Growth Inhibition Research Articles

Identification of mechanism of the oncogenic role of FGFR1 in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most prevalent malignancy of the thyroid. Fibroblast growth factor receptor 1 (FGFR1) is highly expressed in PTC and works as an oncogenic protein in this disease. In this report, we wanted to uncover a new mechanism that drives overexpression of FGFR1 in PTC. Analysis of FGFR1 expression in clinical specimens and PTC cells revealed that FGFR1 expression was enhanced in PTC. Using siRNA/shRNA silencing experiments, we found that FGFR1 downregulation impeded PTC cell growth, invasion, and migration and promoted apoptosis in vitro, as well as suppressed tumor growth in vivo. Bioinformatic analyses predicted the potential USP7-FGFR1 interplay and the potential binding between YY1 and the FGFR1 promoter. The mechanism study found that USP7 stabilized FGFR1 protein via deubiquitination, and YY1 could promote the transcription of FGFR1. Our rescue experiments showed that FGFR1 re-expression had a counteracting effect on USP7 downregulation-imposed in vitro alterations of cell functions and in vivo suppression of xenograft growth. In conclusion, our study identifies the deubiquitinating enzyme USP7 and the oncogenic transcription factor YY1 as potent inducers of FGFR1 overexpression. Designing inhibitors targeting FGFR1 or its upstream inducers USP7 and YY1 may be foreseen as a promising strategy to control PTC development.

Covalent Organic Framework-Coated Polyimide Ion-Track-Etched Separator with High Thermal Stability for Developing Lithium-Ion Batteries with Long Lifespans.

Separators play a crucial role in inhibiting thermal runaway in lithium-ion batteries (LIBs). In this study, the doctor blade coating method and heavy-ion track etching technology were used to prepare a polyimide-based covalent organic framework (PI_COF) separator with excellent thermal stability and a long cycle life. Specifically, COF300 was simply coated on the surface of a polyimide-based track-etched membrane (PI_TEM) with straight through holes, which provided a rigid framework and high-temperature stability at 300 °C. These features were conducive to inhibiting thermal runaway, while porous COF300 with large holes increased the wettability of the electrolyte, facilitating lithium-ion migration and suppression of lithium dendrite growth; consequently, LIBs with an excellent cycling performance and a high rate capacity were obtained. The cell with the PI_COF separator delivered a high capacity of 90.0 mA h g-1 after 1000 cycles. The PI_COF separator with high thermal stability exhibited a long cycle life in LIBs. These features are beneficial for improving the safety characteristics of LIBs as well as for accelerating the practical application process of the PI_COF separator.

Evaluation of mRNA lipoplexes prepared using modified ethanol injection method as a tumor vaccine

We have previously demonstrated that messenger RNA (mRNA) lipoplexes composed of N-hexadecyl-N,N-dimethylhexadecan-1-aminium bromide (DC-1-16), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), and polyethylene glycol-cholesteryl ether (PEG-Chol) exhibited high protein expression in the lungs and spleen of mice after intravenous injection and induced high levels of antigen-specific IgG1 upon immunization. In this study, we optimized PEG modification in mRNA lipoplexes to reduce mRNA accumulation in the lungs and evaluated the suppression of tumor growth in mice bearing mouse lymphoma E.G7-ovalbumin (OVA) tumors by immunizing them with an intravenous injection of OVA mRNA lipoplexes. PEGylation of mRNA lipoplexes with 3 mol% PEG-Chol (LP-DC-1-16-3PCL) prevented agglutination of erythrocytes and reduced accumulation in the lungs. Intravenous injection of LP-DC-1-16-3PCL lipoplexes containing OVA mRNA into mice induced high levels of anti-OVA IgG1 (83,000 mU/mL) in serum, and exhibited a high cytotoxic activity (97%) against E.G7-OVA cells by the splenocytes of mice. Furthermore, immunization with LP-DC-1-16-3PCL lipoplexes containing OVA mRNA suppressed E.G7-OVA tumor growth compared to control mRNA. Based on these results, LP-DC-1-16-3PCL lipoplexes may be an effective mRNA vaccine for inducing antibody- and cytotoxic cell-mediated immune responses to tumors through intravenous injection.

