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The Journal of Pharmacology and... Jun 2024Estrogen receptor (ER)-negative breast cancers are known to be aggressive and unresponsive to anti-estrogen therapy, and triple negative breast cancers are associated...
Estrogen receptor (ER)-negative breast cancers are known to be aggressive and unresponsive to anti-estrogen therapy, and triple negative breast cancers are associated with poor prognosis and metastasis. Thus, new targeted therapies are needed. FOXM1 is abundantly expressed in human cancers and implicated in protecting tumor cells from oxidative stress by reducing the levels of intracellular reactive oxygen species (ROS). Aspirin, a prototypical anti-cancer agent with deleterious side effects, has been modified to release nitric oxide and hydrogen sulfide, called NOSH-aspirin (NOSH-ASA), generating a 'safer' class of new anti-inflammatory agents. We evaluated NOSH-ASA against (ER)-negative breast cancer using cell lines and a xenograft mouse model. NOSH-ASA strongly inhibited growth of MDA-MB-231 and SKBR3 breast cancer cells with low ICs of 90{plus minus}5 and 82{plus minus}5 nM, respectively, with marginal effects on a normal breast epithelial cell line. NOSH-ASA inhibited cell proliferation, caused G/G phase arrest, increased apoptosis, and was associated with increases in ROS. In MDA-MB-231 cell xenografts, NOSH-ASA reduced tumor size markedly, which was associated with reduced proliferation (decreased PCNA expression), induction of apoptosis (increased TUNEL positive cells), and increased ROS, while NF-kB and FoxM1 that were high in untreated xenografts were significantly reduced. mRNA data for FoxM1, p21 and CyclinD1 corroborated with the respective protein expressions and arrest of cells. Taken together, these molecular events contribute to NOSH-ASA mediated growth inhibition and apoptotic death of (ER)-negative breast cells in vitro and in vivo. Additionally, as a ROS-inducer and FOXM1-inhibitor, NOSH-ASA has potential as a targeted therapy. In this investigation, we examined the cellular effects and xenograft tumor inhibitory potential of NOSH-aspirin, an NO and HS-donating hybrid, against ER-negative breast cancer, which currently lacks effective therapeutic options. The induction of reactive oxygen species and subsequent downregulation of FOXM1 represents a plausible mechanism contributing to the observed decrease in cell proliferation and concurrent increase in apoptosis. NOSH-ASA demonstrated a remarkable reduction in tumor size by 90% without inducing any observable gross toxicity, underscoring its promising translational potential.
PubMed: 38936976
DOI: 10.1124/jpet.124.002240 -
PloS One 2024Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in...
Sickle cell disease (SCD) decreases the oxygen-carrying capacity of red blood cells. Children with SCD have reduced/restricted cerebral blood flow, resulting in neurocognitive deficits. Hydroxyurea is the standard treatment for SCD; however, whether hydroxyurea influences such effects is unclear. A key area of SCD-associated neurocognitive impairment is working memory, which is implicated in other cognitive and academic skills. The neural correlates of working memory can be tested using n-back tasks. We analyzed functional magnetic resonance imaging (fMRI) data of patients with SCD (20 hydroxyurea-treated patients and 11 controls, aged 7-18 years) while they performed n-back tasks. Blood-oxygenation level-dependent (BOLD) signals were assessed during working memory processing at 2 time points: before hydroxyurea treatment and ~1 year after treatment was initiated. Neurocognitive measures were also assessed at both time points. Our results suggested that working memory was stable in the treated group. We observed a treatment-by-time interaction in the right cuneus and angular gyrus for the 2- >0-back contrast. Searchlight-pattern classification of the 2 time points of the 2-back tasks identified greater changes in the pattern and magnitude of BOLD signals, especially in the posterior regions of the brain, in the control group than in the treated group. In the control group at 1-year follow-up, 2-back BOLD signals increased across time points in several clusters (e.g., right inferior temporal lobe, right angular gyrus). We hypothesize that these changes resulted from increased cognitive effort during working memory processing in the absence of hydroxyurea. In the treated group, 0- to 2-back BOLD signals in the right angular gyrus and left cuneus increased continuously with increasing working memory load, potentially related to a broader dynamic range in response to task difficulty and cognitive effort. These findings suggest that hydroxyurea treatment helps maintain working memory function in SCD.
