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Ultrasound stimulated microbubbles (USMB) are being investigated for their potential to promote the uptake of anticancer agents into tumor tissue by exploiting their ability to enhance microvascular permeability. At sufficiently high ultrasound transmit amplitudes it has also recently been shown that USMB treatments can, on their own, induce vascular damage, shutdown blood flow, and inhibit tumor growth. The objective of this study is to examine the antitumor effects of ‘antivascular’ USMB treatments in conjunction with chemotherapy, which differs from previous work which has sought to enhance drug uptake with USMBs by increasing vascular permeability. Conceptually this is a strategy similar to combining vascular disrupting agents with a chemotherapy, and we have selected the taxane docetaxel (Taxotere) for evaluating this approach as it has previously been shown to have potent antitumor effects when combined with small molecule vascular disrupting agents. Experiments were conducted on PC3 tumors implanted in athymic mice. USMB treatments were performed at a frequency of 1 MHz employing sequences of 50 ms bursts (0.00024 duty cycle) at 1.65 MPa. USMB treatments were administered on a weekly basis for 4 weeks with docetaxel (DTX) being given intravenously at a dose level of 5 mg/kg. The USMB treatments, either alone or in combination with DTX, induced an acute reduction in tumor perfusion which was accompanied at the 24 hour point by significantly enhanced necrosis and apoptosis. Longitudinal experiments showed a modest prolongation in survival but no significant growth inhibition occurred in DTX–only and USMB-only treatment groups relative to control tumors. The combined USMB-DTX treatment group produced tumor shrinkage in weeks 4–6, and significant growth inhibition and survival prolongation relative to the control (p

The transcriptional repressor BCL11A is involved in hematological malignancies, B-cell development, and fetal-to-adult hemoglobin switching. However, the molecular mechanism by which it promotes the development of myeloid leukemia remains largely unknown. We find that Bcl11a cooperates with the pseudokinase Trib1 in the development of acute myeloid leukemia (AML). Bcl11a promotes the proliferation and engraftment of Trib1-expressing AML cells in vitro and in vivo. Chromatin immunoprecipitation sequencing analysis showed that, upon DNA binding, Bcl11a is significantly associated with PU.1, an inducer of myeloid differentiation, and that Bcl11a represses several PU.1 target genes, such as Asb2, Clec5a, and Fcgr3. Asb2, as a Bcl11a target gene that modulates cytoskeleton and cell-cell interaction, plays a key role in Bcl11a-induced malignant progression. The repression of PU.1 target genes by Bcl11a is achieved by sequence-specific DNA-binding activity and recruitment of corepressors by Bcl11a. Suppression of the corepressor components HDAC and LSD1 reverses the repressive activity. Moreover, treatment of AML cells with the HDAC inhibitor pracinostat and the LSD1 inhibitor GSK2879552 resulted in growth inhibition in vitro and in vivo. High BCL11A expression is associated with worse prognosis in humans with AML. Blocking of BCL11A expression upregulates the expression of PU.1 target genes and inhibits the growth of HL-60 cells and their engraftment to the bone marrow, suggesting that BCL11A is involved in human myeloid malignancies via the suppression of PU.1 transcriptional activity.

Targeting the cystine/glutamate exchange transporter, system xc -, is a promising anticancer strategy that induces ferroptosis, which is a distinct form of cell death mediated by iron-dependent lipid peroxidation. The concentration of L-cystine in culture medium is higher than the physiological level. This study was aimed to evaluate the effects of L-cystine concentration on the efficacy of ferroptosis inducers in hepatocellular carcinoma cells. This study showed that treatment with sulfasalazine or erastin, a system xc - inhibitor, decreased the viability of Huh6 and Huh7 cells in a dose-dependent manner, and the degree of growth inhibition was greater in medium containing a physiological L-cystine concentration of 83 μM than in commercial medium with a concentration of 200 μM L-cystine. However, RSL3, a glutathione peroxidase 4 inhibitor, decreased cell viability to a similar extent in media containing both L-cystine concentrations. Sulfasalazine and erastin significantly increased the percentages of propidium iodide-positive cells in media with 83 μM L-cystine, but not in media with 200 μM L-cystine. Sulfasalazine- or erastin-induced accumulation of lipid peroxidation as monitored by C11-BODIPY probe was higher in media with 83 μM L-cystine than in media with 200 μM L-cystine. In contrast, the changes in the percentages of propidium iodide-positive cells and lipid peroxidation by RSL3 were similar in both media. These results showed that sulfasalazine and erastin, but not RSL3, were efficacious under conditions of physiological Lcystine concentration, suggesting that medium conditions would be crucial for the design of a bioassay for system xc - inhibitors.

Recent studies show that triclosan (TCS) exposure causes reduction in pigments, suppression of photosynthesis, and induction of oxidative stress at the physiological level, resulting in morphological alteration and growth inhibition in algae including Raphidocelis subcapitata (R. subcapitata, a freshwater model green alga). However, the underlying molecular mechanisms remain to be elucidated, especially at environmentally relevant concentrations. The present study uncovered the transcriptional profiles and molecular mechanisms of TCS toxicity in R. subcapitata using next-generation sequencing. The algal growth was drastically inhibited following a 7-day exposure at both 75 and 100 μg/L TCS, but not at 5 μg/L (environmentally realistic level). The transcriptomic analysis shows that molecular signaling pathways including porphyrin and chlorophyll metabolism, photosynthesis – antenna proteins, and photosynthesis were suppressed in all three TCS treatments, and the perturbations of these signaling pathways were exacerbated with increased TCS exposure concentrations. Additionally, signaling of replication-coupled DNA repair was only activated in 100 μg/L TCS treatment. These results indicate that photosynthesis systems were sensitive targets of TCS toxicity in R. subcapitata, which is distinct from the inhibition of lipid synthesis by TCS in bacteria. This study provides novel knowledge on molecular mechanisms of TCS toxicity in R. subcapitata.

The current study was conducted to evaluate the effect of eight Palestinian indigenous plant essential oils (EOs) under in vitro and in vivo conditions against Botrytis cinerea Pers.: Fr., Penicillium italicum Wehmer, and Penicillium digitatum (Pers.) Sacc., three common post- harvest pathogens of tomato and strawberry fruits. In vivo tests showed that thyme, sesame and sage EOs exhibited high antifungal activity against B. cinerea on strawberry and toma- to fruits, compared with rosemary, mint and eucalyptus. In vitro agar, disk-diffusion tests showed that B. cinerea, P. digitatum and P. italicum mycelium growth was completely inhi- bited when treated with clove and sage EOs caused 50% inhibition of B. cinerea and P. itali- cum mycelium growth. Fruit decay and fruit quality index values measured in total soluble solids and fruit flesh firmness showed that EO coated strawberries had significantly less fruit decaying and ripping compared to control, while EO coated tomatoes showed no sig- nificant difference compared to control. EO constituents fall into different chemical classes, including sterols, caffeoylquinic acids, flavonoids, terpenoids, coumarins, and acetylenes. Chemical analysis of the EO preparations using gas chromatography-mass spectrometry determined that the main components in sesame oil were octadecenoic acid-(56%) and hexadecanoic acid (26%), while clove oil consisted of eugenol (53%). In the other EOs, the principal compounds were: menthol (44% in mint oil), eucalyptol (37% in sage oil), while bornanone (18% in rosemary oil) and γ-terpinene (21% in thyme oil) were present at lower concentrations. The EO of sage plants could potentially be a useful alternative to synthetic pesticides to control post-harvest diseases and prolong the shelf life of fruit products.