Onvansertib treatment overcomes olaparib resistance in high-grade ovarian carcinomas

Occurrence of resistance to olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor (PARPi) approved in ovarian carcinoma, has already been shown in clinical settings. Identifying combination treatments to sensitize tumor cells and/or overcome resistance to olaparib is critical. Polo-like kinase 1 (PLK1), a master regulator of mitosis, is also involved in the DNA damage response promoting homologous recombination (HR)-mediated DNA repair and in the recovery from the G2/M checkpoint. We hypothesized that PLK1 inhibition could sensitize tumor cells to PARP inhibition. Onvansertib, a highly selective PLK1 inhibitor, and olaparib were tested in vitro and in vivo in BRCA1 mutated and wild-type (wt) ovarian cancer models, including patient-derived xenografts (PDXs) resistant to olaparib. The combination of onvansertib and olaparib was additive or synergic in different ovarian cancer cell lines, causing a G2/M block of the cell cycle, DNA damage, and apoptosis, much more pronounced in cells treated with the two drugs as compared to controls and single agents treated cells. The combined treatment was well tolerated in vivo and resulted in tumor growth inhibition and a statistically increased survival in olaparib-resistant-BRCA1 mutated models. The combination was also active, although to a lesser extent, in BRCA1 wt PDXs. Pharmacodynamic analyses showed an increase in mitotic, apoptotic, and DNA damage markers in tumor samples derived from mice treated with the combination versus vehicle. We could demonstrate that in vitro onvansertib inhibited both HR and non-homologous end-joining repair pathways and in vivo induced a decrease in the number of RAD51 foci-positive tumor cells, supporting its ability to induce HR deficiency and favoring the activity of olaparib. Considering that the combination was well tolerated, these data support and foster the clinical evaluation of onvansertib with PARPis in ovarian cancer, particularly in the PARPis-resistant setting.

Knockdown of CPSF4 Inhibits Bladder Cancer Cell Growth by Upregulating NRF1.

Increasing studies have shown that nuclear respiratory factor 1 (NRF1) deficiency frequently occurs in many human diseases, and its activation can protect neurons and other cells from degenerative diseases and malignant tumors. However, how NRF1 is regulated in bladder cancer remains unknown. Our research aims to reveal the role of leavage and polyadenylation-specific factor 4 (CPSF4) on the growth inhibition effect of bladder cancer and clarify its relationship with NRF1. Here, cell proliferation assay, transwell migration assay and multicellular tumor spheroids (MCTS) formation assay in the bladder cancer cell lines were carried out to measure tumor cell growth. Western bolt assay was carried out to identify the relationship between NRF1 and CPSF4. Also, subcutaneous xenograft tumors in nude mice were established to further validate the inhibition effect of CPSF4 on bladder tumor and the regulation on NRF1. The results in vitro showed that knockdown of CPSF4 strongly reduced the proliferation and migration, and inhibited MCTS formation in 5637 and HT1376 cell lines, while an additional knockdown of increased NRF1 induced by CPSF4 knockdown partially abolished these effects. The results in vivo showed that knockdown of CPSF4 strongly reduced the volume and weight of subcutaneous tumor, and decreased the expression of Ki-67 in tumor tissue, while NRF1 knockdown partially reversed these effects induced by CPSF4 knockdown. Western bolt assay demonstrated that CPSF4 could negatively regulate NRF1. Our results indicated that knock-down of CPSF4 inhibited bladder cancer cell growth by upregulating NRF1, which might provide evidence of CPSF4 as a therapeutic target for bladder cancer.

A picomolar inhibitor of the Plasmodium falciparum IPP pathway.

We identified MMV026468 as a picomolar inhibitor of blood-stage Plasmodium falciparum. Phenotyping assays, including isopentenyl diphosphate rescue of parasite growth inhibition, demonstrated that it targets MEP isoprenoid precursor biosynthesis. MMV026468-treated parasites showed an overall decrease in MEP pathway intermediates, which could result from inhibition of the first MEP enzyme DXS or steps prior to DXS such as regulation of the MEP pathway. Selection of MMV026468-resistant parasites lacking DXS mutations suggested that other targets are possible. The identification of MMV026468 could lead to a new class of antimalarial isoprenoid inhibitors.

Gallic Acid Enhances the Efficacy of BCR::ABL1 Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia through Inhibition of Mitochondrial Respiration and Modulation of Oncogenic Signaling Pathways.

