL and 156 µg/mL, respectively. Additionally, the extract exhibited potent anticancer effects against diverse cancer cell lines of the breast (MCF-7), liver (HepG2), cervix (HeLa), and colon (HCT116) (IC50 for HCT116: 83 ± 2.5, HepG2: 53.3 ± 0.6, MCF-7: 41.5 ± 0.6, and HeLa: 33.3 ± 3.6) by apoptosis after arresting the cells in the G1 phase of the cell cycle. Conclusions: These results suggest that M. communis leaf extract is a potential source of secondary metabolites that could be further developed as potential anticancer and antimycobacterial agents to treat diverse types of cancers and mycobacterial infections.

Activity of Mangrove-Derived Fusarium equiseti 20CB07RF Extract Against Clinical, Antibacterial-Resistant Pseudomonas aeruginosa

Endophytic fungi originating from mangroves are potential sources of secondary metabolites with varying bioactivities. This research explores the bioactive metabolites produced by endophytes derived from mangrove plants. Endophytic fungi were collected from various parts of several mangrove plants (roots, stems, and leaves, as well as the surrounding mud). A total of 17 endophytics fungi were obtained. The isolates were derived from the leaves (1 isolate), stems (8 isolates), roots (5 isolates), and surrounding mud (3 isolates). A single fungal colony was cultured using solid-state fermentation for 14 days. The fermented fungal biomass was extracted using ethyl acetate (EtOAc) and evaluated for its antibacterial activity against clinical pathogenic bacteria. In the preliminary screening, the EtOAc extract of the CB07RF1 isolate exhibited notable growth-inhibitory effects against Pseudomonas aeruginosa. The isolate was verified by molecular identification using a study of the rDNA internal transcribed spacer (ITS) sequence, revealed that isolate CB07RF1 was very similar to Fusarium equiseti (99% similarity). Isolate 20CB07RF1, obtained by solid-state fermentation using a rice medium indicated as peptide compound group, and featured active components that exhibited potent growth inhibitory activity against Pseudomonas aeruginosa at a concentration of 12.5 mg/mL. This study demonstrates, for the first time, that Fusarium equiseti extracts grown in a rice medium contain antimicrobial compounds that can inhibit the growth of P. aeruginosa, an important clinical pathogen known for its antibacterial resistance. These findings accent mangrove endophytic fungi as important sources of bioactive compounds and will advance related research in the fields of biotechnology, pharmacology, and life sciences.

PH-Sensitive doxorubicin delivery using zinc oxide nanoparticles as a rectified theranostic platform: in vitro anti-proliferative, apoptotic, cell cycle arrest and in vivo radio-distribution studies.

Despite enormous advancements in its management, cancer is the world's primary cause of mortality. Therefore, tremendous strides were made to produce intelligent theranostics with mitigated side effects and improved specificity and efficiency. Thus, we developed a pH-sensitive theranostic platform composed of dextran immobilized zinc oxide nanoparticles, loaded with doxorubicin and radiolabeled with the technetium-99m radionuclide (99mTc-labelled DOX-loaded ZnO@dextran). The platform measured 11.5 nm in diameter with -12 mV zeta potential, 88% DOX loading efficiency and 98.5% radiolabeling efficiency. It showed DOX release in a pH-responsive manner, releasing 93.1% cumulatively at pH 5 but just 7% at pH 7.4. It showed improved intracellular uptake, which resulted in a high growth suppressive effect against MCF-7 cancer cells as compared to the free DOX. It boasted a 4 times lower IC50 than DOX, indicating its significant anti-proliferative potential (0.14 and 0.55 μg ml-1, respectively). The in vitro biological evaluation revealed that its molecular mode of anti-proliferative action included downregulating Cdk-2, which provoked G1/S cell cycle arrest, and upregulating both the intracellular ROS level and caspase-3, which induced apoptosis and necrosis. The in vivo experiments in Ehrlich-ascites carcinoma bearing mice demonstrated that DOX-loaded ZnO@dextran showed a considerable 4-fold increase in anti-tumor efficacy compared to DOX. Moreover, by utilizing the diagnostic radionuclide (99mTc), the radiolabeled platform (99mTc-labelled DOX-loaded ZnO@dextran) was in vivo monitored in tumor-bearing mice, revealing high tumor accumulation (14% ID g-1 at 1 h p.i.) and reduced uptake in non-target organs with a 17.5 T/NT ratio at 1 h p.i. Hence, 99mTc-labelled DOX-loaded ZnO@dextran could be recommended as a rectified tumor-targeted theranostic platform.

