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In the present study, the synthesis of gold nanoparticles (AuNPs) loaded with methotrexate (MTX) has been carried out in order to obtain controlled size and monodispersed nanocarriers of around 20 nm. The characterization study shows metallic AuNPs with MTX polydispersed on the surface. MTX is linked by the replacement of citrate by the MTX carboxyl group. The drug release profiles show faster MTX release when it is conjugated, which leads to the best control of plasma concentration. Moreover, the enhanced release observed at pH 5 could take advantage of the pH gradients that exist in tumor microenvironments to achieve high local drug concentrations. AuNP–MTX conjugates were tested by flow cytometry against lung (A-549) and colon (HTC-116) cancer cell lines. Results for A-549 showed a weaker dose–response effect than for colon cancer ones. This could be related to the presence of folate receptors in line HTC-116 in comparison to line A-549, supporting the specific uptake of folate-conjugated AuNP–MTX by folate receptor positive tumor cells. Conjugates exhibited considerably higher cytotoxic effects compared with the effects of equal doses of free MTX. Annexin V-PI tests sustained the cell death mechanism of apoptosis, which is normally disabled in cancer cells.

The article titled "Cover Feature: Cellular Mechanistic Considerations on Cytotoxic Mode of Action of Phosphino Ru(II) and Ir(III) Complexes" explores the cellular mechanism of action of phosphino Ru(II) and Ir(III) complexes as potential chemotherapeutics. The cover feature of the article depicts a boxing match between a cancer cell and a phosphino Ru (or Ir) organometallic compound. The cancer cell is portrayed as an ugly, green monster wearing a yellow-orange t-shirt and red boxing gloves, while the Ru organometallic compound is shown in an X-ray structure with orange phosphorus, dark green ruthenium, and light green chloride ions. The article provides more detailed information on this research. [Extracted from the article]

Keywords: Chemotherapeutics; gold; heterometallic phosphanes; platinum; TNBC EN Chemotherapeutics gold heterometallic phosphanes platinum TNBC 1 1 1 10/26/23 20231023 NES 231023 B In the war against cancer b , two cytotoxic metallic fragments - gold and platinum, symbolically represented as superheroes - join forces in a single molecule. Chemotherapeutics, gold, heterometallic phosphanes, platinum, TNBC Cover Feature: Platinum(IV)-Gold(I) Agents with Promising Anticancer Activity: Selected Studies in 2D and 3D Triple-Negative Breast Cancer Models (Chem. Eur. J. 59/2023). [Extracted from the article]

• The use of X-ray absorption spectroscopy (XAS) method performed in laboratory conditions to study prospective anticancer compounds – dichloro(1,10-phenanthroline) copper (II), copper(II) tetraphenyl porphyrin and referential copper samples is reported. • Comparison of laboratory and synchrotron XAS examination and its results are presented. • Methodology of analysing XAS data is proposed. From the commonly known metal-based chemotherapeutics, like cisplatin, there is ongoing interest in searching for some of their alternatives, including copper complexes containing organic groups. In this paper, we report the results of the preliminary examination of copper-based compounds, which are studied with the use of the laboratory XAS setup, that are compared with data obtained at the synchrotron facility. Identification of spectral features and oxidation state of copper was successfully performed based only on the laboratory data, however, some limitation of this test apparatus is also reported. Additionally, we performed first testing of the laboratory XAS spectrometer to study more complex compounds, which could be used in anticancer therapy, than metallic foils, which are usually used to estimate the experimental capabilities of such setups. [ABSTRACT FROM AUTHOR]

Brain tumors include primary tumors of various intracranial tissue and secondary intracranial tumors that transferred from other parts of the body. Secondary intracranial tumors are especially prevalent in patients with lung cancer. The mechanisms of lung cancer with brain metastases are complicated, they are affected by a variety of factors. Thus, identifying the mechanisms of lung cancer with brain metastases will have far-reaching meanings both for clinic pharmacy research and for a better quality of life for patients; Brain metastases from lung cancer represent a prevalent and challenging clinical dilemma, and some research suggests that the outcomes and characteristics of brain metastases that result from lung cancer primary sites are perhaps different than those from other primary sites, therefore increasing the difficulty of clinical treatment. Despite steady research developments during recent years, the survival rates remain poor. The mechanisms and therapeutic options for treating brain metastases arising from lung cancer are review in this article.

Following the discovery of cisplatin over 50 years ago, platinum-based drugs have been a widely used and effective form of cancer therapy, primarily causing cell death by inducing DNA damage and triggering apoptosis. However, the dose-limiting toxicity of these drugs has led to the development of second and third generation platinum-based drugs that maintain the cytotoxicity of cisplatin but have a more acceptable side-effect profile. In addition to the creation of new analogs, tumor delivery systems such as liposome encapsulated platinum drugs have been developed and are currently in clinical trials. In this study, we have created the first PEGylated liposomal form of nedaplatin using thin film hydration. Nedaplatin, the main focus of this study, has been exclusively used in Japan for the treatment of non-small cell lung cancer, head and neck, esophageal, bladder, ovarian and cervical cancer. Here, we investigate the cytotoxic and genotoxic effects of free and liposomal nedaplatin on the human non-small cell lung cancer cell line A549 and human osteosarcoma cell line U2OS. We use a variety of assays including ICP MS and the highly sensitive histone H2AX assay to assess drug internalization and to quantify DNA damage induction. Strikingly, we show that by encapsulating nedaplatin in PEGylated liposomes, the platinum uptake cytotoxicity and genotoxicity of nedaplatin was significantly enhanced in both cancer cell lines. Moreover, the enhanced platinum uptake as well as the cytotoxic/antiproliferative effect of liposomal nedaplatin appears to be selective to cancer cells as it was not observed on two noncancer cell lines. This is the first study to develop PEGylated liposomal nedaplatin and to demonstrate the superior cell delivery potential of this product.

