Intestinal Epithelial Creatine Transporter SLC6A8 Dysregulation in Inflammation and in Response to Adherent Invasive E. coli Infection.

Creatine transporter (CrT1) mediates cellular uptake of creatine (Cr), a nutrient pivotal in maintaining energy homeostasis in various tissues including intestinal epithelial cells (IECs). The impact of CrT1 deficiency on the pathogenesis of various psychiatric and neurological disorders has been extensively investigated. However, there are no studies on its regulation in IECs in health and disease. Current studies have determined differential expression of CrT1 along the length of the mammalian intestine and its dysregulation in inflammatory bowel disease (IBD)-associated inflammation and Adherent Invasive E. coli (AIEC) infection. CrT1 mRNA and protein levels in normal intestines and their alterations in inflammation and following AIEC infection were determined in vitro in model IECs (Caco-2/IEC-6) and in vivo in SAMP1/YitFc mice, a model of spontaneous ileitis resembling human IBD. CrT1 is differentially expressed in different regions of mammalian intestines with its highest expression in jejunum. In vitro, CrT1 function (Na+-dependent 14C-Cr uptake), expression and promoter activity significantly decreased following TNFα/IL1ß treatments and AIEC infection. SAMP1 mice and ileal organoids generated from SAMP1 mice also showed decreased CrT1 mRNA and protein compared to AKR controls. Our studies suggest that Cr deficiency in IECs secondary to CrT1 dysregulation could be a key factor contributing to IBD pathogenesis.

Total ablative stereotactic body radiotherapy to primary and oligometastatic renal cell carcinoma in medically inoperable cases: An institutional analysis.

Introduction: Stereotactic body radiotherapy (SBRT) has been found to be an effective and safe modality with excellent oncological outcome in medically inoperable primary renal cell carcinoma (RCC) and oligometastases. There is scarcity of data on the synchronous delivery of SBRT to primary and oligometastatic RCC in patients unfit for nephrectomy. Here, we report the findings of a retrospective study of prospectively collected data on "total ablative SBRT." Methods: Oligometastatic RCC patients with intact primary tumors were enrolled between May 2021 and June 2022. SBRT was synchronously delivered to the primary tumor and metastases. Demographics, treatment, oncologic outcomes, and toxicity were assessed. Kaplan-Meier estimates were generated for oncologic outcomes. The primary endpoint of this study was feasibility and tolerability. Results: Eleven patients were enrolled between May 2021 and June 2022. One patient died at 2 months after SBRT due to viral pneumonitis (possibly COVID pneumonia). Nine patients (82%) had metastatic disease, while 2 (18%) were stage II. The average maximal diameter of primary was 68.7 mm (range, 23-128 mm). The SBRT doses for primary and metastasis ranged from 40 to 55 Gray (Gy) in 5 to 7 fractions and 22 to 40Gy in 2 to 5 fractions, respectively. The median follow-up period was 10.5 months (Range: 4-15 months). Response assessment was available for ten patients. Local control, marginal control, regional control and initial oligometastatic control (OMC) rates were 100%. OMC declined to 87.5% as one patient had recurrence in irradiated subcarinal lymphnode at 7 months. The metastatic control rate was 80% and loco-regional progression-free survival was 8 months (range, 4-15 months). Toxicities were minimal and manageable. At the last follow-up, 7 of 11 patients were alive with an overall survival of 63.5%. Six patients received systemic therapy after SBRT. Conclusions: Synchronous delivery of SBRT to primary and oligometastatic sites in patients unfit for nephrectomy was feasible and tolerable with good locoregional control. The total ablative SBRT strategy needs to be explored in similar cohorts.

Antimicrobial Peptide Conjugated on Graphene Oxide-Containing Sulfonated Polyetheretherketone Substrate for Effective Antibacterial Activities against Staphylococcus aureus.