While BCR::ABL1 tyrosine kinase inhibitors have transformed the treatment paradigm for chronic myeloid leukemia (CML), disease progression and treatment resistance due to BCR::ABL1-dependent and BCR::ABL1-independent mechanisms remain a therapeutic challenge. Natural compounds derived from plants have significantly contributed to cancer pharmacotherapy. This study investigated the efficacy of an active component of Leea indica, a local medicinal plant, in CML. Using high-performance liquid chromatography-electrospray ionization-mass spectrometry, a chemical constituent from L. indica extract was isolated and identified as gallic acid. Commercially obtained gallic acid was used as a chemical standard. Gallic acid from L. indica inhibited proliferation and induced apoptosis in CML cell lines, as did the chemical standard. Furthermore, gallic acid induced apoptosis and decreased the colony formation of primary CML CD34+ cells. The combination of isolated gallic acid or its chemical standard with BCR::ABL1 tyrosine kinase inhibitors resulted in a significantly greater inhibition of colony formation and cell growth compared to a single drug alone. Mechanistically, CML cells treated with gallic acid exhibited the disruption of multiple oncogenic pathways including ERK/MAPK, FLT3 and JAK/STAT, as well as impaired mitochondrial respiration. Rescue studies showed that gallic acid is significantly less effective in inducing apoptosis in mitochondrial respiration-deficient ρ0 cells compared to wildtype cells, suggesting that the action of gallic acid is largely through the inhibition of mitochondrial respiration. Our findings highlight the therapeutic potential of L. indica in CML and suggest that gallic acid may be a promising lead chemical constituent for further development for CML treatment.

Exogenous GA3 Enhances Nitrogen Uptake and Metabolism under Low Nitrate Conditions in 'Duli' (Pyrus betulifolia Bunge) Seedlings.

'Duli' (Pyrus betulifolia Bunge) is one of the main rootstocks of pear trees in China. Gibberellin (GA) is a key plant hormone and the roles of GA in nitrate (NO3-) uptake and metabolism in plants remain unclear. In this study, we investigated the effects of exogenous GA3 on the N metabolism of 'Duli' seedlings under NO3- deficiency. The results showed that exogenous GA3 significantly improves 'Duli' growth under NO3- deficiency. On the one hand, GA3 altered the root architecture, increased the content of endogenous hormones (GA3, IAA, and ZR), and enhanced photosynthesis; on the other hand, it enhanced the activities of N-metabolizing enzymes and the accumulation of N, and increased the expression levels of N absorption (PbNRT2) and the metabolism genes (PbNR, PbGILE, PbGS, and PbGOGAT). However, GA3 did not delay the degradation of chlorophyll. Paclobutrazol had the opposite effect on growth. Overall, GA3 can increase NO3- uptake and metabolism and relieve the growth inhibition of 'Duli' seedlings under NO3- deficiency.

Study on the Identification, Biological Characteristics, and Fungicide Sensitivity of the Causal Agent of Strawberry Red Core Root Rot

Strawberry red core root rot disease affects the growth and yield of strawberry (Fragaria ananassa Duch), which leads to economic losses in China. The study employed a tissue separation method to isolate and identify the causal agent responsible for strawberry red core root rot. This was achieved by the observation of its morphological characteristics, sequencing analyses, and pathogenicity tests. The sensitivity of five chemical fungicides against the two species of Fusarium was determined using the mycelial growth rate method, and the biological characteristics of the two species were examined. The pathogens were identified as Fusarium solani and Fusarium oxysporum. The optimal conditions for the mycelial growth of F. solani and F. oxysporum were determined to be potato sucrose agar at 25 °C and pH 6, and potato dextrose agar at 30 °C and pH 8, respectively, with a 24:24 light cycle. The most suitable carbon and nitrogen sources for the mycelial growth of F. solani were sucrose and sodium nitrate (NaNO3), while for F. oxysporum, they were glucose and peptone. A fungicide sensitivity test indicated that Prochloraz had a good inhibitory effect on the growth of F. solani and F. oxysporum with EC50 values of 0.088 mg L−1 and 0.162 mg. The growth inhibition effect of Azoxystrobin to F. solani and Carbendazim to F. oxysporum was not obvious. This study provides a theoretical basis for further research on strawberry red core root disease and its prevention.

Eryngial: An α,β-Unsaturated Fatty Aldehyde as the Major Phytotoxin in Spiny Coriander (Eryngium foetidum L.) Essential Oil.