Development and Evaluation of Bioconverted Milk with Anti-Microbial Effect against Periodontal Pathogens and α-Glucosidase Inhibitory Activity

To decrease periodontal pathogens and increase the number of beneficial bacteria, probiotics and bioactive compounds made via microbial bioconversion are recently used. In addition, the interest regarding probiotics-mediated bioconversion with popular medicinal plants is increasing. Artemisia herba-alba, a type of wormwood, has recently been attention as a medicinal plant due to its various bioactive compounds. Therefore, we developed bioconverted milk containing A. herba-alba that effectively inhibited periodontal pathogens and α-glucosidase. To select the appropriate lactic acid bacteria for the probiotic candidate strain, 74 strains of lactic acid bacteria were screened. Among them, Lactiplantibacillus plantarum SMFM2016-RK was chosen as the probiotic due to its beneficial characteristics such as high acid and bile tolerance, antioxidant activity, and α-glucosidase inhibition. Based on the minimal bactericidal concentration against three periodontal pathogens, the following appropriate concentrations of Artemisia herba-alba extract were added to milk: 5 mg/mL of A. herba-alba ethanol extract and 25 mg/mL of A. herba-alba hot-water extract. Four bioconverted milks (BM), BM1, BM2, BM3, and BM4, were produced by combining L. plantarum SMFM2016-RK alone, L. plantarum SMFM2016-RK and ethanol extract, L. plantarum SMFM2016-RK and hot-water extract, and L. plantarum SMFM2016-RK with both extracts. As a result of antimicrobial activity, BM3 inhibited the growth of Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis the most, and BM4 suppressed the growth of Fusobacterium nucleatum the most. In addition, bioconverted milk containing A. herba-alba (BM2, BM3, and BM4) inhibited α-glucosidase more effectively than BM1. The whole genome of L. plantarum SMFM2016-RK was obtained, and 3135 CDS, 67 tRNA, and 16 RNA were predicted. The genome annotation of L. plantarum SMFM2016-RK revealed 11 CDS related to proteolysis and amino acid metabolism and 2 CDS of phenolic acid-metabolizing enzymes. In conclusion, A. herba-alba-added milk bioconverted by L. plantarum SMFM2016-RK displayed both the growth inhibitory effect on periodontal pathogens and the α-glucosidase inhibitory activity; thus, it necessitates to evaluate the effects on the alleviation of periodontal diseases and glycemic control through future animal experiments.

ANTIMICROBIAL EFFECT OF TOOTHPASTES CONTAINING BIRCH EXTRACT AND NANO-HYDROXYAPATITES

The study investigates the antimicrobial efficacy of toothpaste formulations incorporating nano-hydroxyapatite (nHAP) and birch extract. Toothpastes were evaluated for their ability to inhibit bacterial growth, with observations revealing varied sensitivities among bacterial species to different formulations. Notably, toothpastes containing both nHAP and zinc exhibited heightened antimicrobial activity, while the addition of birch extract introduced variability in inhibition reactions across species. Further analysis delineated differences in effectiveness between nHAP-only and nHAP-birch extract formulations, suggesting the role of secondary metabolites in enhancing antibacterial properties. The study highlights toothpaste P11 as the most effective inhibitor of bacterial growth, offering a balanced combination of remineralization and antibacterial properties, except for S. mutans strain. Future research directions include time-course tests to assess long-term efficacy and oral microbiome studies to understand broader effects on oral microflora, informing the development of more targeted oral care products.