Because current mainstream anti-glycolipid GD2 therapeutics for neuroblastoma (NB) have limitations, such as severe adverse effects, improved therapeutics are needed. In this study, we developed a GD2 aptamer (DB99) and constructed a GD2-aptamer-mediated multifunctional nanomedicine (ANM) with effective, precise, and biocompatible properties, which functioned both as chemotherapy and as gene therapy for NB. DB99 can bind to GD2+ NB tumor cells but has minimal cross-reactivity to GD2− cells. Furthermore, ANM is formulated by self-assembly of synthetic aptamers DB99 and NB-specific MYCN small interfering RNA (siRNA), followed by self-loading of the chemotherapeutic agent doxorubicin (Dox). ANM is capable of specifically recognizing, binding, and internalizing GD2+, but not GD2−, NB tumor cells in vitro. Intracellular delivery of ANM activates Dox release for chemotherapy and MYCN-siRNA-induced MYCN silencing. ANM specifically targets, and selectively accumulates in, the GD2+ tumor site in vivo and further induces growth inhibition of GD2+ tumors in vivo; in addition, ANM generates fewer or no side effects in healthy tissues, resulting in markedly longer survival with fewer adverse effects. These results suggest that the GD2-aptamer-mediated, targeted drug delivery system may have potential applications for precise treatment of NB., Graphical abstract, Multifunctional nanomedicine (ANM), with effective, precise, and biocompatible properties based on a GD2 aptamer, to achieve both chemotherapy and gene therapy of neuroblastoma was constructed by Zhang et al. This GD2-aptamer-mediated, targeted, multifunctional nanomedicine system may open a new avenue and have potential applications for precision treatment of NB.

BACKGROUND Anisomycin, a potential anticancer therapeutic drug, exerts an antitumor effect on melanoma cells at a lower concentration than that required for other cancer cells. However, the molecular mechanisms remain unclear. MATERIALS AND METHODS The sensitivity to and cytotoxicity of anisomycin, as well as the effects of anisomycin on glucose metabolism and relative mRNA expression of senescence- and cancer-associated genes, were studied using B16 mouse melanoma cells. RESULTS The viability of anisomycin-treated cells decreased in a concentration-dependent manner, and the growth of cell spheroids was suppressed by 50 nM anisomycin. Glucose metabolism was reduced by anisomycin treatment, and the mRNA expression of genes responsible for growth inhibition, such as p21, p53 and Txnip was upregulated. CONCLUSION The results suggest that anisomycin may be a promising future anticancer drug that is effective at low concentrations against melanoma by reducing glucose metabolism, causing cell senescence-like phenomena.

The objective of the present study was to elucidate the mechanism by which oxalic acid (OA) alleviates cadmium (Cd) stress. Chickpea (Cicer arietinum L.) seeds were treated with 200 µM CdCl2 for 6 days or 3 days followed by the combination 200 µM Cd + 100 µM OA for three additional days. Exogenous OA mitigated the growth inhibition by Cd of both roots and shoots. This positive effect can be attributed to the increased OA exudation from roots and the alleviation of the Cd-induced depletion of endogenous OA in shoots (80% increase versus Cd-stressed). The combination Cd + OA proved to be effective in protecting cell membrane integrity. This beneficial effect was reflected by 36 and 24% decrease in lipoxygenase (LOX) activity in roots and shoots, respectively, and 60% decrease in the accumulation of the harmful aldehyde, 4-hydroxy-2-nonenal (4-HNE) in roots when compared to Cd-treated samples. Besides, OA restored the Cd-imposed disruption of the plasma membrane function. This effect was depicted by an optimal H+-ATPase activity and proton exudation rate. Oxalic acid counteracted the Cd-induced overproduction of hydroxyl radical (OH•) and NADPH-oxidase activity increase, leading to restore a steady cellular redox state. Furthermore, OA modulated the impact of Cd on Cu/Zn-superoxide dismutase (Cu/Zn-SOD), ascorbate peroxidase (APX), and catalase (CAT) activities in chickpea seedlings. Present results indicate that OA is able to alleviate Cd toxicity by protecting plasma membrane integrity and modulating antioxidant activities. Moreover, our findings shed light on the interplay between plasma membrane H+-ATPase and the accumulation and root exudation of OA.

The infection caused by Entamoeba histolytica is still a serious public health problem, especially in developing countries. The goal of this study was to evaluate the effect of terfenadine against Entamoeba histolytica. The trophozoites were exposed to 1, 2, 3, and 4 μM of terfenadine, for 24 and 48 h. Consequently, the viability of cells was determined by trypan blue exclusion test. The effect of terfenadine on adhesion of Entamoeba histolytica was evaluated in Caco-2 cells. In addition, the effect of terfenadine on the erythrophagocytic capacity of the parasite was investigated. The results show that terfenadine affects the growth and cell viability in a time- and dose-dependent manner. The higher inhibitory effects were observed with 4 µM at 48 h; 91.6% of growth inhibition and only 22.5% of trophozoites were viable. Additionally, we demonstrate that terfenadine is highly selective for the parasite and has low toxicity on Caco-2 cells. Furthermore, adhesion to Caco-2 cells and erythrophagocytic capacity were significantly inhibited. These findings demonstrate that terfenadine exerts significant effects on the virulence of Entamoeba histolytica. This is the first study demonstrating the amoebicidal activity of terfenadine and the results suggest it may be effective in the treatment of amoebiasis.