Weed species many times possess allelochemicals as a part of their survival strategy. These metabolites can be potential targets in search of natural phytotoxins. This study aims to evaluate the phytotoxic ability of fatty aldehyde-rich essential oil from spiny coriander (Eryngium foetidum) leaves, also known as fitweed or spiritweed and to further identify the active phytotoxins. This oil dose-dependently inhibited the wheatgrass coleoptile and radicle growth in multiple bioassays with half maximal inhibitory concentration (IC50) 30.6-56.7 μg/mL, while exhibiting a less pronounced effect on the germination (IC50 181.8 μg/mL). The phytotoxicity assessment of two oil constituents identified eryngial (trans-2-dodecenal), exclusively major fatty aldehydic constituent as the potent growth inhibitor with IC50 in the range 20.8-36.2 μg/mL during an early phase of wheatgrass emergence. Eryngial-inspired screening of eleven saturated fatty aldehydes and alcohols did not find a significantly higher phytotoxic potency. In an open vessel, eryngial as the supplementation in agar medium, dose-dependently inhibited the growth of pre-germinated seeds of one monocot (bermudagrass) and one dicot (green amaranth) weed species with IC50 in the range 23.8-65.4 μg/mL. The current study identified eryngial, an α,β-unsaturated fatty aldehyde of coriander origin to be a promising phytotoxic candidate for weed control.

Synthesis, Characterization, DNA Binding, Biological Significance, and Molecular Docking Approaches of a Palladium(II) Complex with Ciprofloxacin for More Efficient Therapy.

To evaluate the biotransformation and the mechanism of binding as well as the biological impact of metal-based- drugs involving Pd(II), known to have high potency and low toxicity for use as anticancer therapeutics, in the present study, a newly synthesized palladium (II) complex, [Pd(CPF)(OH2)2]2+ (where CPF is ciprofloxacin), has been synthesized and characterized and thoroughly evaluated for its antimicrobial properties. The interaction of the diaqua complex with CT-DNA and BSA was studied through various techniques, including UV-vis spectroscopy, thermal denaturation, viscometry, gel electrophoresis, ethanol precipitation, and molecular docking studies. The results indicate that the complex exhibits a robust binding interaction with CT-DNA, possibly via minor groove binding and (or) electrostatic interactions. Furthermore, the complex displays good binding affinity towards BSA, indicating its potential as a target for DNA and BSA in biological media. The invitro cytotoxicity assay reveals that this complex can be classified as a promising cell growth inhibitor against MCF-7, HT-29, and A549. Thus, this newly synthesized palladium (II) complex is a promising candidate for further exploration as a potential anticancer therapeutic.

Anticandidal activity of a wild Bacillus subtilis NAM against clinical isolates of pathogenic Candida albicans

BackgroundResistance to antifungal medications poses a significant obstacle in combating fungal infections. The development of novel therapeutics for Candida albicans is necessary due to the increasing resistance of candidiasis to the existing medications. The utilization of biological control is seen as a more advantageous and less hazardous strategy therefore the objective of this study is to identify the antifungal properties of Bacillus subtilis against pathogenic C. albicans.ResultsWe conducted a study to evaluate the antifungal properties of three bacterial isolates against the human pathogen Candida albicans. One of the bacterial isolates exhibited a potent antifungal activity against this fungal pathogen. This bacterium was identified as Bacillus subtilis based on the 16Sr RNA gene sequence. It exhibited inhibitory efficacy ranging from 33.5 to 44.4% against 15 Candida isolates. The optimal incubation duration for achieving the maximum antifungal activity was determined to be 48 h, resulting in a mean inhibition zone diameter of 29 ± 0.39 mm. The Potato Dextrose agar (PDA) medium was the best medium for the most effective antifungal activity. Incubation temperature of 25oC and medium pH value of 8.0 were the most favorable conditions for maximum antagonistic activity that resulted fungal growth inhibition of 40 ± 0.16 and 36 ± 0.94 mm respectively. Furthermore, the addition of 10.5 mg/ml of bacterial filtrate to C. albicans colonies resulted in 86.51%. decrease in the number of germinated cells. The fungal cell ultrastructural responses due to exposure to B. subtilis filtrate after 48 h were investigated using transmission electron microscopy (TEM). It revealed primary a drastic abnormality that lead to cellular disintegration including folding and lysis of the cell wall, total collapse of the yeast cells, and malformed germ tube following the exposure to the filtrate. However, the control culture treatment had a characteristic morphology of the normal fungal cells featuring a consistently dense central region, a well-organized nucleus, and a cytoplasm containing several components of the endomembrane system. The cells were surrounded by a uniform and intact cell wall.ConclusionThe current study demonstrates a notable antifungal properties of B. subtilis against C. albicans as a result of production of bioactive components of the bacterial exudate. This finding could be a promising natural antifungal agent that could be utilized to combat C. albicans.