CsABCG11.2 mediates theanine uptake to alleviate cadmium toxicity in tea plants (Camellia sinensis)

Theanine (Thea) is a unique metabolite in tea plants, but its physiological functions remain elusive. A low soil pH increases cadmium (Cd) availability, affecting the quality of tea plant products. In this study, we found that Thea reversed the Cd-induced reduction in free amino acid (FAA) and caffeine (CAF) in the young tea leaves, as well as the down-regulation in the expression of nitrate transporters CsNRT1.2 and CsNRT2.5, and genes responsible for the nitrogen (N) assimilation. We demonstrated that Thea could alleviate Cd-induced oxidative stresses and enhance photosynthesis. Moreover, an ATP-binding cassette (ABC) transporter, CsABCG11.2, could uptake distinct Cd substrates and the five major amino acids in tea plants. Heterologous expression of CsABCG11.2 in yeast indicated a competitive absorption between Cd and Thea in a concentration-dependent pattern. CsABCG11.2-overexpressing Arabidopsis plants exhibited increased sensitivity to Cd due to enhanced Cd concentration, accumulation in the shoots, and reduction in the primary root length. Exogenous application of Thea at environmentally regular levels attenuated the adverse effects of Cd-induced growth inhibition and chlorosis in CsABCG11.2-overexpressing Arabidopsis plants. Knockdown of CsABCG11.2 tea plants significantly lowered Cd levels in young shoots. Our results suggest that Thea plays beneficial roles in alleviating Cd stress directly or indirectly by modulating CsABCG11.2-mediated Cd uptake and translocation within plants.

ITGB6 as an inhibitor of T-cell killing via modulation of paracrine TGFβ signaling in pancreatic ductal adenocarcinoma.

e16334 Background: Immunotherapy has experienced limited success in PDAC, with αPD-1 therapy being approved only in a subset that makes up < 2% of all PDAC cancers. TGFβ is a contributor to T-cell suppression in the PDAC tumor microenvironment. However, the success of blocking TGFβ in preclinical models has failed to translate into the clinic due to the off-target effects of systemic TGFβ blockade. Integrin ITGB6 is an activator of the inert latent TGFβ into the active, immunosuppressive form. Consequently, inhibition of ITGB6 is a potent and targeted therapeutic approach for disrupting TGFβ to overcome T-cell suppression in PDAC. Methods: Analysis of TCGA molecular and survival data was performed to determine the specificity and prognostic value of ITGB6 in PDAC. Subsequently, candidate cell lines were screened for ITGB6 expression using flow cytometry to facilitate an in vitro model. Using a lentiviral system, PDAC cells were transduced with a doxycycline-inducible short hairpin RNA (shRNA) knockdown (KD) of ITGB6. Both KD and control shRNA cell lines were induced with doxycycline and subsequently co-cultured with TALL-104 T-cells. Furthermore, conditioned media was analyzed for secreted active TGFβ levels using a luciferase-based TGFβ reporter cell line. Finally, a clonogenic assay was performed to determine the autocrine effects of TGFβ activation in PDAC. Results: ITGB6 is highly specific to PDAC and also shows upregulation in comparison to normal pancreatic tissue (FC 3.38, p < 0.0001). Capan-2 cells were chosen as a model for high integrin PDAC (Capan-2 99.73% cells ITGB6+, negative control: HCT116WT 0.96% cells ITGB6+). Fluorescent microscopy of the co-culture revealed that the KD of ITGB6 increased T-cell killing over 24 hours (Capan-2 CTRL shRNA 7.71%±3.63 dead vs. Capan-2 ITGB6 shRNA 21.68%±4.57 dead, p < 0.05). Media from ITGB6 KD cells contained significantly decreased TGFβ (+TGFβ: 673000 RLU vs. CTRL: 175500 RLU, p = 0.015). A clonogenic assay of Capan-2 cells treated with active-TGFβ demonstrates that PDAC cells resist the autocrine growth inhibitory effects of TGFβ through loss of SMAD4. TCGA survival data revealed ITGB6 as prognosis marker in PDAC (high ITGB6 median survival 16.79 mos, vs. low ITGB6 21.88 mos, HR = 2.730, p < 0.004). Conclusions: Survival data that clearly demonstrates the poor prognosis of ITGB6 expression, as well as the presently proposed mechanism of immunosuppression, provide ample justification for deploying anti-ITGB6 combination therapies to in vivo studies that facilitate translation of our findings into therapeutic clinical trials.