In the present study, the antimicrobial peptide nisin was successfully conjugated onto the surface of sulfonated polyetheretherketone (SPEEK), which was decorated with graphene oxide (GO) to investigate its biofilm resistance and antibacterial properties. The PEEK was activated with sulfuric acid, resulting in a porous structure. The GO deposition fully covered the porous SPEEK specimen. The nisin conjugation was accomplished using the crosslinker 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) through a dip-coating method. The surface micrographs of the SPEEK-GO-nisin sample indicated that nisin formed discrete islets on the flat GO surface, allowing both the GO and nisin to perform a bactericidal effect. The developed materials were tested for bactericidal efficacy against Staphylococcus aureus (S. aureus). The SPEEK-GO-nisin sample had the highest antibacterial activity with an inhibition zone diameter of 27 mm, which was larger than those of the SPEEK-nisin (19 mm) and SPEEK-GO (10 mm) samples. Conversely, no inhibitory zone was observed for the PEEK and SPEEK samples. The surface micrographs of the bacteria-loaded SPEEK-GO-nisin sample demonstrated no bacterial adhesion and no biofilm formation. The SPEEK-nisin and SPEEK-GO samples showed some bacterial attachment, whereas the pure PEEK and SPEEK samples had abundant bacterial colonies and thick biofilm formation. These results confirmed the good biofilm resistance and antibacterial efficacy of the SPEEK-GO-nisin sample, which is promising for implantable orthopedic applications.

Elucidation of the Anticancer Mechanism of Durian Fruit (Durio zibethinus) Pulp Extract in Human Leukemia (HL-60) Cancer Cells.

Durian (Durio zibethinus L.) grows widely in Southeast Asia. The pulp of the durian fruit contains carbohydrates, proteins, lipids, fibers, various vitamins, minerals, and fatty acids. This study was carried out to elucidate the anticancer mechanism of action of the methanolic extract of the fruit of Durio zibethinus (D. zibethinus) on human leukemia (HL-60) cells. The methanolic extract of D. zibethinus fruits exhibited its anticancer effect on HL-60 cells by inducing DNA damage and apoptosis. The DNA damage was confirmed by comet and DNA fragmentation assays. The methanolic extract of D. zibethinus fruits has been shown to cause cell cycle arrest in HL-60 cells during the S phase and G2/M phase. Additionally, the methanolic extract caused induction of the apoptotic pathway in the HL-60 cell line. This was confirmed by increased expression in pro-apoptotic proteins, viz., Bax protein expression, and a substantial reduction (p < 0.001) in anti-apoptotic proteins, viz., Bcl-2 and Bcl-xL expressions. Therefore, this study confirms that the methanolic extract of D. zibethinus exerts its anticancer effects on the HL-60 cell line, causing cell cycle arrest and induction of apoptosis by an intrinsic mechanism.

Comparison of Ultrashort TE Lung MRI and HRCT Lungs for Detection of Pulmonary Nodules in Oncology Patients.

Purpose The purpose of this study is to evaluate the detection rate of pulmonary nodules in ultrashort echo time (UTE) lung magnetic resonance imaging (MRI) and to compare it with computed tomography (CT) in oncology patients. Materials and Methods All individuals undergoing radiotherapy/chemotherapy/regular follow-up or visiting the oncology department and referred to radiology department for nodule detection, during the period of 1 year, were subjected to UTE lung MRI using the sequence Flash 3d_spiralvibe coronal 1.25 mm iso and high-resolution CT lungs and the images were analyzed. Results Among the total number of nodules detected in both lungs of all patients, nodules detected by CT were 241, and nodules detected by MRI were 212. The nodule detection rate by MRI was 87.96%. The detection rate of nodules for size equal to or more than 5 mm was nearly 100%. For nodules less than 5 mm, and equal to or more than 4 mm, MRI showed a comparable detection rate of 75%, while for nodules less than 4 mm, the detection rate was only 25%. Conclusion Our study results indicate that lung MRI had a near-complete detection rate for nodules equal to or more than 5 mm in size. Hence, in oncology patients who are undergoing regular follow-up of the lung nodules, lung MRI using UTE can replace low-dose CT, which in turn reduces the radiation dose to the patient.