Antibacterial agents are commonly present in aquatic environment at low concentrations. Terrestrial animal farms, human medicine and aquaculture are main sources of water contamination with antibacterials. Antibiotics were proved to be directly toxic to fish causing oxidative stress, general stress response, histopathological lesions, hematological, metabolic, and reproductive disorders, as well as immunosuppressive and genotoxic effects. Environmentally realistic low concentrations of antibiotics also disturb aquatic bacterial communities causing alterations in fish symbiotic microbiota and induce emergence of antibiotic-resistant pathogenic bacteria by exerting selective pressure on spread of antibiotic-resistance genes.

The Clinical Laboratory Standards Institute lowered the fluoroquinolone minimum inhibitory concentration (MIC) susceptibility breakpoints for Enterobacteriaceae and glucose non-fermenting Gram-negative bacilli in January 2019. This retrospective cohort study describes the impact of this reappraisal on ciprofloxacin susceptibility overall and in patients with risk factors for antimicrobial resistance. Gram-negative bloodstream isolates collected from hospitalized adults at Prisma Health-Midlands hospitals in South Carolina, USA, from January 2010 to December 2014 were included. Matched pairs mean difference (MD) with 95% confidence intervals (CI) were calculated to examine the change in ciprofloxacin susceptibility after MIC breakpoint reappraisal. Susceptibility of Enterobacteriaceae to ciprofloxacin declined by 5.2% (95% CI: −6.6, −3.8; p < 0.001) after reappraisal. The largest impact was demonstrated among Pseudomonas aeruginosa bloodstream isolates (MD −7.8, 95% CI: −14.6, −1.1; p = 0.02) despite more conservative revision in ciprofloxacin MIC breakpoints. Among antimicrobial resistance risk factors, fluoroquinolone exposure within the previous 90 days was associated with the largest change in ciprofloxacin susceptibility (MD −9.3, 95% CI: −16.1, −2.6; p = 0.007). Reappraisal of fluoroquinolone MIC breakpoints has a variable impact on the susceptibility of bloodstream isolates by microbiology and patient population. Healthcare systems should be vigilant to systematically adopt this updated recommendation in order to optimize antimicrobial therapy in patients with bloodstream and other serious infections.

Helicase-like transcription factor (HLTF) and SNF2, histone-linker, PHD and RING finger domain-containing helicase (SHPRH), the two human homologs of yeast Rad5, are believed to have a vital role in DNA damage tolerance (DDT). Here we show that HLTF, SHPRH and HLTF/SHPRH knockout cell lines show different sensitivities towards UV-irradiation, methyl methanesulfonate (MMS), cisplatin and mitomycin C (MMC), which are drugs that induce different types of DNA lesions. In general, the HLTF/SHPRH double knockout cell line was less sensitive than the single knockouts in response to all drugs, and interestingly, especially to MMS and cisplatin. Using the SupF assay, we detected an increase in the mutation frequency in HLTF knockout cells both after UV- and MMS-induced DNA lesions, while we detected a decrease in mutation frequency over UV lesions in the HLTF/SHPRH double knockout cells. No change in the mutation frequency was detected in the HLTF/SHPRH double knockout cell line after MMS treatment, even though these cells were more resistant to MMS and grew faster than the other cell lines after treatment with DNA damaging agents. This phenotype could possibly be explained by a reduced activation of checkpoint kinase 2 (CHK2) and MCM2 (a component of the pre-replication complex) after MMS treatment in cells lacking SHPRH. Our data reveal both distinct and common roles of the human RAD5 homologs dependent on the nature of DNA lesions, and identified SHPRH as a regulator of CHK2, a central player in DNA damage response.

Objective: Breast cancer (BC) is a highly malignant neoplasm with resistance to therapeutics that are related to genes associated with multidrug resistance. The excessive expression of ATP-binding cassette transporters (ABCs) genes, including ABCA1 and ABCA3, is a primary factor contributing to the increased effluent of cell-toxic drugs and subsequent treatment resistance. Therefore, the current work aimed to explore the role of ABCA1 and ABCA3 in chemoresistance activity against cisplatin in breast cancer cells., Methods: The current study compared the AMJ13 breast cancer cells derived from a woman Iraqi patient, which are hormone receptor-negative, with MCF-7 breast cancer cells, which are hormone receptor-positive.  Cytotoxic assay (CCK-8 assay) is used to measure the cell's viability and cytotoxic activity after it has been treated with cisplatin. Morphological Study using crystal violet stain to examine cytological changes was conducted. Quantitative RT-PCR is used to measure how much the ABCA1, and 3 genes mRNA are being expressed before and after treatment., Results: The CCK-8 assay found that IC50 values of cisplatin in AMJ13 and MCF-7 cells were 202.2 µg/ml and 90.23 µg/ml, respectively. The IC50 value of AMJ13 is 2-fold higher than in MCF-7 cells. The QPCR study revealed that breast cancer cell lines AMJ13 and MCF-7 subjected to cisplatin showed upregulated levels of ABCA1 and ABCA3 expression. Experiments with cytotoxicity assays demonstrate that higher expression of ABCA1 and ABCA3 in AMJ13 and MCF-7 breast cancer cell lines is linked to their resistance.  Conclusion: The findings of this study suggest that the ABCA1 and ABCA3 transporters play a significant role in the resistance to cisplatin and,.