Phase II study of a PARP inhibitor, talazoparib, in HER2- metastatic breast cancer (MBC) with a somatic BRCA1/2mutation identified in a cell-free DNA or tumor tissue genotyping assay.

TPS1143 Background: PARP inhibitors are approved for germline BRCA1/2mutant MBC but the applicability of these well-tolerated oral targeted therapies is limited, as germline BRCA1/2mutations account for 5% of breast cancer. We demonstrated that pathogenic somatic BRCA1/2mutations are detectable in cell-free DNA and tumor tissue genotyping assays in a subset of HER2- MBC, in patients who are not known germline BRCA1/2carriers. In a circulating tumor cell culture model derived from a patient with a pathogenic somatic BRCA1 mutation, we demonstrated that the growth inhibitory effect of a PARP inhibitor paralleled germline BRCA1/2mutant cultures. We hypothesize that somatic BRCA1/2mutations may be amenable to PARP inhibition. In this study, we are evaluating the efficacy of a PARP inhibitor in somatic BRCA1/2mutant MBC. The results may expand the population of patients who benefit from PARP inhibitors. Methods: In this phase II investigator-initiated clinical trial, 30 patients with HER2- MBC with pathogenic somatic BRCA1/2mutations (in the absence of a known germline BRCA1/2mutation) identified in a CLIA certified cell-free DNA or tumor tissue genotyping assay are being enrolled at 7 academic centers. Mutations are vetted for pathogenicity by genetic counselors using validated genomic databases such as ClinVar. Patients with metastatic triple-negative or hormone receptor positive (HR)+/HER2- breast cancer who received ≥1 prior therapy in the metastatic setting are eligible. Any number of prior therapies are acceptable, including a prior platinum (in absence of disease progression). Patients must have adequate baseline performance status and organ function. Patients are treated with talazoparib 1 mg/day until disease progression. Disease assessments occur at baseline and every 3 months via CT chest, abdomen, and pelvis, and bone scan. The primary endpoint is progression free survival (PFS) via RECIST 1.1. This study has 81% power to demonstrate the 12-week PFS is ≥53% (4% alpha). Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory endpoints, determined using serial cell-free DNA collected at baseline and monthly, include identifying resistance mutations, and evaluating the impact of mutant allele fraction and BRCA1/2reversion mutations on response. The Cancer Risk B (CR-B) assay, a novel method to identify double-strand break repair mutations in circulating blood cells, will be correlated with response. The study (NCT03990896) is open at Massachusetts General Hospital, University of California San Francisco, MD Anderson, Emory, Northwestern, and Vanderbilt and will open at Cornell, with 17 patients enrolled as of 2/2024. Clinical trial information: NCT03990896 .

The Effects of Metabolites from Three Vaginal Bacteria on the Syndecan-1 of Cervical Epithelial Cells