Prismatic Silver Nanoparticles Decorated on Graphene Oxide Sheets for Superior Antibacterial Activity.

Spherical silver nanoparticles (Ag NPs) and silver nanoprisms (Ag NPrsms) were synthesized and decorated on graphene oxide (GO) nanosheets. The Ag contents were 29% and 23% in the GO−Ag NPs and GO−Ag NPrsms, respectively. The Ag NPrsms exhibited stronger (111) crystal signal than Ag NPs. The GO−Ag NPrsms exhibited higher Ag (I) content (75.6%) than GO-Ag NPs (69.9%). Increasing the nanomaterial concentration from 25 to 100 µg mL−1 improved the bactericidal efficiency, and the antibacterial potency was in the order: GO−Ag NPrsms > GO−Ag NPs > Ag NPrsms > Ag NPs > GO. Gram-positive Staphylococcus aureus (S. aureus) was more vulnerable than Gram-negative Escherichia coli (E. coli) upon exposure to these nanomaterials. The GO−Ag NPrsms demonstrated a complete (100%) bactericidal effect against S. aureus at a concentration of 100 µg mL−1. The GO−Ag composites outperformed those of Ag or GO due to the synergistic effect of bacteriostatic Ag particles and GO affinity toward bacteria. The levels of reactive oxygen species produced in the bacteria−nanomaterial mixtures were highly correlated to the antibacterial efficacy values. The GO−Ag NPrsms are promising as bactericidal agents to suppress biofilm formation and inhibit bacterial infection.

Swelling-Resistant, Crosslinked Polyvinyl Alcohol Membranes with High ZIF-8 Nanofiller Loadings as Effective Solid Electrolytes for Alkaline Fuel Cells.

The present work investigates the direct mixing of aqueous zeolitic imidazolate framework-8 (ZIF-8) suspension into a polyvinyl alcohol (PVA) and crosslinked with glutaraldehyde (GA) to form swelling-resistant, mechanically robust and conductivity retentive composite membranes. This drying-free nanofiller incorporation method enhances the homogeneous ZIF-8 distributions in the PVA/ZIF-8/GA composites to overcome the nanofiller aggregation problem in the mixed matrix membranes. Various ZIF-8 concentrations (25.4, 40.5 and 45.4 wt.%) are used to study the suitability of the resulting GA-crosslinked composites for direct alkaline methanol fuel cell (DAMFC). Surface morphological analysis confirmed homogeneous ZIF-8 particle distribution in the GA-crosslinked composites with a defect- and crack-free structure. The increased ionic conductivity (21% higher than the ZIF-free base material) and suppressed alcohol permeability (94% lower from the base material) of PVA/40.5%ZIF-8/GA resulted in the highest selectivity among the prepared composites. In addition, the GA-crosslinked composites' selectivity increased to 1.5−2 times that of those without crosslink. Moreover, the ZIF-8 nanofillers improved the mechanical strength and alkaline stability of the composites. This was due to the negligible volume swelling ratio (<1.4%) of high (>40%) ZIF-8-loaded composites. After 168 h of alkaline treatment, the PVA/40.5%ZIF-8/GA composite had almost negligible ionic conductivity loss (0.19%) compared with the initial material. The maximum power density (Pmax) of PVA/40.5%ZIF-8/GA composite was 190.5 mW cm−2 at 60 °C, an increase of 181% from the PVA/GA membrane. Moreover, the Pmax of PVA/40.5%ZIF-8/GA was 10% higher than that without GA crosslinking. These swelling-resistant and stable solid electrolytes are promising in alkaline fuel cell applications.

Separation Mechanisms and Anti-Fouling Properties of a Microporous Polyvinylidene Fluoride-Polyacrylic Acid-Graphene Oxide (PVDF-PAA-GO) Composite Membrane with Salt and Protein Solutions.