Nanotechnology provides effective methods for precisely delivering chemotherapeutics to cancer cells, thereby improving efficacy and reducing off-target side effects. The targeted delivery of nanoscale chemotherapeutics is accomplished by two different approaches, namely the exploitation of leaky tumor vasculature (EPR effect) and the surface modification of nanoparticles (NPs) with various tumor-homing peptides, aptamers, oligonucleotides, and monoclonal antibodies (mAbs). Because of higher binding affinity and specificity, mAbs have received a lot of attention for the detection of selective cancer biomarkers and also for the treatment of various types of cancer. Antibody-conjugated nanoparticles (ACNPs) are an effective targeted therapy for the efficient delivery of chemotherapeutics specifically to the targeted cancer cells. ACNPs combine the benefits of NPs and mAbs to provide high drug loads at the tumor site with better selectivity and delivery efficiency. The mAbs on the NP surfaces recognize their specific receptors expressed on the target cells and release the chemotherapeutic agent in a controlled manner. Appropriately designed and synthesized ACNPs are essential to fully realize their therapeutic benefits. In blood stream, ACNPs instantly interact with biological molecules, and a protein corona is formed. Protein corona formation triggers an immune response and affects the targeting ability of the nanoformulation. In this review, we provide recent findings to highlight several antibody conjugation methods such as adsorption, covalent conjugation, and biotin-avidin interaction. This review also provides an overview of the many effects of the protein corona and the theranostic applications of ACNPs for the treatment of cancer., Competing Interests: The authors declare no competing interests., (Copyright © 2023, Kumari et al.)

Background: Choosing the most effective chemotherapeutic agent with safest side effect profile is a common challenge in cancer treatment. Although there are standardized chemotherapy protocols in place, protocol changes made after extensive clinical trials demonstrate significant improvement in the efficacy and tolerability of certain drugs. The pharmacokinetics, pharmacodynamics, and tolerance of anti-cancer medications are all highly individualized. A driving force behind these differences lies within a person's genetic makeup., Recent Findings: Pharmacogenomics, the study of how an individual's genes impact the processing and action of a drug, can optimize drug responsiveness and reduce toxicities by creating a customized medication regimen. However, these differences are rarely considered in the initial determination of standardized chemotherapeutic protocols and treatment algorithms. Because pharmacoethnicity is influenced by both genetic and nongenetic variables, clinical data highlighting disparities in the frequency of polymorphisms between different ethnicities is steadily growing.  Recent data suggests that ethnic variations in the expression of allelic variants may result in different pharmacokinetic properties of the anti-cancer medication. In this article, the clinical outcomes of various chemotherapy classes in patients of different ethnicities were reviewed., Conclusion: Genetic and nongenetic variables contribute to the interindividual variability in response to chemotherapeutic drugs. Considering pharmacoethnicity in the initial determination of standard chemotherapeutic protocols and treatment algorithms can lead to better clinical outcomes of patients of different ethnicities., (© 2023 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Osteosarcoma is among the most common malignant bone tumors in human skeletal system. The conventional treatment of osteosarcoma mainly consists of combining neoadjuvant chemotherapy with surgical approach. However, it is crucial to design an artificial implant that possesses excellent biomechanical properties and is capable of sustaining local release of chemotherapeutics. In this study, we envision that the highly efficient combination of gemcitabine (GEM) hydrochloride loaded liposomes with gelatin methacryloyl (GelMA) of in situ photocrosslinkable hydrogel will lead to a multifunctional implant with unique antitumor, mechanical, and biodegradable properties. A sustained controlled release was observed; more specifically, the release of GEM in vitro lasted for 4 days long. Furthermore, its capability in killing MG63 cells was further explored by using the lixivium of GEM-Lip@Gel and GEM-GelMA hydrogel in vitro (composite hydrogel by GEM loaded liposomes blending with GelMA, short for GEM-Lip@Gel), which agreed with the drug release outcome. In addition, these hydrogel showed excellent ability in inhibiting osteosarcoma in vivo by Balb/c mice bearing MG63 cells. Therefore, GEM-loaded lipo-hydrogel certainly has presented itself as a promising strategy for the development of implant in the field of osteosarcoma treatment. [ABSTRACT FROM AUTHOR]