Introduction Leishmania aethiopica (L. aethiopica) is responsible for different forms of cutaneous leishmaniasis (CL) in Ethiopia. Treatment heavily depends on limited drugs, together with drawbacks like toxicity and microbial resistance. The current research aimed to investigate in vitro growth inhibitory activity of Medicines for Malaria Ventures - Pathogen Box (MMV - PB) compounds against L. aethiopica clinical isolate. Methodology Four hundred MMV – PB compounds were screened against L. aethiopica using resazurin based colourimetric assay. Compounds with > 70% inhibition were further tested using macrophage based intracellular amastigote assay. Cytotoxic and hemolytic activity of candidate hits were assessed on THP1- cells and sheep red blood cells (RBCs), respectively. In vitro drug interaction study was also conducted for the most potent hit using the combination index method. Results At the test concentration of 1 μM, twenty-three compounds showed > 50% inhibition of promastigotes parasite growth, of which 11 compounds showed > 70% inhibition. The 50% growth inhibition (IC50) of the 11 compounds was ranged from 0.024 to 0.483 μM in anti-promastigote assay and from 0.064 to 0.899 μM in intracellular amastigote assay. Candidate compounds demonstrated good safety on sheep RBCs and THP-1 cell lines. MMV688415 demonstrated a slight hemolytic activity on sheep RBC (5.3% at 25 μM) and THP-1 cell line (CC20 = 25 μM) while MMV690102 inhibited half of THP-1 cells at 36.5 μM (selectivity index = 478). No synergistic activity was observed from the combinations of MMV690102 and amphotericin B (CI > 1), and MMV690102 and Pentamidine (CI > 1) at lower and higher combination points. Conclusion The present study identified a panel of compounds that can be used as a novel starting point for lead optimization. MMV690102 appears to be the most potent inhibitor against L. aethiopica promastigotes and amastigotes. Future works should investigate the antileishmanial mechanism of action and in vivo antileishmanial activities of identified hits.

Background: Glioblastoma Multiforme (GBM) is a deadly tumor with poor prognosis. Resistance to apoptosis considered as an important factor in treatment failure. Therefore, identification of new compounds that facilitates apoptosis is crucial. Natural Anti-inflammatory compounds have emerged as potential anti-cancer agents and should be explored for their apoptotic activity against GBM. Therefore, the present study aims to evaluate growth inhibitory and apoptotic activity of a natural anti-inflammatory compound “Opuntiol” against GBM cell line U87. Methods: MTT assay was performed to determine the effect of Temozolomide and Opuntiol on growth inhibition of U87 cell. While, TUNEL assay was used to assess their apoptotic activity. To further assess apoptosis, nuclear condensation and nuclear area factor (NAF) was evaluated through DAPI staining. Whereas, active caspase-3 protein expression determined using immunocytochemistry. Results: Significant growth inhibition was observed in U87 cells treated with Temozolomide (IC50 380 µM) and Opuntiol (IC50 357 µM). Temozolomide (p

Cancer cells develop several hallmark changes over the progress of the tumor process. Cell assistance in multicellular organisms is regulated by the division of cell coordination by aggressive growth modulation. In this perspective, the use of molecular indicators triggering cell division is a mystery, because a cancer cell can manipulate any molecule that induces and helps growth, disturbing cellular assistance. An effective alteration proceeding to tumors must develop to be competitive, allowing a cancer cell to pass a signal resulting in better selection chances. The subjective simulation of physiological systems has become increasingly valuable in recent years, and there is now a wide range of mathematical models of signalling pathways that have contributed to some groundbreaking discoveries and hypotheses as to how this system works. Here we discuss various modeling methods and their application to the physiology of medical systems, focusing on the identification of parameters in ordinary differential equation models and their significance for forecasting cellular decisions in network modeling. In situations of global and local cell-to-cell rivalry, we quantify how this mechanism impacts a mutated cell's fixing chance of producing such a signal, and consider that this process will play a vital role in reducing cancer.

The investigation on the n-hexane lipophilic extractives of Swietenia mahagoni, alongside the antifungal and antioxidant properties was conducted. The leaf sample was collected from 2- and 3-years-old trees in Perhutani enterprise of Temanggung, Central Java, Indonesia. In addition, the antifungal activity was tested using the white-rot of Phanerochaete chrysosporium, while the antioxidant property involved the DPPH (1,1-diphenyl-2-picrylhydrazyl) method. The results show antifungal of 28.6% and 37.5% growth inhibition in 2- and 3 -years-old leaf, respectively, while 21.7% and 25.4% antioxidant activity were also recorded. Furthermore, the GC-MS results showed the domination of S. mahagoni leaf by fatty acids and hydo-carbons, while the terpenoids and steroids were in minor quantities. These components possibly exhibit growth inhibitory and antioxidant effects against P. chrysosporium and DPPH radicals, respectively.

Plant fungal diseases cause major problems for the global economy. Antimicrobial peptides have aroused great interest in the control of phytopathogens, as they are natural molecules and have a broad spectrum of inhibitory activity. Herein, we have tried to identify and characterize antimicrobial peptides present in fruits of Capsicum chinense and to evaluate their enzymatic and antifungal activities. The retained fraction obtained in the anion exchange chromatography with strong antifungal activity was subjected to molecular exclusion chromatography and obtained four fractions named G1, G2, G3, and G4. The 6.0-kDa protein band of G2 showed similarity with protease inhibitors type II, and it was able to inhibit 100% of trypsin and α-amylase activities. The protein band with approximately 6.5 kDa of G3 showed similarity with sequences of protease inhibitors from genus Capsicum and showed growth inhibition of 48% for Colletotrichum lindemuthianum, 49% for Fusarium lateritium, and 51% for F. solani and F. oxysporum. Additionally, G3 causes morphological changes, membrane permeabilization, and ROS increase in F. oxysporum cells. The 9-kDa protein band of G4 fraction was similar to a nsLTP type 1, and a protein band of 6.5 kDa was similar to a nsLTP type 2. The G4 fraction was able to inhibit 100% of the activities of glycosidases tested and showed growth inhibition of 35 and 50% of F. oxysporum and C. lindemuthianum, respectively. C. chinense fruits have peptides with antifungal activity and enzyme inhibition with biotechnological potential.

Dietary interventions can change metabolite levels in the tumour microenvironment, which might then affect cancer cell metabolism to alter tumour growth1–5. Although caloric restriction (CR) and a ketogenic diet (KD) are often thought to limit tumour progression by lowering blood glucose and insulin levels6–8, we found that only CR inhibits the growth of select tumour allografts in mice, suggesting that other mechanisms contribute to tumour growth inhibition. A change in nutrient availability observed with CR, but not with KD, is lower lipid levels in the plasma and tumours. Upregulation of stearoyl-CoA desaturase (SCD), which synthesises monounsaturated fatty acids, is required for cancer cells to proliferate in a lipid-depleted environment, and CR also impairs tumour SCD activity to cause an imbalance between unsaturated and saturated fatty acids to slow tumour growth. Enforcing cancer cell SCD expression or raising circulating lipid levels through a higher-fat CR diet confers resistance to the effects of CR. By contrast, although KD also impairs tumour SCD activity, KD-driven increases in lipid availability maintain the unsaturated to saturated fatty acid ratios in tumours, and changing the KD fat composition to increase tumour saturated fatty acid levels cooperates with decreased tumour SCD activity to slow tumour growth. These data suggest that diet-induced mismatches between tumour fatty acid desaturation activity and the availability of specific fatty acid species determine whether low glycaemic diets impair tumour growth. Lien et al. show that low glycemic diets can reduce tumour growth by deregulating lipid metabolism.