This study aims to explore the impact of metabolites from three vaginal bacteria on the expression of Syndecan 1 (SDC-1). Human cervical epithelial cells (HcerEpic) were separately incubated with the cell-free supernatants of Lactobacillus crispatus (LCS group), Gardnerella vaginalis (GVS group), and Atopobium vaginalis (AVS group). LCS showed a proliferative effect on HcerEpic, with the most significant effect observed at a concentration of 30% (P < 0.001). GVS and AVS exhibited some cytotoxicity, with significant growth inhibitory effects observed at concentrations of 30% and 40% (P < 0.01). Therefore, subsequent experiments were conducted using 30% LCS, 40% GVS, and 40% AVS. In terms of cellular morphology, compared to the Control group, the LCS group showed more frequent fusion of cell sheets, with no obvious changes in the morphology of individual cells. In the GVS and AVS groups, some individual cells became round and smaller, with reduced protrusions and even a small amount of floating cells. The metabolic products of the three vaginal bacteria significantly upregulated the expression of IL-1β, IL-6, and TNF-α in HcerEpic (P < 0.05). In the GVS and AVS groups, the level of SDC-1 on the surface of HcerEpic was significantly decreased (P < 0.01), while the concentration of SDC-1 in the cell culture supernatant was significantly increased (P < 0.0001). Additionally, the level of SDC-1 mRNA was significantly downregulated (P < 0.01). In the LCS group, no significant changes were observed in SDC-1 protein and mRNA expression (P > 0.05). LCS promotes HcerEpic proliferation, without significant impact on SDC-1 expression and shedding. This provides molecular evidence for LCS as a protective factor against human papillomavirus infection in the cervix. Metabolites of GV and AV inhibit HcerEpic proliferation, induce cytokine secretion, suppress SDC-1 transcription and expression, and promote SDC-1 shedding.

Preparation and biological evaluation of coumarin amide derivatives bearing fluorine as potential fungicides and anticancer agents

In order to find new potential fungicides and anticancer agents, a series of new coumarin amide derivatives bearing fluorine were synthesized and characterized spectroscopically. Compounds A6, B11, C2 and C7 were confirmed by X-ray diffraction further. The antifungal bioassays against five typical pathogenic fungi showed that compound C5 exhibited more remarkable fungicidal activities against Alternaria alternata (EC50 = 11.5 μg/mL), Colletotrichum gloeosporioides (EC50 = 18.0 μg/mL), Pyricularia grisea (EC50 = 33.8 μg/mL), surpassing kresoxim-methyl. Molecular docking result indicated that C5 displayed high binding affinity to chitinase, which plays crucial role in degradation and remodeling of fungal cell walls. In addition, the anticancer bioassays against three cancer cells demonstrated that compound A4 displayed excellent growth inhibitory effect against Hela cells with IC50 value of 8.13 μM, and low cytotoxicity against human normal cells BEAS-2B. Flow cytometric analysis further demonstrated that A4 significantly arrested cell cycle at the S phase and trigger apoptosis. With the above interesting biological profile, these coumarin derivatives could be used as anfungicides and anticancer candidates.

Melt electrowritten poly-lactic acid /nanodiamond scaffolds towards wound-healing patches

Multifunctional wound dressings, enriched with biologically active agents for preventing or treating infections and promoting wound healing, along with cell delivery capability, are highly needed. To address this issue, composite scaffolds with potential in wound dressing applications were fabricated in this study. The poly-lactic acid/nanodiamonds (PLA/ND) scaffolds were first printed using melt electrowriting (MEW) and then coated with quaternized β-chitin (QβC). The NDs were well-dispersed in the printed filaments and worked as fillers and bioactive additions to PLA material. Additionally, they improved coating effectiveness due to the interaction between their negative charges (from NDs) and positive charges (from QβC). NDs not only increased the thermal stability of PLA but also benefitted cellular behavior and inhibited the growth of bacteria. Scaffolds coated with QβC increased the effect of bacteria growth inhibition and facilitated the proliferation of human dermal fibroblasts. Additionally, we have observed rapid extracellular matrix (ECM) remodeling on QβC-coated PLA/NDs scaffolds. The scaffolds provided support for cell adhesion and could serve as a valuable tool for delivering cells to chronic wound sites. The proposed PLA/ND scaffold coated with QβC holds great potential for achieving fast healing in various types of wounds.

Development of a PAK4-targeting PROTAC for renal carcinoma therapy: concurrent inhibition of cancer cell proliferation and enhancement of immune cell response

Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation invitro and invivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.