Topics: Humans; Hydroxyurea; Anemia, Sickle Cell; Memory, Short-Term; Child; Adolescent; Male; Female; Magnetic Resonance Imaging; Antisickling Agents; Brain; Case-Control Studies
PubMed: 38935785
DOI: 10.1371/journal.pone.0296196 -
Frontiers in Cell and Developmental... 2024Even with sufficient oxygen, tumor cells use glycolysis to obtain the energy and macromolecules they require to multiply, once thought to be a characteristic of tumor... (Review)
Review
Even with sufficient oxygen, tumor cells use glycolysis to obtain the energy and macromolecules they require to multiply, once thought to be a characteristic of tumor cells known as the "Warburg effect". In fact, throughout the process of carcinogenesis, immune cells and stromal cells, two major cellular constituents of the tumor microenvironment (TME), also undergo thorough metabolic reprogramming, which is typified by increased glycolysis. In this review, we provide a full-scale review of the glycolytic remodeling of several types of TME cells and show how these TME cells behave in the acidic milieu created by glucose shortage and lactate accumulation as a result of increased tumor glycolysis. Notably, we provide an overview of putative targets and inhibitors of glycolysis along with the viability of using glycolysis inhibitors in combination with immunotherapy and chemotherapy. Understanding the glycolytic situations in diverse cells within the tumor immunological milieu will aid in the creation of subsequent treatment plans.
PubMed: 38933335
DOI: 10.3389/fcell.2024.1416472 -
Regenerative Biomaterials 2024Cancer is one of the most challenging diseases in the world. Recently, iron oxide nanoparticles (IONPs) are emerging materials with rapid development and high...
Cancer is one of the most challenging diseases in the world. Recently, iron oxide nanoparticles (IONPs) are emerging materials with rapid development and high application value, and have shown great potential on tumor therapy due to their unique magnetic and biocompatible properties. However, some data hint us that IONPs were toxic to normal cells and vital organs. Thus, more data on biosafety evaluation is urgently needed. In this study, we compared the effects of silicon-coated IONPs (Si-IONPs) on two cell types: the tumor cells (Hela) and the normal cells (HEK293T, as 293 T for short), compared differences of protein composition, allocation and physical characteristics between these two cells. The major findings of our study pointed out that 293 T cells death occurred more significant than that of Hela cells after Si-IONPs treatment, and the rate and content of endocytosis of Si-IONPs in 293 T cells was more prominent than in Hela cells. Our results also showed Si-IONPs significant promoted the production of reactive oxygen species and disturbed pathways related to oxidative stress, iron homeostasis, apoptosis and ferroptosis in both two types of cells, however, Hela cells recovered from these disturbances more easily than 293 T. In conclusion, compared with Hela cells, IONPs are more likely to induce 293 T cells death and Hela cells have their own unique mechanisms to defense invaders, reminding scientists that future in vivo and in vitro studies of nanoparticles need to be cautious, and more safety data are needed for further clinical treatment.
PubMed: 38933085
DOI: 10.1093/rb/rbae065 -
Pharmaceutics Jun 2024Graphene has become a prominent material in cancer research in recent years. Graphene and its derivatives also attract attention as carriers in drug delivery systems. In...
Graphene has become a prominent material in cancer research in recent years. Graphene and its derivatives also attract attention as carriers in drug delivery systems. In this study, we designed a graphene oxide (GO)-based methotrexate (MTX)-loaded and folic acid (FA)-linked drug delivery system. MTX and FA were bound to GO synthesized from graphite. MTX/FA/GO drug delivery system and system components were characterized using Fourier transform infrared spectroscopy (FTIR), differential calorimetric analysis (DSC), scanning electron microscopy (SEM), transmission electron microscopy (TEM), zeta potential analysis, and dimension measurement (DLS) studies. SEM and TEM images confirmed the nanosheet structure of GO synthesized from graphite, and it was shown that MTX/FA binding to GO transformed the two-dimensional GO into a three-dimensional structure. FTIR and DSC graphs confirmed that oxygen atoms were bound to GO with the formation of carboxylic, hydroxyl, epoxide, and carbonyl groups as a result of the oxidation of graphite, and GO was successfully synthesized. Additionally, these analyses showed that MTX and FA bind physicochemically to the structure of GO. The in vitro Franz diffusion test was performed as a release kinetic test. The release kinetics mathematical model and correlation coefficient (R2) of MTX-loaded GO/FA nanomaterials were found to be the Higuchi model and 0.9785, respectively. Stiffness analyses showed that adding FA to this release system facilitated the entry of the drug into the cell by directing the system to target cells. As a result of the stiffness analyses, the stiffness values of the control cell group, free MTX, and MTX/FA/GO applied cells were measured as 2.34 kPa, 1.87 kPa, and 1.56 kPa, respectively. According to these results, it was seen that MTX/FA/GO weakened the cancer cells. Combined use of the MTX/FA/GO drug delivery system had a higher cytotoxic effect than free MTX on the MDA-MB-231 breast cancer cell line. The results showed that the synthesized MTX/FA/GO material has promising potential in cancer cell-specific targeted therapy for MTX as a drug delivery system.