The therapeutic efficacy of temozolomide (TMZ) is hindered by inherent and acquired resistance. Biomarkers such as MGMT expression and MMR proficiency are used as predictors of response. However, not all MGMTlow/−ve/MMRproficient patients benefit from TMZ treatment, indicating a need for additional patient selection criteria. We explored the role of ATR in mediating TMZ resistance and whether ATR inhibitors (ATRi) could reverse this resistance in multiple cancer lines. We observed that only 31% of MGMTlow/−ve/MMRproficient patient-derived and established cancer lines are sensitive to TMZ at clinically relevant concentrations. TMZ treatment resulted in DNA damage signaling in both sensitive and resistant lines, but prolonged G2/M arrest and cell death were exclusive to sensitive models. Inhibition of ATR but not ATM, sensitized the majority of resistant models to TMZ and resulted in measurable DNA damage and persistent growth inhibition. Also, compromised homologous recombination (HR) via RAD51 or BRCA1 loss only conferred sensitivity to TMZ when combined with an ATRi. Furthermore, low REV3L mRNA expression correlated with sensitivity to the TMZ and ATRi combination in vitro and in vivo. This suggests that HR defects and low REV3L levels could be useful selection criteria for enhanced clinical efficacy of an ATRi plus TMZ combination.

The goal of this study was to investigate whether Ducrosia flabellifolia and Savignya parviflora methanol extract the have effect on colon and prostate cancer cell lines. Analysis of total content of phenolics and flavonoids of each plant extract was carried out. Cytotoxic effect, cell cycle analysis, induction of apoptosis and gene expression of Bcl-2 and Bax genes were studied. Obtained results indicated that, the plant extracts exhibit growth inhibition of used cancer cell lines and induced apoptosis as well as arresting of cell cycle. At the molecular level, changes in gene expression were detected via qPCR and confirmed by western blotting. The exhibited anticancer potentialities of plant extracts against utilized cancer cell lines are due to its containing bioactive compounds. Further detailed isolation, fractionation and characterization of bioactive compounds are needed.

The development of novel drugs against Gram-negative bacteria represents an urgent medical need. To overcome their outer cell membrane, we synthesized conjugates of antibiotics and artificial siderophores based on the MECAM core, which are imported by bacterial iron uptake systems. Structures, spin states, and iron binding properties were predicted in silico using density functional theory. The capability of MECAM to function as an effective artificial siderophore in Escherichia coli was proven in microbiological growth recovery and bioanalytical assays. Following a linker optimization focused on transport efficiency, five β-lactam and one daptomycin conjugates were prepared. The most potent conjugate 27 showed growth inhibition of Gram-positive and Gram-negative multidrug-resistant pathogens at nanomolar concentrations. The uptake pathway of MECAMs was deciphered by knockout mutants and highlighted the relevance of FepA, CirA, and Fiu. Resistance against 27 was mediated by a mutation in the gene encoding ExbB, which is involved in siderophore transport.

Introduction: Heavy metal exposure has been previously reported to decrease bacterial growth. During the growing antibiotic crisis in healthcare settings, metals may reduce bacterial burden in hospital environments. Despite proving successful, this has driven the evolution of metal-resistant strains like methicillin-resistant Staphylococcus aureus (MRSA). By expelling cadmium and zinc through surface efflux pumps such as CadA, MRSA is able to thrive in metal-rich environments. This protocol investigates the inhibitory activity of Scinapsin, a novel small-molecule inhibitor designed to bind the catalytic site of CadA. Scinapsin could be applied to clinical settings to combat metal resistance in MRSA populations amidst the COVID-19 pandemic. Methods: Computational biochemistry is used to characterize the structure of the S. aureus CadA protein. Small-molecule library screening generated a hit compound, which after modification to improve binding affinity produced the final Scinapsin structure. Several MSRA strains were screened for the presence of CadA from which the most favourable strain for the experiment is chosen (i.e. prevalence in hospitals, CadA expression levels). For the experimental protocol, MRSA strains with metal resistance are incubated with increasing concentrations of Scinapsin, either in the presence or absence of zinc and cadmium (at 50% of predetermined MIC). Samples are then diluted and plated to allow for CFU counting. Results: Scinapsin is anticipated to have an inhibitory effect on MRSA growth in the presence of metals at 50% MIC, confirming the successful inactivation of CadA function. A saturation point may also occur at higher concentrations of Scinapsin where no further growth inhibition is achieved. Discussion: Docking analysis has confirmed the theoretical feasibility for Scinapsin to act as a CadA-specific inhibitor. In an in vitro setting like the one presented, Scinapsin should allow for excess zinc and cadmium to accumulate in the cytoplasm and ultimately cause cell death. Further experiments could aim to confirm the proposed biological mechanism of antibacterial activity. Conclusion: Scinapsin holds promise in reversing metal resistance in hospital MRSA populations and may pave the way for other small-molecule antibacterial drugs. Future research is needed to determine safe levels of Scinapsin exposure for humans and how this inhibitor affects other hospital microbes.

Because carcinogenesis is a multi-step process, Sporn (1976)suggested that the best time to control cancer is in its “preneoplastic” phase, before it has a chance to develop into “invasive” cancer. Therefore, the aim of the present work was to evaluate the effect of TQ on the dysplasia induced in that model, through IHC expression of both enzymes.6 weeks of DMBA painting resulted in irreversible genetic changes that did not resolve by the studied repair enzymes. So it can be proposed that TQ had resulted in regression of the carcinogenesis process through the following mechanisms. First: TQ as a potent antioxidant that antagonizes the adverse effect resulting from elevated ROS levels due to carcinogenesis i.e. reduction of the intracellular ROS allowed the repair enzymes to fulfill their main target.Second: TQ through inactivation of the TNF-Nf-κB pathway, and in turn induced p53 activation, i.e. stimulated apoptosis of malignant cells. Third: TQ has the ability to arrest cells at different phases of the cell cycle leading to growth inhibition, so allowing repair of mutated cells

Prosopis strombulifera (Lam.) Benth. is a halophytic shrub abundant in high-salinity areas in central Argentina, with high tolerance against NaCl but strong growth inhibition by Na2SO4. In the present study, the modulation of the antioxidant systems (enzymatic and non-enzymatic components) was analyzed under different salt treatments (NaCl, Na2SO4 and the iso-osmotic mixture) in hydroponic cultivation. Na2SO4-treated plants showed strong indications of oxidative stress (H2O2 and O2-• increase). Modifications in antioxidant enzymes activities were observed mainly under Na2SO4 treatment, where CAT seems to play an important role in early detoxification of H2O2 in roots, whereas SOD and APX have a predominant role in leaves. As part of the non-enzymatic system, 21 compounds were identified in leaves, being polyphenols the most abundant. Control plants contained the major variety of detected phytochemicals (14). Na2SO4-treated plants contained 10 compounds and NaCl-treated plants nine compounds, but with a different profile. NaCl-treated plants showed the highest antioxidant capacity. Our findings confirm that different types of salt treatments provoke a differential modulation of the antioxidant systems. Polyphenols and other ROS-detoxifying compounds, in a joint action with the enzymatic antioxidant system, are proposed to have a fundamental role in the cellular protection of P. strombulifera plants under severe oxidative stress. Our findings also highlight the potential of this halophyte as a valuable source of bioactive compounds with high antioxidant activity and health benefits.