Anti-mPEG/anti-human epidermal growth factor receptor 2 (HER2) bispecific antibodies (BsAbs) non-covalently bound to a docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micellar drug delivery system (LsbMDDs) were endowed with active targetability to improve the chemotherapeutic efficacy of DTX. DTX-loaded mPEGylated LsbMDDs formulations were prepared using lecithin/DSPE-PEG(2K or 5K) nanosuspensions to hydrate the thin film, and then they were subjected to ultrasonication. Two BsAbs (anti-mPEG/anti-DNS or anti-HER2) were simply mixed with the LsbMDDs to form BsAbs-LsbMDDs formulations, respectively, referred as the DNS-LsbMDDs and HER2-LsbMDDs. Results demonstrated that the physical characteristics of the BsAbs-LsbMDDs were similar to those of the plain LsbMDDs but more slowly released DTX than that from the LsbMDDs. Results also showed that the HER2-LsbMDDs suppressed the growth of HER2-expressing MCF-7/HER2 tumors, increasing the amount taken up via an endocytosis pathway leading to high drug accumulation and longer retention in the tumor. In conclusion, the BsAbs-LsbMDDs preserved the physical properties of the LsbMDDs and actively targeted tumors with a drug cargo to enhance drug accumulation in tumors leading to greater antitumor activity against antigen-positive tumors. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the anti-gingivitis efficacy of a novel oral hygiene routine consisting of a two-step stannous fluoride dentifrice and hydrogen peroxide whitening gel system, an interactive oscillating-rotating electric toothbrush, and expanded polytetrafluoroethylene floss. Methods: A total of 52 participants (n=52; mean age 35.8±11.23 years) were enrolled in the study and randomized 1:1 to the experimental hygiene group or control (dental prophylaxis followed by use of standard sodium fluoride dentifrice and a manual toothbrush). Participants were instructed to brush twice daily; those in the experimental group were instructed to floss once daily. Oral examinations were conducted at Baseline, Week 2, Week 4, and Week 6. Results: Both groups experienced significant declines in the mean number of bleeding sites from Baseline at all time points, evident as early as Week 2. Bleeding sites continued to decline throughout the trial in the experimental group, whereas they showed an increasing trend between Weeks 2 and 6 in the control group. The experimental group had 55% fewer bleeding sites at Week 2, 85% fewer bleeding sites at Week 4, and 98% fewer bleeding sites at Week 6 (p≤0.0001 for all) as compared to the control group. At Week 6, 84% of participants in the experimental group had no bleeding, while all participants in the control group had bleeding. Conclusion: The experimental oral hygiene group showed significantly greater reductions in gingival bleeding than the control oral hygiene group, with benefits seen as early as Week 2 and increasing over the six-week study. [ABSTRACT FROM AUTHOR]

The present study aimed to determine the role of metabotropic glutamate receptor 8 (mGluR8) in tumor biology. Using various molecular approaches (RNAi or GRM8 cDNA), cell clones with downregulated (human neuroblastoma SH-SY5Y and human glioma LN229) or overexpressed (human glioma U87-MG and LN18 cell lines) mGluR8 were generated. Next, comparative studies on cell proliferation and migration rates, induction of apoptosis and chemosensitivity were performed among these clones. The mGluR8-downregulated SH-SY5Y clones proliferated faster and were more resistant to cytotoxic action of staurosporine, doxorubicin, irinotecan and cisplatin when compared to control cells. Moreover, these clones were characterized by a lower activity of caspases, calpains and some kinases (GSK-3β, Akt and JNK). The mGluR8-downregulated LN229 clones migrated faster and were less prone to cell-damaging effect of staurosporine and irinotecan when compared with relevant control cells. In contrast, in GRM8-overexpressing U87-MG and LN18 clones, a decreased cell proliferation, increased apoptosis and elevated vulnerability to some cytotoxic agents were found. Altogether, our in vitro data for the first time evidenced a tumor suppressor and chemosensitizing role of mGluR8. [ABSTRACT FROM AUTHOR]

Abstract Purple acid phosphatases (PAPs) are metalloenzymes that catalyse the hydrolysis of phosphate esters under acidic conditions. Their active site contains a Fe(III)Fe(II) metal centre in mammals and a Fe(III)Zn(II) or Fe(III)Mn(II) metal centre in plants. In humans, elevated PAP levels in serum strongly correlate with the progression of osteoporosis and metabolic bone malignancies, which make PAP a target suitable for the development of chemotherapeutics to combat bone ailments. Due to difficulties in obtaining the human enzyme, the corresponding enzymes from red kidney bean and pig have been used previously to develop specific PAP inhibitors. Here, existing lead compounds were further elaborated to create a series of inhibitors with K i values as low as ∼30 μM. The inhibition constants of these compounds were of comparable magnitude for pig and red kidney bean PAPs, indicating that relevant binding interactions are conserved. The crystal structure of red kidney bean PAP in complex with the most potent inhibitor in this series, compound 4f , was solved to 2.40 Å resolution. This inhibitor coordinates directly to the binuclear metal centre in the active site as expected based on its competitive mode of inhibition. Docking simulations predict that this compound binds to human PAP in a similar mode. This study presents the first example of a PAP structure in complex with an inhibitor that is of relevance to the development of anti-osteoporotic chemotherapeutics. Graphical abstract Image 1 Highlights • A lead inhibitor against Purple acid phosphatase has been further developed. • Compounds are active against both pig and red kidney bean Purple acid phosphatases. • A crystal structure of an inhibitor in complex with the red kidney bean enzyme (2.40 Å) is reported. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate the effects of repeated scaling and root planing (SRP), with or without locally-delivered minocycline microspheres (MM) on residual pockets in patients undergoing periodontal maintenance (PMT). Methods: Patients on PMT were randomized into two groups for treatment of one posterior interproximal inflamed pocket (≥5 mm) with a history of bleeding on probing every 6 months: SRP plus MM (n=30) or exclusively SRP (n=30). Baseline and 24-month measurements included radiographic interproximal alveolar bone height, probing depths (PD), clinical attachment level (CAL), bleeding on probing (BOP), gingival crevicular fluid (GCF), and salivary interleukin (IL) - 1β, (24 month only). Results were analyzed for baseline data or change in measurements after 24 months of treatment between different treatment groups, as well as whether significant changes occurred after 24 months of treatment for each treatment group individually. Results: Alveolar bone height and GCF IL-1β remained stable over the 24 months. The SRP + MM and SRP groups each demonstrated reduced PD (0.8 ± 0.9 mm and 1.1 ±0.6 mm, respectively, p < 0.001 each), CAL (0.8 ± 0.9 mm and 1.0 ± 0.6 mm, respectively, p < 0.001 each) and BOP (55% and 48%, respectively, p = 0.001 each). However, there were no differences between groups over the 24-month study period. Conclusion: Scaling and root planning alone, of moderately inflamed periodontal pockets at 6-month intervals, produced stable interproximal alveolar bone height as well as sustained improvements in probing depths, clinical attachment level, bleeding on probing over 24 months; minocycline microspheres were not shown to enhance these results. [ABSTRACT FROM AUTHOR]