Synthesis and Antimicrobial Evaluation of 1H-1,2,3-Triazole-Linked Quinoline-Phenolic Natural Product Conjugates

A new library of quinoline–natural product conjugates bearing 1,2,3-triazole moiety as a linker has been synthesized using the copper(I) catalyzed azide-alkyne [3 + 2] cycloaddition reaction (CuAAC) methodology. The structure characterization of the synthesized compounds was achieved using NMR and HRMS analysis. The compounds were subsequently screened for their antimicrobial efficacies against methicillin resistant Staphylococcus aureus (MRSA), MDR Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Candida albicans, and Cryptococcus neoformans. The studied compounds generally displayed stronger inhibition of microbial cell growth compared to their parent phenolic natural products. Eugenol, thymol, guaiacol, and o-vanillin based 1H-1,2,3-triazole compounds exhibited the best antimicrobial profiles while the pathogen, A. baumannii showed the highest susceptibility to the hybrids. Precisely, hybrids 19a, 20b, and 25b derived from eugenol, thymol, and o-vanillin, respectively, exhibited over 50% growth inhibition of the pathogen. K. pneumoniae was however strongly resistant to the compound series. In silico docking studies of the representative compounds further explored the characteristic binding orientations of these compounds in the active sites of the bacterial and fungal proteins. Overall, we perceive that rational scaffold hopping of these compounds holds promise to offer novel antimicrobial agents with enhanced potency.

Ex vivo susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African Plasmodium falciparum, 2016-2023: a genotype-phenotype association study.

Given the altered responses to both artemisinins and lumefantrine in Eastern Africa, monitoring antimalarial drug resistance in all African countries is paramount. We measured the susceptibility to six antimalarials using ex vivo growth inhibition assays (IC50) for a total of 805 Plasmodium falciparum isolates obtained from travelers returning to France (2016-2023), mainly from West and Central Africa. Isolates were sequenced using molecular inversion probes (MIPs) targeting fourteen drug resistance genes across the parasite genome. Ex vivo susceptibility to several drugs has significantly decreased in 2019-2023 versus 2016-2018 parasite samples: lumefantrine (median IC50: 23·0 nM [IQR: 14·4-35·1] in 2019-2023 versus 13·9 nM [8·42-21·7] in 2016-2018, p<0·0001), monodesethylamodiaquine (35·4 [21·2-51·1] versus 20·3 nM [15·4-33·1], p<0·0001), and marginally piperaquine (20·5 [16·5-26·2] versus 18.0 [14·2-22·4] nM, p<0·0001). Only four isolates carried a validated pfkelch13 mutation. Multiple mutations in pfcrt and one in pfmdr1 (N86Y) were significantly associated with altered susceptibility to multiple drugs. The susceptibility to lumefantrine was altered by pfcrt and pfmdr1 mutations in an additive manner, with the wild-type haplotype (pfcrt K76-pfmdr1 N86) exhibiting the least susceptibility. Our study on P. falciparum isolates from West and Central Africa indicates a low prevalence of molecular markers of artemisinin resistance but a significant decrease in susceptibility to the partner drugs that have been the most widely used since a decade -lumefantrine and amodiaquine. These phenotypic changes likely mark parasite adaptation to sustained drug pressure and call for intensifying the monitoring of antimalarial drug resistance in Africa. This work was supported by the French Ministry of Health (grant to the French National Malaria Reference Center) and by the Agence Nationale de la Recherche (ANR-17-CE15-0013-03 to JC). JAB was supported by NIH R01AI139520. JR postdoctoral fellowship was funded by Institut de Recherche pour le Développement.

Ex vivo susceptibility to antimalarial drugs and polymorphisms in drug resistance genes of African Plasmodium falciparum, 2016-2023: a genotype-phenotype association study.