Wen-Ting Cheng,1,&ast; Hsiu-O Ho,1,&ast; Shyr-Yi Lin,2,3 Der-Zen Liu,4 Ling-Chun Chen,5 Ming-Thau Sheu1 1School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan, Republic of China; 2Division of Gastroenterology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan, Republic of China; 3Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, Republic of China; 4Graduate Institute of Biomedical Materials and Engineering, Taipei Medical University, Taipei, Taiwan, Republic of China; 5Department of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, Hsinchu, Taiwan, Republic of China&ast;These authors contributed equally to this workCorrespondence: Ming-Thau SheuSchool of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wu-Hsing Street, Taipei, 11031, Taiwan, Republic of ChinaTel/Fax +886 2 2377 1942Email mingsheu@tmu.edu.twLing-Chun ChenDepartment of Biotechnology and Pharmaceutical Technology, Yuanpei University of Medical Technology, No. 306, Yuanpei Street, Hsinchu, 30015, Taiwan, Republic of ChinaTel/Fax +886 2 2377 1942Email d8801004@mail.ypu.edu.twPurpose: Therapeutic efficacy of pancreatic adenocarcinomas (PACs) with combined therapy of carfilzomib (CFZ) and paclitaxel (PTX) co-loaded in human serum albumin (HSA) nanoparticles (NPs) was examined.Methods: CFZ and PTX were encapsulated individually or combined into HSA NPs by a simple reverse self-assembly method developed to achieve an optimal combination ratio for synergistic therapy. CFZ or/and PTX loaded HSA nanoparticles were physically characterized and the evaluation of combination index, drug release, pharmacokinetic, anti-tumor, and biodistribution studies were conducted.Results: All resultant drug-loaded HSA NPs were spherical with a particle size of < 150 nm and a zeta potential of − 21.1∼− 23.0 mV. Drug loading rates and entrapment efficiencies were 9.1%∼ 10.1% and 90.7%∼ 97.1%, respectively. CFZ and PTX demonstrated synergistic effects in an MIA PaCa-2 cytotoxicity at a 1:2 ratio (CI50 were 0.01∼ 0.25). In vitro dissolution revealed that the CFZ/PTX ratio released from the co-loaded HSA NPs (CFZ/PTX/HSA NPs) was about 1.77∼ 2.08, which conformed to the designated loaded ratio. In vivo evaluation showed that the combined therapy of CFZ and PTX at a 1:2 ratio co-loaded in HSA NPs (CFZ/PTX/HSA NPs) demonstrated optimal synergistic improvement of the growth inhibition of MIA PaCa-2 cells with less systematic toxicity, even though the pharmacokinetic profiles observed did not show obvious beneficial and their biodistributions in tumors were found to be smaller.Conclusion: The one-pot reverse assembly method developed was environmentally friendly and capable of co-loading an optimal combination ratio of two chemodrugs into HSA NPs for synergistic therapy.Keywords: human serum albumin, nanoparticles, carfilzomib, paclitaxel, co-loading, synergism

Inhibition of tight junction formation between two malaria parasite proteins, apical membrane antigen 1 and rhoptry neck protein 2, crucial for red blood cell invasion, prevents the disease progression. In this work, we have utilized a unique approach to design a chimeric peptide, prepared by fusion of the best features of two peptide inhibitors, that has displayed parasite growth inhibition, in-vitro, with nanomolar IC50, which is hundredfold better than any of its parent peptides. Further, to gain structural insights, we computationally modeled the hybrid peptide on its receptor.

Fibroblast activation protein (FAP) has become an attractive target for diagnosis and therapy, and a series of FAP inhibitor (FAPI) based radiotracers have been developed and performed excellent diagnosis outcome in clinical applications. Yet, their fast clearance and insufficient tumor retention have hampered their further clinical applications for cancer treatment. In this study, we developed two albumin binder-conjugated FAPI radiotracers, TEFAPI-06 and TEFAPI-07. They are derived from FAPI-04, and optimized by conjugating two types of well-studied albumin binders, 4-(p-iodophenyl) butyric acid moiety (TEFAPI-06) and truncated Evans blue moiety (TEFAPI-07), to try to overcome the above limitations at the expense of prolonging the blood circulation. Methods: TEFAPI-06 and TEFAPI-07 were synthesized and labeled with 68Ga, 86Y and 177Lu successfully. A series of cell assays were performed to identify the binding affinity and FAP specificity in vitro. PET imaging, SPECT imaging and biodistribution study were performed to evaluate the pharmacokinetics in the pancreatic cancer patient-derived xenografts (PDX) animal models. The cancer treatment efficacy of 177Lu-TEFAPI-06 and 177Lu-TEFAPI-07 have been evaluated and the comparative study with 177Lu-FAPI-04 has also been performed in pancreatic cancer PDX-bearing mice. Results: The binding affinity (Kd) to FAP of 68Ga-TEFAPI-06 and 68Ga-TEFAPI-07 is 10.16 ± 2.56 nM and 7.81 ± 2.28 nM, respectively, which were comparable with that of 68Ga-FAPI-04. Comparative PET imaging of HT-1080-FAP and HT-1080 tumor-bearing mice and blocking study showed the FAP targeting ability in vivo of these two tracers. Compared with 177Lu-FAPI-04, PET imaging, SPECT imaging and biodistribution studies of TEFAPI-06 and TEFAPI-07 have demonstrated their remarkably enhanced tumor accumulation and retention, respectively. Notable tumor growth inhibitions of 177Lu-TEFAPI-06 and 177Lu-TEFAPI-07 have been observed, while the control groups and the group treated by 177Lu-FAPI-04. Conclusion: Two albumin binder-conjugated FAPI radiopharmaceuticals have been developed and evaluated in vitro and in vivo. Notably improved tumor uptake and retention have been observed compared to the original FAPI tracer. Both 177Lu-TEFAPI-06 and 177Lu-TEFAPI-07 showed remarkable growth inhibition to PDX tumors while the side effect is negligible, showing that they are promising for further clinical translational studies.