Polyphenols, chemically characterized by a polyhydroxylated phenolic structure, are well known for their widespread pharmacological properties: anti-inflammatory, antibiotic, antiseptic, antitumor, antiallergic, cardioprotective and others. Their distribution in food products is also extensive especially in plant foods such as vegetables, cereals, legumes, fruits, nuts and certain beverages. The latest scientific literature outlines a resilient interconnection between cancer modulation and dietary polyphenols by sphingolipid-mediated mechanisms, usually correlated with a modification of their metabolism. We aim to extensively survey this relationship to show how it could be advantageous in cancer treatment or prevention by nutrients. From this analysis it emerges that a combination of classical chemotherapy with nutrients and especially with polyphenols dietary sources may improve efficacy and decreases negative side effects of the antineoplastic drug. In this multifaceted scenario, sphingolipids play a pivotal role as bioactive molecules, emerging as the mediators of cell proliferation in cancer and modulator of chemotherapeutics. [ABSTRACT FROM AUTHOR]

Targeted delivery of chemotherapeutics through the respiratory system is a potential approach to improve drug accumulation in the lung tumor, while decreasing their negative side effects. However, elimination by the pulmonary clearance mechanisms, including the mucociliary transport system, and ingestion by the alveolar macrophages, rapid absorption into the blood, enzymatic degradation, and low control over the deposition rate and location remain the main complications for achieving an effective pulmonary drug delivery. Therefore, particle-based delivery systems have emerged to minimize pulmonary clearance mechanisms, enhance drug therapeutic efficacy, and control the release behavior. A successful implementation of a particle-based delivery system requires understanding the influential parameters in terms of drug carrier, inhalation technology, and health status of the patient's respiratory system. This review aims at investigating the parameters that significantly drive the clinical outcomes of various particle-based pulmonary delivery systems. This should aid clinicians in appropriate selection of a delivery system according to their clinical setting. It will also guide researchers in addressing the remaining challenges that need to be overcome to enhance the efficiency of current pulmonary delivery systems for aerosols. [ABSTRACT FROM AUTHOR]

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Breast cancer (BC) prevention and therapy in the context of life-style risk factors and biological drivers is a major focus of developmental therapeutics in oncology. Obesity, alcohol, chronic estrogen signaling and smoking have distinct BC precipitating and facilitating effects that may act alone or in combination. A spectrum of signaling events including enhanced oxidative stress and changes in estrogen-receptor (ER)-dependent and -independent signaling drive the progression of BC. Breast tumors modulate ERa/ERp ratio, upregulate proliferative pathways driven by ERa and HER2 with a parallel loss and/or downregulation of tumor suppressors such as TP53 and PTEN which together impact the efficacy of therapeutic strategies and frequently lead to emergence of drug resistance. Natural phytochemicals modulate oxidative stress, leptin, integrin, HER2, MAPK, ERK, Wnt/p-catenin and NFκB signaling along with regulating ERa and ERp, thereby presenting unique opportunities for both primary and combinatorial interventions in BC. In this regard, this article focuses on critical analyses of the evidence from multiple studies on the efficacy of natural phytochemicals in BC. In addition, areas in which the combinations of such effective natural phytochemicals with approved and/or developing anticancer agents can be translationally beneficial are discussed to derive evidence-based inference for addressing challenges in BC control and therapy. [ABSTRACT FROM AUTHOR]

Aim: Analysis of the properties and chemotherapeutics delivery potential of spheres made of bioengineered spider silks MS1 and MS2. Materials & methods: MS1 and MS2 derived from Nephila clavipes dragline silks - MaSp1 and MaSp2, respectively - formed spheres that were compared in terms of physicochemical properties, cytotoxicity and loading/release of chemotherapeutics. Results: MS2 spheres were more dispersed, smaller, of solid core, of higher beta-sheet structure content, and of opposite (negative) charge than MS1 spheres. Preloaded MS2 showed greater applicability for mitoxantrone, while postloaded for etoposide delivery compared with MS1 spheres. However, MS1 spheres were a better choice for doxorubicin delivery than MS2. Conclusion: Bioengineered silks can be tailored to develop a system with optimal drug loading and release properties. [ABSTRACT FROM AUTHOR]

Nanoparticles govern an all-important role, in this day and age, in determining the tissue distribution of either hydrophobic or hydrophilic anti-cancer drugs by encapsulating them or by covalent attachment. The whole purpose is to systematically improve upon the existing anti-tumour efficacy of these drugs. Selective delivery of these chemotherapeutic agents to the compromised or diseased tissue is the key to avoid any potential toxicity problems. Certain types of nanoparticles, through various mechanisms such as active targeting or reversing multi-drug resistance, display immense potential in adding to the existing anti-tumour efficacy profile. Determining the optimal composition of the polymers or size of the nanoparticles or appropriately tailoring the surface of these nanoparticles with molecular ligands are the key components in governing the successful biological fate of these nanoparticles. [ABSTRACT FROM AUTHOR]