PubMed: 38931957
DOI: 10.3390/pharmaceutics16060837 -
Pharmaceutics Jun 2024spp. are Gram-positive bacteria that cause mild to severe infections, many associated with the oral cavity, such as periapical infections and healthcare-associated... (Review)
Review
spp. are Gram-positive bacteria that cause mild to severe infections, many associated with the oral cavity, such as periapical infections and healthcare-associated infections (HAIs). Many of these infections become serious diseases that are difficult to resolve, specifically when multidrug-resistant (MDR) strains cause them. In recent years, the number of MDR strains of spp. has increased significantly. This increased prevalence of MDR strains produces significant pressure to generate more antimicrobial therapies, but there is a decline in the production of new antibiotics, driving the development of complementary therapies, such as photodynamic therapy (PDT). PDT combines a photosensitizer agent (PS), light, and oxygen to cause photooxidative stress in bacterial cells. PDT can eradicate spp. contaminations, improve the classic cleaning processes, and eradicate the bacteria in dental pieces. PDT's effectiveness can be improved with nanoparticles that function as carriers. Our work aims to describe the advances in PDT against spp. as a complement to antibiotic therapy, focusing on infections by and , dental hygiene, and using nanoparticles to improve the antimicrobial effect. A systematic bibliographic search without a meta-analysis was conducted on various databases, using inclusion and exclusion criteria to identify the most relevant research. Of the 193 non-redundant articles found, 65 were selected for a systematic review, from which a summary table was created and a manual description was made. Photodynamic therapy for treating and is a widely studied area, with promising results concerning bactericidal effectiveness and reductions in biofilm formation, particularly in regard to dental hygiene. Because most of the studies were conducted in vitro or ex vivo, the results indicated that there were not sufficient data to initiate clinical trials for safety and efficacy studies on humans.
PubMed: 38931945
DOI: 10.3390/pharmaceutics16060825 -
Pharmaceutics Jun 2024DOX/TPOR@CB[7] was synthesized via self-assembly, and its physicochemical properties and ability to generate reactive oxygen species (ROS) were evaluated. The impact of...
DOX/TPOR@CB[7] was synthesized via self-assembly, and its physicochemical properties and ability to generate reactive oxygen species (ROS) were evaluated. The impact of photodynamic therapy on SH-SY5Y cells was assessed using the MTT assay, while flow cytometry analysis was employed to detect cell apoptosis. Confocal laser scanning microscopy was utilized to observe the intracellular distribution of DOX/TPOR@CB[7] in SH-SY5Y cells. Additionally, fluorescence imaging of DOX/TPOR@CB[7] in nude mice bearing SH-SY5Y tumors and examination of the combined effects of photodynamic and chemical therapies were conducted. The incorporation of CB[7] significantly enhanced the optical properties of DOX/TPOR@CB[7], resulting in increased ROS production and pronounced toxicity towards SH-SY5Y cells. Moreover, both the apoptotic and mortality rates exhibited significant elevation. In vivo experiments demonstrated that tumor growth inhibition was most prominent in the DOX/TPOR@CB[7] group. π-π interactions facilitated the binding between DOX and photosensitizer TPOR, with TPOR's naphthalene hydrophilic groups encapsulated within CB[7]'s cavity through host-guest interactions with CB[7]. Therefore, CB[7] can serve as a nanocarrier to enhance the combined application of chemical therapy and photodynamic therapy, thereby significantly improving treatment efficacy against neuroblastoma tumors.
PubMed: 38931942
DOI: 10.3390/pharmaceutics16060822 -
Pharmaceutics Jun 2024Insufficient endosomal escape presents a major hurdle for successful nucleic acid therapy. Here, for the first time, a chemical electron transfer (CET) system was...