The rise of antimicrobial resistance for infectious bacteria has become an alarming issue to human health. New antimicrobial drugs are in dire need and pivotal to overcome this issue. In this study, aspirinate azo ligands bearing different halogens L1-5 has been prepared via diazo-coupling reaction. The ligands L1-5 were coordinated with silver, Ag (I) metal to produce Ag (I) aspirin-azo complexes C1-5. The antibacterial properties of L1-5 and C1-5 were evaluated against Staphylococcus aureus and Escherichia coli using turbidimetric kinetic method. The complexes C1-5 showed comparable growth inhibition activity towards E. coli (MIC 82-105 ppm) and S. aureus (MIC 80-105 ppm) compared to ligands L1-5 with E. coli (MIC 83-200 ppm), S. aureus (80-131 ppm) and ampicillin (MIC 93 and 124 ppm, respectively). The excellent bacterial resistance of both L1-5 and C1-5 indicates the potential of aspirinate azo and their complexes as new antibacterial agents, which significantly benefit to the pharmaceutical industries.

Epidemiologic and pre-clinical studies have shown that marine n-3 polyunsaturated fatty acids (n-3 PUFAs) elicit promising chemoprevention against breast cancer. Docosahexaenoic acid monoglyceride (MAG-DHA), a docosahexaenoic acid sn-1-monoacylglyceroldoes not required pancreatic lipase to be absorbed, eliciting a better bioavailability when compared with other formulations such as DHA-free fatty acid, DHA-triglycerol, or DHA-ethyl ester. However, the anti-cancer actions and underlying mechanisms of MAG-DHA on breast cancer remain to be assessed. In this study, MAG-DHA induced significant growth inhibition in MCF-7 and MDA-MB-231 breast cancer cells in a dose-dependent manner. MAG-DHA treatment (80μM) led to 83.8% and 94.3% growth inhibition between MCF-7 and MDA-MB-231 cells, respectively. MAG-DHA-induced growth inhibition was tightly associated with apoptosis, as evidenced by increased active forms of caspase-3, poly (ADP-ribose) polymerase (PARP) and caspase-12. In particular, MAG-DHA-induced apoptosis was triggered by oxidative stress-mediated endoplasmic reticulum (ER) stress, as evidenced by activation of the PERK-eIF2α pathway in ER. MAG-DHA treatment also strongly suppressed the growth of E0771 murine breast cancer xenografts, significant differences of tumor volume were found between MAG-DHA group (0.271 cm3) and control group (0.875cm3) after 15 daily MAG-DHA treatments. The in vitro anti-breast cancer mechanism of MAG-DHA was supported by the in vivo xenograft model. In addition, MAG-DHA-induced ER stress concomitantly triggered autophagy in these cancer cells, and the induction of autophagy suppressed its ability to induce apoptotic cell death. Our data suggested that MAG-DHA as dietary supplement, in combination with autophagy inhibitors may be a useful therapeutic strategy in treating breast cancer.

The growing burden of antibiotic resistance worldwide calls for developing new classes of antimicrobial strategy. Recently years, the use of adjuvants that rescue antibiotics identified as a promising strategy for overcoming bacterial resistance. In this study, three ruthenium complexes functionalized with furan-substituted ligands([Ru(phen)2 (CAPIP)](ClO4 )2 (Ru(Ⅱ)-1), [Ru(dmp)2 (CAPIP)](ClO4 )2 (Ru(Ⅱ)-2) and [Ru(dmb)2 (CAPIP)](ClO4 )2 (Ru(Ⅱ)-3) (dmb=4,4'-dimethyl-2,2'-bipyridine, phen=1,10-phenanthroline, dmp=2,9-dimethyl-1,10-phenanthroline, CAPIP=(E)-2- (2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phenanthroline)) were designed and synthesized. The antimicrobial activities of all compounds against S. aureus were assessed by growth inhibition assays. The MIC values of three complexes range from 0.015 to 0.050 mg/ml. Subsequently, the Ru(II)-2 complexes which exhibited strongest antibacterial activity were further tested against bacteria biofilms formation and toxin secretion. In addition, aimed to test whether ruthenium complexes have potential value as antimicrobial adjuvants, the synergism between Ru(Ⅱ)-2 and some antibiotics against S. aureus were examined through checkerboard method. Interestingly, Ru(Ⅱ)-2 could not only effectively inhibit biofilms formation of S. aureus and inhibit the hemolysin toxin secretion, but also selectivity show synergism with two common antibiotics. More importantly, mouse infection study also verified Ru(Ⅱ)-2 were highly effective against S. aureus in vivo.

The TGF‐β type V receptor (TβR‐V) mediates growth inhibition by IGFBP‐3 and TGF‐β in epithelial cells and loss of TβR‐V expression in these cells leads to development of carcinoma. The mechanisms by which TβR‐V mediates growth inhibition (tumor suppressor) signaling remain elusive. Previous studies revealed that IGFBP‐3 and TGF‐β inhibit growth in epithelial cells by stimulating TβR‐V‐mediated IRS‐1/2‐dependent activation and cytoplasm‐to‐nucleus translocation of IGFBP‐3‐ or TGF‐β‐stimulated protein phosphatase (PPase), resulting in dephosphorylation of pRb‐related proteins (p107, p130) or pRb, and growth arrest. To define the signaling, we characterized/identified the IGFBP‐3‐ and TGF‐β‐stimulated PPases in cell lysates and nucleus fractions in Mv1Lu cells treated with IGFBP‐3 and TGF‐β, using a cell‐free assay with 32P‐labeled casein as a substrate. Both IGFBP‐3‐ and TGF‐β‐stimulated PPase activities in cell lysates are abolished when cells are co‐treated with TGF‐β/IGFBP‐3 antagonist or RAP (LRP‐1/TβR‐V antagonist). However, the IGFBP‐3‐stimulated PPase activity, but not TGF‐β‐stimulated PPase activity, is sensitive to inhibition by okadaic acid (OA). In addition, OA or PP2Ac siRNA reverses IGFBP‐3 growth inhibition, but not TGF‐β growth inhibition, in Mv1Lu and 32D cells. These suggest that IGFBP‐3‐ and TGF‐β‐stimulated PPases are identical to PP2A and PP1, respectively. By Western blot/phosphorimager/immunofluorescence‐microscopy analyses, IGFBP‐3 and TGF‐β stimulate TβR‐V‐mediated IRS‐2‐dependent activation and cytoplasm‐to‐nucleus translocation of PP2Ac and PP1c, resulting in dephosphorylation of p130/p107 and pRb, respectively, and growth arrest. Small molecule TGF‐β enhancers, which potentiate TGF‐β growth inhibition by enhancing TβR‐I–TβR‐II‐mediated canonical signaling and thus activating TβR‐V‐mediated tumor suppressor signaling cascade (TβR‐V/IRS‐2/PP1/pRb), could be used to prevent and treat carcinoma.