The incidence of numerous types of cancer has been increasing over recent years, representing the second-most frequent cause of death after cardiovascular diseases. Even though, the number of effective anticancer drugs is increasing as well, a large number of patients suffer from severe side effects (e.g., cardiomyopathies) caused by these drugs. This adversely affects the patients' well-being and quality of life. On the molecular level, tumor cells that survive treatment modalities can become chemotherapy-resistant. In addition, adverse impacts on normal (healthy, stromal) cells occur concomitantly. Strategies that minimize these negative impacts on normal cells and which at the same time target tumor cells efficiently are needed. Recent studies suggest that redox-based combinational nanotherapies may represent one option in this direction. Here, we discuss recent advances in the application of nanoparticles, alone or in combination with other drugs, as a promising anticancer tool. Such novel strategies could well minimize harmful side effects and improve patients' health prognoses. [ABSTRACT FROM AUTHOR]

Molecular hybridization is considered as an effective tactic to develop drugs for the treatment of cancer. A series of novel hybrid compounds of isatin and Michael acceptor were designed and synthesized on the basis of association principle. These hybrid compounds were tested for cytotoxic potential against human cancer cell lines namely, BGC-823, SGC-7901 and NCI-H460 by MTT assay. Most compounds showed good anti-growth activities in all tested human cancer cells. SAR and QSAR analysis may provide vital information for the future development of novel anti-cancer inhibitors. Notably, compound 6a showed potent growth inhibition on BGC-823, SGC-7901 and NCI-H460 with the IC 50 values of 3.6 ± 0.6, 5.7 ± 1.2, 3.2 ± 0.7 μM, respectively. Besides, colony formation assays, wound healing assays and flow cytometry analysis indicated 6a exhibited a potent anti-growth and anti-migration ability in a concentration-dependence manner through arrested cells in the G2/M phase of cell cycle. Moreover, 6a significantly repressed tumor growth in a NCI-H460 xenograft mouse model. Overall, our findings suggested isatin analogues inspired Michael acceptor may provide promising lead compounds for the development of cancer chemotherapeutics. [ABSTRACT FROM AUTHOR]

As aquaculture evolves from extensive pond culture to intensive tank and cage systems, chemical dips and baths are increasingly being used to treat a concomitant increase in ectoparasitic and bacterial infestations. Some of the main disease-causing agents are ectoparasites on the skin and gills of fish. Consequently, application of chemotherapeutics is increasing in aquaculture industries in order to control outbreaks of parasitic infestations. However, the toxic effect of commonly used chemotherapeutic agents on specific aquacultured fish species is often unknown. The present work was performed to test the effect of four commonly used chemical treatments on rabbitfish, Siganus rivulatus. The lethal concentrations for 50% of population (LC50) of formalin, copper sulfate, potassium permanganate, and hydrogen peroxide for S. rivulatus juveniles treated for 1 h were assessed. Formalin and potassium permanganate tolerance values were determined by calculating 72-h LC50 values through probit analysis. The 72-h LC50 values for the formalin toxicity tests were 551.0 and 1.68 mg/L, respectively. LC50 of copper sulfate and hydrogen peroxide could not be determined from the concentrations tested but were found to be >3 and >700 mg/L, respectively. Accordingly, treatment concentrations of formalin and potassium permanganate used for other fish species could be lethal to S. rivulatus, but the species appears to be quite tolerant to copper sulfate and hydrogen peroxide. [ABSTRACT FROM AUTHOR]

Purple acid phosphatases (PAPs) are ubiquitous binuclear metallohydrolases that have been isolated from various animals, plants and some types of fungi. In humans and mice, elevated PAP activity in osteoclasts is associated with osteoporosis, making human PAP an attractive target for the development of anti-osteoporotic drugs. Based on previous studies focusing on phosphonate scaffolds, as well as a new crystal structure of a PAP in complex with a derivative of a previously synthesized α-aminonaphthylmethylphosphonic acid, phosphonates 24–40 were designed as new PAP inhibitor candidates. Subsequent docking studies predicted that all of these compounds are likely to interact strongly with the active site of human PAP and most are likely to interact strongly with the active site of pig PAP. The seventeen candidates were synthesized with good yields and nine of them (26–28 , 30 , 33–36 and 38) inhibit in the sub-micromolar to nanomolar range against pig PAP, with 28 and 35 being the most potent mammalian PAP inhibitors reported with K i values of 168 nM and 186 nM, respectively. This study thus paves the way for the next stage of drug development for phosphonate inhibitors of PAPs as anti-osteoporotic agents. [Display omitted] • Purple acid phosphatase (PAP) plays a crucial role in bone resorption. • Overexpression of PAP is directly linked to osteoporosis. • PAP inhibitors are promising candidates for novel treatments for osteoporosis. • Highly efficient PAP inhibitors with K i values < 200 nM are described here. • Structural and docking data provide crucial information for drug development. [ABSTRACT FROM AUTHOR]