Insufficient endosomal escape presents a major hurdle for successful nucleic acid therapy. Here, for the first time, a chemical electron transfer (CET) system was integrated into small interfering RNA (siRNA) lipid nanoparticles (LNPs). The CET acceptor can be chemically excited using the generated energy between the donor and hydrogen peroxide, which triggers the generation of reactive oxygen species (ROS), promoting endosomal lipid membrane destabilization. Tetra-oleoyl tri-lysino succinoyl tetraethylene pentamine was included as an ionizable lipopeptide with a U-shaped topology for effective siRNA encapsulation and pH-induced endosomal escape. LNPs loaded with siRNA and CET components demonstrated a more efficient endosomal escape, as evidenced by a galectin-8-mRuby reporter; ROS significantly augmented galectin-8 recruitment by at least threefold compared with the control groups, with a value of 0.03. Moreover, CET-enhanced LNPs achieved a 24% improvement in apoptosis level by knocking down the tumor-protective gene nuclear factor erythroid 2-related factor 2, boosting the CET-mediated ROS cell killing.
PubMed: 38931900
DOI: 10.3390/pharmaceutics16060779 -
Pharmaceutics May 2024This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health... (Review)
Review
This review paper examines the evolution of photodynamic therapy (PDT) as a novel, minimally invasive strategy for treating atherosclerosis, a leading global health concern. Atherosclerosis is characterized by the accumulation of lipids and inflammation within arterial walls, leading to significant morbidity and mortality through cardiovascular diseases such as myocardial infarction and stroke. Traditional therapeutic approaches have primarily focused on modulating risk factors such as hypertension and hyperlipidemia, with emerging evidence highlighting the pivotal role of inflammation. PDT, leveraging a photosensitizer, specific-wavelength light, and oxygen, offers targeted treatment by inducing cell death in diseased tissues while sparing healthy ones. This specificity, combined with advancements in nanoparticle technology for improved delivery, positions PDT as a promising alternative to traditional interventions. The review explores the mechanistic basis of PDT, its efficacy in preclinical studies, and the potential for enhancing plaque stability and reducing macrophage density within plaques. It also addresses the need for further research to optimize treatment parameters, mitigate adverse effects, and validate long-term outcomes. By detailing past developments, current progress, and future directions, this paper aims to highlight PDT's potential in revolutionizing atherosclerosis treatment, bridging the gap from experimental research to clinical application.
PubMed: 38931851
DOI: 10.3390/pharmaceutics16060729 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Efforts have been made to improve the therapeutic efficiency of tumor treatments, and metal-organic frameworks (MOFs) have shown excellent potential in tumor therapy....
Efforts have been made to improve the therapeutic efficiency of tumor treatments, and metal-organic frameworks (MOFs) have shown excellent potential in tumor therapy. Monotherapy for the treatment of tumors has limited effects due to the limitation of response conditions and inevitable multidrug resistance, which seriously affect the clinical therapeutic effect. In this study, we chose to construct a multiple cascade synergistic tumor drug delivery system MIL-101(Fe)-DOX-TCPP-MnO@PDA-Ag (MDTM@P-Ag) using MOFs as drug carriers. Under near-infrared (NIR) laser irradiation, 5,10,15,20-tetrakis(4-carboxyphenyl)porphyrin (TCPP) and Ag NPs loaded on MDTM@P-Ag can be activated to generate cytotoxic reactive oxygen species (ROS) and achieve photothermal conversion, thus effectively inducing the apoptosis of tumor cells and achieving a combined photodynamic/photothermal therapy. Once released at the tumor site, manganese dioxide (MnO) can catalyze the decomposition of hydrogen peroxide (HO) in the acidic microenvironment of the tumor to generate oxygen (O) and alleviate the hypoxic environment of the tumor. Fe/Mn will mediate a Fenton/Fenton-like reaction to generate cytotoxic hydroxyl radicals (·OH), while depleting the high concentration of glutathione (GSH) in the tumor, thus enhancing the chemodynamic therapeutic effect. The successful preparation of the tumor drug delivery system and its good synergistic chemodynamic/photodynamic/photothermal therapeutic effect in tumor treatment can be demonstrated by the experimental results of material characterization, performance testing and in vitro experiments.
PubMed: 38931479
DOI: 10.3390/ph17060812