Two series of 3-mercapto-1,2,4-triazole derivatives containing alkoxy substituents different in size and position were synthesized and their structures were characterized by FT-IR, 1H NMR, 13C NMR spectroscopy and elemental analysis. The synthesized compounds were assessed for their antiproliferative activity against colon cancer cell line (SW480). The results indicated that the size and position of the alkoxy group significantly influenced the antiproliferative activity. The highest cancer cell growth inhibition values were observed for the compounds containing 3,4,5-trimethoxyphenyl groups in their structures (57.74, 54.14 and 60.70% at 50 μM for compounds 5a, 12b and 14, respectively). The synthesized compounds were also subjected to DPPH protocol for evaluating the antioxidant activity. The results showed that all compounds had moderate to high levels of antioxidant capacity as compared to ascorbic acid as standard, the highest free radical scavenging capacity of 75% was observed for compound 4a at 50 μM.

Multidrug-resistant (MDR)Salmonellais a threat to public health. Non-antibiotic therapies could serve as important countermeasures to control MDRSalmonellaoutbreaks. In this study, antimicrobial activity of cationic α-helical bovine NK-lysin-derived antimicrobial peptides was evaluated against MDRSalmonellaoutbreak isolates. NK2A and NK2B strongly inhibited MDRSalmonellagrowth while NK1 and NK2C showed minimum-to-no growth inhibition. Scrambled-NK2A, which is devoid of α-helicity but has the same net positive charge as NK2A, also failed to inhibit bacterial growth. Incubation of negatively charged MDRSalmonellawith NK2A showed increased Zeta potential, indicating bacterial-peptide electrostatic attraction. Confocal and transmission electron microscopy studies revealed NK2A-mediated damage to MDRSalmonellamembranes. LPS inhibited NK2A-mediated growth suppression in a dose-dependent response, suggesting irreversible NK2A-LPS binding. LPS-NK2A binding and bacterial membrane disruption was also confirmed via electron microscopy using gold nanoparticle-NK2A conjugates. Finally, NK2A-loaded polyanhydride nanoparticles showed sustained peptide delivery and anti-bacterial activity. Together, these findings indicate that NK2A α-helicity and positive charge are prerequisites for antimicrobial activity and that MDRSalmonellakilling is mediated by direct interaction of NK2A with LPS and the inner membrane, leading to bacterial membrane permeabilization. With further optimization using nano-carriers, NK2A has the potential to become a potent anti-MDRSalmonellaagent.

Pneumocandin B0, the precursor of the antifungal drug caspofungin, is a lipohexapeptide produced by the fungus Glarea lozoyensis. Oxidative stress and the resulting production of reactive oxygen species (ROS) are known to be involved in the regulation of pneumocandin B0 biosynthesis. In this study, the Glyap1 gene of Glarea lozoyensis, a homologue of the yeast redox regulator YAP1, was knocked out. The intracellular ROS levels of the resulting ΔGlyap1 strain were higher than in the wild-type strain, which was caused by the downregulated expression of superoxide dismutase (SOD) and catalase (CAT). Compared with the wild-type strain, ΔGlyap1 exhibited an oxidative phenotype throughout its life cycle, which resulted in significantly higher pneumocandin B0 production per unit biomass. In addition, ΔGlyap1 showed growth inhibition and decreased pneumocandin B0 production in the presence of CCl4, which leads to strong oxidative stress. To overcome the strain’s sensitivity, a three-stage antioxidant addition strategy was developed. This approach significantly improved the growth of ΔGlyap1 while maintaining a high pneumocandin B0 production per unit biomass, which reached 38.78 mg/g DCW. Notably, this result represents a 50% increase over the wild-type strain. These findings provide new insights into the regulatory mechanisms that control pneumocandin B0 production under oxidative stress, which may be applied to improve the production of other secondary metabolites. • Glyap1 is involved in expression of redox and pneumocandin B0 synthesis-related genes. • Addition of a three-stage antioxidant alleviated the sensitivity of ΔGlyap1 strain. • The yield of pneumocandin B0 per unit biomass of ΔGlyap1 strain was 38.78 mg/g DCW.

Lung cancer is a major cause of cancer-related deaths worldwide. Stimulus-sensitive hydrogels, which can be formed by responding to stimuli in the cancer microenvironment, have been widely studied as controlled-release carriers for hydrophobic anticancer drugs. In this study, self-assembling peptide RADA16-I was used to encapsulate the hydrophobic drug emodin (EM) under magnetic stirring to form a colloidal suspension, and the colloidal suspension (RADA16-I-EM) was introduced into environments with physiological pH/ionic strength to form hydrogels in situ. The results showed that RADA16-I had good cell compatibility and the RADA16-I-EM in situ hydrogels can obviously reduce the toxicity of EM to normal cells. In addition, compared with free EM (in water suspensions without peptide) at equivalent concentrations, RADA16-I-EM in situ hydrogels significantly reduced the survival fraction of LLC lung cancer cells, while increased the uptake of EM by the cells, and it also induced apoptosis and cell cycle arrest in the G2/M phase more significantly and reduced the migration, invasion, and clone abilities of the cells in vitro. The RADA16-I-EM in situ hydrogels also showed better cancer growth inhibition effects in cancer models (mice bearing LLC cells xenograft cancer), which induced cell apoptosis in the cancer tissue and reduced the toxic side effects of EM on normal tissues and organs in vivo compared with the free EM. It was revealed that RADA16-I can be exploited as a promising carrier for hydrophobic anticancer drugs and has the potential to improve the administration of anticancer drugs to treat cancer effectively with enhanced chemotherapy.

Docosahexaenoic acid (DHA) and lutein are important nutrients for brain health. Whether there were synergistic effects of DHA and lutein on the protection against neuronal cell damage induced by oxidative stress remained unclear. The present study was designed to investigate the synergistic effects of DHA and lutein against hydrogen peroxide (H2O2)-induced oxidative challenge in PC12 cells. PC12 cells were divided into different groups and received H2O2 (80 μM), lutein (20 μM)+H2O2 (80 μM), DHA (25 μM)+H2O2 (80 μM), and lutein (20 μM)+DHA (25 μM)+H2O2 (80 μM), respectively. The results indicated that pre-treatment of cells with lutein, DHA and DHA+lutein could significantly antagonize the H2O2-mediated growth inhibition and morphological changes in PC12 cells (p

Purpose To determine the effect of low-intensity ultrasound on cancer cell proliferation in vitro and tumor growth in vivo. Methods In vitro, several cancer cell lines were exposed to low-intensity ultrasound at 0.11 W/cm2 for 2 min. Of the cell lines screened, melanoma C32 is one of the cell lines that showed sensitivity to growth inhibition by ultrasound and was therefore used in succeeding experiments. In vivo, under the same ultrasound conditions used in vitro, C32 tumors in mice were exposed to ultrasound daily for 2 weeks, and the tumor volumes were monitored weekly using sonography. Results In vitro, C32 cell growth was inhibited, attaining 43.2% inhibition on the 3rd day. In vivo, tumor growth was significantly inhibited, with the treated tumors exhibiting 2.7-fold slowed tumor growth vs. untreated tumors at week 2. Such inhibition was not associated with increased cell death. Several genes related to the cell cycle and proliferation were among those significantly regulated. Conclusion These findings highlight the potential of low-intensity ultrasound to inhibit tumor growth in a noninvasive, safe, and easy-to-administer way. In addition, this may suggest that the mechanical stress induced by ultrasound on C32 cells may have affected the intrinsic biomolecular mechanism related to the cell growth of this particular cell line. Further research is needed to identify which of the regulated genes played key roles in growth inhibition.