Additive manufacturing has great potential for personalized medicine in osseous fixation surgery, including maxillofacial and orthopedic applications. The purpose of this study was to demonstrate 3D printing methods for the fabrication of patient-specific fixation implants that allow for localized drug delivery. 3D printing was used to fabricate gentamicin (GS) and methotrexate (MTX)-loaded fixation devices, including screws, pins, and bone plates. Scaffolds with different infill ratios of polylactic acid (PLA), both without drugs and impregnated with GS and MTX, were printed into cylindrical and rectangular-shaped constructs for compressive and flexural strength mechanical testing, respectively. Bland PLA constructs showed significantly higher flexural strength when printed in a Y axis at 100% infill compared to other axes and infill ratios; however, there was no significant difference in flexural strength between other axes and infill ratios. GS and MTX-impregnated constructs had significantly lower flexural and compressive strength as compared to the bland PLA constructs. GS-impregnated implants demonstrated bacterial inhibition in plate cultures. Similarly, MTX-impregnated implants demonstrated a cytotoxic effect in osteosarcoma assays. This proof of concept work shows the potential of developing 3D printed screws and plating materials with the requisite mechanical properties and orientations. Drug-impregnated implants were technically successful and had an anti-bacterial and chemotherapeutic effect, but drug addition significantly decreased the flexural and compressive strengths of the custom implants.

Despite advances in treatments like chemotherapy and radiotherapy, metastatic cancer remains a leading cause of death for cancer patients. While many chemotherapeutic agents can efficiently eliminate cancer cells, long-term protection against cancer is not achieved and many patients experience cancer recurrence. Mobilizing and stimulating the immune system against tumor cells is one of the most effective ways to protect against cancers that recur and/or metastasize. Activated tumor specific cytotoxic T lymphocytes (CTLs) can seek out and destroy metastatic tumor cells and reduce tumor lesions. Natural Killer (NK) cells are a front-line defense against drug-resistant tumors and can provide tumoricidal activity to enhance tumor immune surveillance. Cytokines like IFN-γ or TNF play a crucial role in creating an immunogenic microenvironment and therefore are key players in the fight against metastatic cancer. To this end, a group of anthracyclines or treatments like photodynamic therapy (PDT) exert their effects on cancer cells in a manner that activates the immune system. This process, known as immunogenic cell death (ICD), is characterized by the release of membrane-bound and soluble factors that boost the function of immune cells. This review will explore different types of ICD inducers, some in clinical trials, to demonstrate that optimizing the cytokine response brought about by treatments with ICD-inducing agents is central to promoting anti-cancer immunity that provides long-lasting protection against disease recurrence and metastasis. [ABSTRACT FROM AUTHOR]

Off-target cardiotoxicity has been a significant impediment to the development of new drugs. Traditional platforms for screening for cardiotoxicity are both overly sensitive and limited in their ability to predict cardiotoxicity that is often only uncovered after years of clinical use. A major impediment has been the lack of a human cardiomyocyte cell line. The recent discovery that adult somatic human cells (white blood cells or skin fibroblasts) can be reprogrammed into pluripotent stem cells (hiPSCs) and then differentiated into beating cardiomyocytes (hiPSC-CMs) provides an exciting new platform for drug cardiotoxicity and efficacy testing. One major advantage of using patient-derived hiPSC-CMs for drug testing is their ability to recapitulate population genetic variations (single nucleotide polymorphisms) that influence drug toxicity, providing a powerful new tool in the field of pharmacogenomics and personalized medicine. [ABSTRACT FROM AUTHOR]

Refractory and relapsed neuroblastoma (NB) present with significant challenges in clinical management. Though primary NBs largely with wild-type p53 respond well to interventions, dysfunctional signaling in the p53 pathways in a MYCN oncogene driven background is found in a number of children with NB. The p53-mutant NB is largely unresponsive to available therapies and p53-independent targeted therapeutics represents a vital need in pediatric oncology. We analyzed the findings on mercapturic acid pathway (MAP) transporter RLIP76, which has broad and critical effects on multiple pathways as essential for carcinogenesis, oxidative stress and drug-resistance, is over-expressed in NB. RLIP76 inhibition by antibodies or depletion by antisense causes apoptosis and sensitization to chemo-radiotherapy in many cancers. In addition, recent studies indicate that the interactions between p53, MYCN, and WNT regulate apoptosis resistance and protein ubiquitination. RLIP76 and p53 interact with each other and colocalize in NB cells. Targeted depletion/inhibition of RLIP76 causes apoptosis and tumor regression in NB irrespective of p53 status. In the present review, we discuss the mechanisms and the role of RLIP76 in oxidative stress, drug-resistance and clathrin-dependent endocytosis (CDE), and analyze the molecular basis for the role of RLIP76 targeted approaches in the context principal drivers of NB pathogenesis, progression and drug-resistance. The evidence from RLIP76 studies in other cancers, when taken in the context of our recent RLIP76 focused mechanistic studies in NB, provides strong basis for further characterization and development of RLIP76 targeted therapies for NB. [ABSTRACT FROM AUTHOR]

Trans -resveratrol ( t-RES) is a natural polyphenolic compound with extensive therapeutic activities; however, its clinical application is circumscribed due to its poor solubility and low bioavailability. The purpose of this study was to prepare stable t-RES nanocrystals ( t-RES-NCs) with different stabilizers to improve its oral bioavailability. t-RES-NCs were fabricated by the probe sonication method and optimized by particles size, poly dispersive index and zeta potential. The pharmaceutical characterization of t-RES-NCs was further performed systematically. The in vitro cellular efficacy and in vivo pharmacokinetics of t-RES-NCs were also evaluated. The optimized NCs were successfully accomplished in a sub-micron particle size (110.28 ± 12.55 nm) with high ζ-potential (−32.96 ± 3.85 mV) value. Scanning electron microscopy (SEM) image indicated that morphology of t-RES-NCs was regular and rod like in shape. Meanwhile, the result of in vitro cellular efficacy against MDA-MB-231 cells revealed that developed t-RES-NCs were more efficacious and potent ( p < 0.05) than plain t-RES. Compared to plain t-RES, t-RES-NCs exhibited significant increase ( p < 0.05) in AUC (3.5-folds) and C (2.2-folds), demonstrating improved oral bioavailability of t-RES after grafting as NCs. The significant increase in oral bioavailability of developed t-RES-NCs represents an ideal vehicle for oral delivery of t-RES which ultimately reflected the clinical efficacy of t-RES. [ABSTRACT FROM AUTHOR]