Background: Given the altered responses to both artemisinins and lumefantrine in Eastern Africa, monitoring antimalarial drug resistance in all African countries is paramount. Methods: We measured the susceptibility to six antimalarials using ex vivo growth inhibition assays (IC 50 ) for a total of 805 Plasmodium falciparum isolates obtained from travelers returning to France (2016-2023), mainly from West and Central Africa. Isolates were sequenced using molecular inversion probes (MIPs) targeting fourteen drug resistance genes across the parasite genome. Findings: Ex vivo susceptibility to several drugs has significantly decreased in 2019-2023 versus 2016-2018 parasite samples: lumefantrine (median IC 50 : 23·0 nM [IQR: 14·4-35·1] in 2019-2023 versus 13·9 nM [8·42-21·7] in 2016-2018, p<0·0001), monodesethylamodiaquine (35·4 [21·2-51·1] versus 20·3 nM [15·4-33·1], p<0·0001), and marginally piperaquine (20·5 [16·5-26·2] versus 18.0 [14·2-22·4] nM, p<0·0001). Only four isolates carried a validated pfkelch13 mutation. Multiple mutations in pfcrt and one in pfmdr1 (N86Y) were significantly associated with altered susceptibility to multiple drugs. The susceptibility to lumefantrine was altered by pfcrt and pfmdr1 mutations in an additive manner, with the wild-type haplotype ( pfcrt K76- pfmdr1 N86) exhibiting the least susceptibility. Interpretation: Our study on P. falciparum isolates from West and Central Africa indicates a low prevalence of molecular markers of artemisinin resistance but a significant decrease in susceptibility to the partner drugs that have been the most widely used since a decade -lumefantrine and amodiaquine. These phenotypic changes likely mark parasite adaptation to sustained drug pressure and call for intensifying the monitoring of antimalarial drug resistance in Africa.

Investigation on the Drug Release Efficacy of the Ibuprofen-Loaded ZIF-8/Fe3O4 NPs Nanocarrier.

In this work, a one-pot multicomponent synthesis of the ibuprofen-loaded Fe3O4 nanoparticles-supported zeolitic imidazolate framework-8 (Ibu-ZIF-8/Fe3O4 NPs) nanohybrid was carried out. The ZIF-8/Fe3O4 NPs nanohybrid was used as a drug carrier for the in vitro release of ibuprofen in a PBS solution. The structure and morphology of the synthesized materials were investigated by powder X-ray diffraction (PXRD) analysis, transmission electron microscopy (TEM) analysis, UV-visible absorption studies, FTIR spectroscopy, and thermogravimetric analysis (TGA). The ibuprofen release kinetics was studied by UV-visible spectroscopy. The mechanism of drug delivery was thoroughly investigated and the Higuchi model was found as the best-fitted model for the ibuprofen release study. The 20 wt % Fe3O4 NPs-supported ZIF-8 nanohybrid exhibited more than 95% ibuprofen release efficiency in phosphate buffer saline of pH 7.4 within 2 h. The separation ability of the nanohybrid was very good, and it was easily separated by a simple commercial magnet. In order to investigate the cell viability, the cytotoxicity of ZIF-8, Fe3O4 NPs, and ZIF-8/20 wt % Fe3O4 NPs was investigated using MTT assays against Leishmania donovani promastigotes. The ZIF-8/20 wt % Fe3O4 NPs nanohybrid carrier exhibited a cell growth inhibition effect with a high correlation coefficient and low probability (p) values. The high release of drug molecules may be due to the more open site of the ZIF-8/Fe3O4 NPs nanohybrid. The drug release profile suggests that the nanohybrid can be potentially used as a drug carrier for targeted drug delivery systems.

STING activation disrupts tumor vasculature to overcome the EPR limitation and increase drug deposition.

The low success rate of cancer nanomedicines has raised debate on the role of the enhanced permeability and retention (EPR) effect on tumor deposition of nanotherapeutics. Here, we report a bifunctional nanoscale coordination polymer (NCP), oxaliplatin (OX)/2',3'-cyclic guanosine monophosphate-adenosine monophosphate (GA), to overcome the EPR limitation through stimulator of interferon genes (STING) activation and enhance chemotherapeutic and STING agonist delivery for tumor eradication. OX/GA encapsulates GA and OX in the NCP to protect GA from enzymatic degradation and improve GA and OX pharmacokinetics. STING activation by OX/GA disrupts tumor vasculatures and increases intratumoral deposition of OX by 4.9-fold over monotherapy OX-NCP. OX/GA demonstrates exceptional antitumor effects with >95% tumor growth inhibition and high cure rates in subcutaneous, orthotopic, spontaneous, and metastatic tumor models. OX/GA induces immunogenic cell death of tumor cells and STING activation of innate immune cells to enhance antigen presentation. NCPs provide an excellent nanoplatform to overcome the EPR limitation for effective cancer therapy.