Toxin–antitoxin (TA) systems are genetic modules composed of a toxin interfering with cellular processes and its cognate antitoxin, which counteracts the activity of the toxin. TA modules are widespread in bacterial and archaeal genomes. It has been suggested that TA modules participate in the adaptation of prokaryotes to unfavorable conditions. The Bosea sp. PAMC 26642 used in this study was isolated from the Arctic lichen Stereocaulon sp. There are 12 putative type II TA loci in the genome of Bosea sp. PAMC 26642. Of these, nine functional TA systems have been shown to be toxic in Escherichia coli. The toxin inhibits growth, but this inhibition is reversed when the cognate antitoxin genes are coexpressed, indicating that these putative TA loci were bona fide TA modules. Only the BoVapC1 (AXW83_01405) toxin, a homolog of VapC, showed growth inhibition specific to low temperatures, which was recovered by the coexpression of BoVapB1 (AXW83_01400). Microscopic observation and growth monitoring revealed that the BoVapC1 toxin had bacteriostatic effects on the growth of E. coli and induced morphological changes. Quantitative real time polymerase chain reaction and northern blotting analyses showed that the BoVapC1 toxin had a ribonuclease activity on the initiator tRNAfMet, implying that degradation of tRNAfMet might trigger growth arrest in E. coli. Furthermore, the BoVapBC1 system was found to contribute to survival against prolonged exposure at 4°C. This is the first study to identify the function of TA systems in cold adaptation.

Thymus daenensis is a native medicinal plant of Iran with high pharmacological effects. The present survey was performed to evaluate the antibacterial effects of T. daenensis extract toward Staphylococcus aureus, Listeria monocytogenes, Escherichia coli and Pseudomonas aeruginosa food-borne bacteria. Ethanolic extract of T. daenensis was prepared from plant’s aerial parts. The diameters of the growth inhibition zones of bacteria against this extract and amoxicillin antibiotic disk was assessed by the disk diffusion test. Minimum inhibitory concentration was assessed using the broth micro-dilution method. The diameter of the growth inhibition zones of different concentrations of T. daenensis extract had the ranges between 7.00±0.54 to 15.00±1.09 mm. These findings revealed that the increase in the concentration of T. daenensis extract have caused significant increase in the diameter of the growth inhibition zone (P ≤0.05). Antibacterial effects of different concentrations of T. daenensis extract were lower than that of amoxicillin disk. T. daenensis extract had the highest antibacterial effects against P. aeruginosa. Additionally, T. daenensis extract had the highest antibacterial effects at lower concentrations (25 mg/mL) toward S. aureus. T. daenensis extract had the lowest MIC against S. aureus (6.00±1.00 mg/mL). The MIC of T. daenensis extract toward P. aeruginosa was 10.00±1.00 mg/mL. Antibacterial effects of T. daenensis ethanolic extract was determined in this survey. According to antibacterial effect of T. daenensis extract against food-borne bacteria, its application as a food preservative should potentially assess.

The simultaneous therapy of tumor recurrence and bone defects resulting from surgical resection of osteosarcoma is still a challenge in the clinic. Combination therapy based on a localized drug-delivery system shows great promise in the treatment of osteosarcoma. Herein, bifunctional polydopamine (PDA)-modified curcumin (CM)-loaded silk fibroin (SF) composite (SF/CM-PDA) nanofibrous scaffolds, which combined photothermal therapy with chemotherapy to synergistically enhance osteosarcoma therapy, were prepared by PDA coating of the SF/CM nanofibrous scaffolds fabricated by supercritical carbon dioxide (SC-CO2) technology. The PDA coating improved hydrophilicity and mechanical strength of the SF/CM scaffolds. The SF/CM-PDA scaffolds present good photothermal conversion capacity and excellent photostability. The low pH and near-infrared (NIR) irradiation could effectively accelerate release of CM in the SF/CM-PDA scaffolds. The in vitro anticancer results indicated that the biocompatible SF/CM-PDA scaffolds had a long-term, stable, and superior anticancer effect compared to pure CM. Furthermore, the SF/CM-PDA scaffolds significantly increased the growth inhibition of osteosarcoma MG-63 cells under NIR irradiation (808 nm and 1.3 W/cm2). Besides, the SF/CM-PDA scaffolds could enhance osteoblast MC3T3-E1 cell proliferation in vitro when the mass ratio of CM was 0.05–0.5%. This work has therefore demonstrated that the bifunctional SF/CM-PDA scaffolds provide a competitive strategy for local osteosarcoma therapy and bone regeneration.

Treatments for toxoplasmosis such as pyrimethamine have shown numerous side effects. It has been reported that the likelihood of relapse associated with pyrimethamine-based therapy in patients with HIV and toxoplasmic encephalitis (TE) can have significant implications, even for patients who often develop new lesions in areas of the brain previously free of infection. This led us to research for new agents against Toxoplasma gondii. Recent findings have shown the potent biological activity of 4-thiazolidinones. We proposed to design and synthesize a new series of 2-hydrazono-4-thiazolidinones derivatives to evaluate the in vitro growth inhibition effect on T. gondii. The growth rates of T. gondii tachyzoites in Human Foreskin Fibroblast (HFF) cell culture were identified by two in vitro methodologies. The first one was by fluorescence in which green fluorescent RH parasites and cherry-red fluorescent ME49 parasites were used. The second one was a colorimetric methodology using β-Gal parasites of the RH strain constitutively expressing the enzyme beta-galactosidase. The 4-thiazolidinone derivatives 1B, 2B and 3B showed growth inhibition at the same level of Pyrimethamine. These compounds showed IC50 values of 1B (0.468–0.952 μM), 2B (0.204–0.349 μM) and 3B (0.661–1.015 μM) against T. gondii. As a measure of cytotoxicity the compounds showed a TD50 values of: 1B (60 μM), 2B (206 μM) and 3B (125 μM). The in vitro assays and molecular modeling results suggest that these compounds could act as possible inhibitors of the Calcium-Dependent Protein Kinase 1 of T. gondii. Further, our results support the fact that of combining appropriate detection technologies, combinatorial chemistry and computational biology is a good strategy for efficient drug discovery. These compounds merit in vivo analysis for anti-parasitic drug detection., Graphical abstract Image 1, Highlights • The structures of 16 4-Thiazolidinones synthesized were characterized by spectral data. • The 2-pyridine that contains 5-substituted 4-thiazolidinone showed low cytotoxicity and high selectivity index. • The 2-hidroxyphenyl and 2-pyridinyl hydrazinyl derivatives showed the best anti-T. gondii activities.