Hepatoprotective Mongolian prescription II (MPII), a mixture of 18 different medicinal herbs, significantly inhibited the growth of human liver cancer cell lines Huh-7 and HepG2 in vitro with different concentrations; MPII (6 mg/mL) inhibited cell proliferation by 80.48%. MPII induced apoptosis in both cell lines, which was observed by light microscopy and flow cytometry. MPII-induced apoptosis and G0/G1 cell cycle arrest were quantified by Annexin V-FITC/PI staining and flow cytometry. At the molecular level, MPII induced caspase-3, caspase-8, caspase-9, and cytochrome c gene expression. In vivo , MPII dramatically inhibited human liver tumor growth in a xenograft model in Kunming mice with no apparent cytotoxicity to the hosts. Apoptotic genes (Bcl-2 and Bax) are up-regulated, suggesting that the ratio of Bcl-2/Bax was statistically significant, indicating that the drugs had affected the expression of apoptosis genes, especially on induce apoptosis gene Bax. We also observed an attenuated effect when MPII was used in combination with chemotherapy drug 5-fluorouracil (5-FU). The mice treated with 5-FU alone did not show a concentration-dependent effect, but 5-FU in combination with MPII displayed concentration-dependent effects on liver cancer cells. Our study suggests that MPII works by inducing apoptosis and cell cycle arrest, and has the potential to be a powerful anticancer agent. [ABSTRACT FROM AUTHOR]

Nanoparticle drug carriers hold potential to improve current cancer therapy by delivering payload to the tumor environment and decreasing toxic side effects. Challenges in nanotechnology drug delivery include plasma instability, site-specific delivery, and relevant biomarkers. We have developed a triblock polymer comprising a hydroxamic acid functionalized center block that chelates iron to form a stabilized micelle that physically entraps chemotherapeutic drugs in the hydrophobic core. The iron-imparted stability significantly improves the integrity of the micelle and extends circulation pharmacokinetics in plasma over that of free drug. Furthermore, the paramagnetic properties of the iron-crosslinking exhibits contrast in the tumors for imaging by magnetic resonance. Three separate nanoparticle formulations demonstrate improved anti-tumor efficacy in xenograft models and decreased toxicity. We report a stabilized polymer micelle that improves the tolerability and efficacy of chemotherapeutic drugs, and holds potential for non-invasive MRI to image drug delivery and deposition in the tumor. [ABSTRACT FROM AUTHOR]

Monogeneans are major parasites of fish and cause large economic losses in aquaculture. Treatment for this parasitic infection is done with products that are mostly toxic to fish and the environment. Essential oils (EOs) of Melaleuca alternifolia and Mentha piperita and the oleoresin (OR) of Copaifera duckei were tested for their in vitro anthelmintic activity against the monogenean parasites ( Anacanthorus penilabiatus and Mymarothecium viatorum ) of pacu Piaractus mesopotamicus . Naturally infected gills were bathed with the herbal solutions (100, 200, 400, 800, and 1600 mg/L) and monitored every 15 min for 4 h. Because of its greater efficacy in vitro ( p < 0.05) compared to the other herbal medicines, C. duckei OR was selected for in vivo testing. The in vivo treatment consisted of 10 and 50 mg/L baths of C. duckei OR for 10 min. Parasitological, hematological, and histological analyses were conducted post-bath and seven days after treatment. Parasite loads decreased by approximately 45% in fish treated with 50 mg/L of C. duckei OR. No hematological changes caused by treatment with C. duckei OR at 10 and 50 mg/L were observed. Histology revealed branchial and hepatic alterations in fish from all groups, whereas spleen and kidney tissues were not affected. Histopathological alterations observed in all fish were due to parasitism or nutritional/farming conditions. Hematological and histological results showed that short baths were safe for fish. Based on the strong anthelmintic activity observed, C. duckei OR offers a promising alternative treatment against monogenean parasites. [ABSTRACT FROM AUTHOR]

Given the high toxicity of the anthracycline antibiotic doxorubicin (DOX), it is relevant to search for nanocarriers that decrease the side effects of the drug and are able to transport it towards a therapeutic target Here, the encapsulation of DOX by p-sulfocalix[6]arene (calix) has been studied. The interaction of DOX with the macrocycle, as well as with DNA, has been investigated and the equilibrium constant for each binding process estimated. The results showed that the binding constant of DOX to DNA, KDNA, is three orders of magnitude higher than that to calix, Kcalix. The ability of calixarenes to encapsulate DOX molecules, as well as the capability of the DOX molecules included into the inner cavity of the macrocycle to bind with DNA have been examined. Cytotoxicity measurements were done in different cancer and normal cell lines to probe the decrease in the toxicity of the encapsulated DOX. The low toxicity of calixarenes has also been demonstrated for different cell lines. [ABSTRACT FROM AUTHOR]