Binary Proton Therapy of Ehrlich Carcinoma Using Targeted Gold Nanoparticles.

Proton therapy can treat tumors located in radiation-sensitive tissues. This article demonstrates the possibility of enhancing the proton therapy with targeted gold nanoparticles that selectively recognize tumor cells. Au-PEG nanoparticles at concentrations above 25 mg/L and 4 Gy proton dose caused complete death of EMT6/P cells in vitro. Binary proton therapy using targeted Au-PEG-FA nanoparticles caused an 80% tumor growth inhibition effect in vivo. The use of targeted gold nanoparticles is promising for enhancing the proton irradiation effect on tumor cells and requires further research to increase the therapeutic index of the approach.

Co-Delivery of Dragon's Blood and Alkanna tinctoria Extracts Using Electrospun Nanofibers: In Vitro and In Vivo Wound Healing Evaluation in Diabetic Rat Model.

The increasing prevalence of diabetic wounds presents a significant challenge due to the difficulty of natural healing and various obstacles. Dragon's blood (DB) and Alkanna tinctoria (AT) are well recognized for their potent healing abilities, which include potent antibacterial and anti-inflammatory activities. In this study, electrospun nanofibers (NFs) based on polyvinyl pyrrolidone (PVP) were co-loaded with both DB and AT, aiming to magnify their efficacy as wound-dressing applications for diabetic wound healing. The evaluation of these NFs as wound dressings was conducted using a streptozotocin-induced diabetic rat model. Electrospun NFs were prepared using the electrospinning of the PVP polymer, resulting in nanofibers with consistent, smooth surfaces. The loading capacity (LC) of AT and DB into NFs was 64.1 and 70.4 µg/mg, respectively, while in the co-loaded NFs, LC was 49.6 for AT and 57.2 µg/mg for DB. In addition, X-ray diffraction (XRD) revealed that DB and AT were amorphously dispersed within the NFs. The loaded NFs showed a dissolution time of 30 s in PBS (pH 7.4), which facilitated the release of AT and DB (25-38% after 10 min), followed by a complete release achieved after 180 min. The antibacterial evaluation demonstrated that the DB-AT mixture had potent activity against Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus). Along with that, the DB-AT NFs showed effective growth inhibition for both P. aeruginosa and S. aureus compared to the control NFs. Moreover, wound healing was evaluated in vivo in diabetic Wistar rats over 14 days. The results revealed that the DB-AT NFs improved wound healing within 14 days significantly compared to the other groups. These results highlight the potential application of the developed DB-AT NFs in wound healing management, particularly in diabetic wounds.

Regulatory feedback loop between circ-EIF4A3 and EIF4A3 Enhances autophagy and growth in colorectal cancer cells

Recent studies indicate that circular RNAs (circRNAs) are crucial in the progression of colorectal cancer (CRC). Eukaryotic translation initiation factor 4A3 (EIF4A3) has been identified as a promoter of circRNA production. The biological roles and mechanisms of EIF4A3-derived circRNA (circEIF4A3) in CRC cell autophagy remain poorly understood. This study explores the effects of circEIF4A3 on CRC cell growth and autophagy, aiming to elucidate the underlying molecular mechanisms. We discovered that EIF4A3 and circEIF4A3 synergistically enhance CRC cell growth. CircEIF4A3 sequesters miR-3126–5p, consequently upregulating EIF4A3. Further, circEIF4A3 increases EIF4A3 expression, which promotes autophagy by stabilizing ATG5 mRNA and enhances ATG7 protein stability through the stabilization of USP14 mRNA, a deubiquitinating enzyme. Upregulation of ATG5 and ATG7 counteracts the growth-inhibitory effects of EIF4A3 knockdown on CRC cells. Moreover, our findings demonstrate that EIF4A3 induces the formation of circEIF4A3 in CRC cells. In conclusion, a positive feedback loop between circEIF4A3 and EIF4A3 supports CRC cell growth by facilitating autophagy.