Novel Piperazine Derivatives of Vindoline as Anticancer Agents.

A series of novel vindoline-piperazine conjugates were synthesized by coupling 6 N-substituted piperazine pharmacophores at positions 10 and 17 of Vinca alkaloid monomer vindoline through different types of linkers. The in vitro antiproliferative activity of the 17 new conjugates was investigated on 60 human tumor cell lines (NCI60). Nine compounds presented significant antiproliferative effects. The most potent derivatives showed low micromolar growth inhibition (GI50) values against most of the cell lines. Among them, conjugates containing [4-(trifluoromethyl)benzyl]piperazine (23) and 1-bis(4-fluorophenyl)methyl piperazine (25) in position 17 of vindoline were outstanding. The first one was the most effective on the breast cancer MDA-MB-468 cell line (GI50 = 1.00 μM), while the second one was the most effective on the non-small cell lung cancer cell line HOP-92 (GI50 = 1.35 μM). The CellTiter-Glo Luminescent Cell Viability Assay was performed with conjugates 20, 23, and 25 on non-tumor Chinese hamster ovary (CHO) cells to determine the selectivity of the conjugates for cancer cells. These compounds exhibited promising selectivity with estimated half-maximal inhibitory concentration (IC50) values of 2.54 μM, 10.8 μM, and 6.64 μM, respectively. The obtained results may have an impact on the design of novel vindoline-based anticancer compounds.

A random mutagenesis screen enriched for missense mutations in bacterial effector proteins.

To remodel their hosts and escape immune defenses, many pathogens rely on large arsenals of proteins (effectors) that are delivered to the host cell using dedicated translocation machinery. Effectors hold significant insight into the biology of both the pathogens that encode them and the host pathways that they manipulate. One of the most powerful systems biology tools for studying effectors is the model organism, Saccharomyces cerevisiae. For many pathogens, the heterologous expression of effectors in yeast is growth inhibitory at a frequency much higher than housekeeping genes, an observation ascribed to targeting conserved eukaryotic proteins. Abrogation of yeast growth inhibition has been used to identify bacterial suppressors of effector activity, host targets, and functional residues and domains within effector proteins. We present here a yeast-based method for enriching for informative, in-frame, missense mutations in a pool of random effector mutants. We benchmark this approach against three effectors from Legionella pneumophila, an intracellular bacterial pathogen that injects a staggering >330 effectors into the host cell. For each protein, we show how in silico protein modeling (AlphaFold2) and missense-directed mutagenesis can be combined to reveal important structural features within effectors. We identify known active site residues within the metalloprotease RavK, the putative active site in SdbB, and previously unidentified functional motifs within the C-terminal domain of SdbA. We show that this domain has structural similarity with glycosyltransferases and exhibits in vitro activity consistent with this predicted function.

Essential Oil of Fractionated Oregano as Motility Inhibitor of Bacteria Associated with Urinary Tract Infections.

In this research, several analyses were carried out on concentrated fractions of Mexican oregano essential oil (Poliomintha longiflora Gray) in order to determine its ability to inhibit the growth and the motility of Escherichia coli (swimming), Pseudomonas aeruginosa (swimming), and Proteus vulgaris (swarming); these Gram-negative bacteria associated with urinary tract infections are motile due to the presence of flagella, which is considered an important virulence factor that favors their motility when trying to reach the target organ and cause an infection. Also, the resistance pattern to antibiotics of each strain was determined. The results showed resistance pattern (8 out of 12 antibiotics tested) for P. aureginosa, while E. coli and P. vulgaris were resistant to 4 antibiotics out of the 12 tested. On the other hand, fractionated oregano caused an inhibition of growth and a reduction in motility, varying between fractions and among bacteria. Fraction 4 showed major growth reduction, with MBC values ranging from 0.002 to 23.7 mg/mL. Treatment with fractionated oregano (F1, F2, F3, F4) reduced the motility by 92-81% for P. vulgaris, 90-83% for E. coli, and 100-8.9% for P. aeruginosa. These results demonstrated a higher performance with a lower application dose due to its high content of Carvacrol and Thymol; unlike other concentrated fractions, this synergy of oxygenated monoterpenes may cause greater antimicrobial activity.