This research demonstrates the preparation of composite membranes containing graphene oxide (GO) and investigates the separation mechanisms of various salts and bovine serum albumin (BSA) solutions. A microporous polyvinylidene fluoride-polyacrylic acid-GO (PVDF-PAA-GO) separation layer was fabricated on non-woven support. The GO-incorporating composite resulted in enlarged pore size (0.16 µm) compared with the control membrane (0.12 µm). The zeta potential of the GO composite was reduced to -31 from -19 mV. The resulting membranes with and without GO were examined for water permeability and rejection efficiency with single salt and BSA solutions. Using the non-woven/PVDF-PAA composite, the permeance values were 88-190 kg/m2hMPa, and the salt rejection coefficients were 9-28% for Na2SO4, MgCl2, MgSO4, and NaCl solutions. These salt removals were based on the Donnan exclusion mechanism considering the ion radii and membrane pore size. Incorporating GO into the separation layer exhibited limited impacts on the filtration of salt solutions, but significantly reduced BSA membrane adhesion and increased permeance. The negatively charged protein reached almost complete removal (98.4%) from the highly negatively charged GO-containing membrane. The GO additive improved the anti-fouling property of the composite membrane and enhanced BSA separation from the salt solution.

Graphene Oxide-Induced Protein Conformational Change in Nasopharyngeal Carcinoma Cells: A Joint Research on Cytotoxicity and Photon Therapy.

The objectives of this work aim to investigate the interaction and cytotoxicity between nanometric graphene oxide (GO) and nasopharyngeal carcinoma cells (NPC-BM1), and possible application in photon therapy. GO nanosheets were obtained in the size range of 100-200 nm, with a negative surface charge. This nanometric GO exhibited a limited (<10%) cytotoxicity effect and no significant dimensional change on NPC-BM1 cells in the tested GO concentration range (0.1-10 µg·mL-1). However, the secondary protein structure was modified in the GO-treated NPC-BM1 cells, as determined through synchrotron radiation-based Fourier transform infrared microspectroscopy (SR-FTIRM) mapping. To further study the cellular response of GO-treated NPC-BM1 cancer cells at low GO concentration (0.1 µg·mL-1), photon radiation was applied with increasing doses, ranging from 2 to 8 Gy. The low radiation energy (<5 Gy) did not cause significant cell mortality (5-7%). Increasing the radiation energy to 6-8 Gy accelerated cell apoptosis rate, especially in the GO-treated NPC-BM1 cells (27%). This necrosis may be due to GO-induced conformational changes in protein and DNA/RNA, resulting in cell vulnerability under photon radiation. The findings of the present work demonstrate the potential biological applicability of nanometric GO in different areas, such as targeted drug delivery, cellular imaging, and radiotherapy, etc.

Phytochemical evaluation and anticancer activity of rambutan (Nephelium lappaceum) fruit endocarp extracts against human hepatocellular carcinoma (HepG-2) cells.

The current investigation was taken to screen the phytoconstituents present in fruit endocarp various extracts of Nephelium lappaceum commonly called as Rambutan fruit and its anticancer property against human hepatocellular carcinoma (HepG-2) cells. Different analytical techniques including qualitative phytochemical analysis, cell viability assay (MTT), apoptotic nuclear staining (DAPI), DNA fragmentation assay, Attenuated total reflection (ATR) and Gas chromatography-mass spectrometry (GC-MS) spectral analysis were carried out. ATR and GC-MS study revealed the presence of functional groups and 9 compounds, respectively in methanol endocarp extract. The results obtained depicts that methanol endocarp extract profoundly controlled cell proliferation and caused shrinkage of HepG-2 cells from polygonal to spherical shape. DAPI staining revealed that methanol endocarp extract caused increased fragmentation of nucleus and DNA fragmentation, which can be taken as a sign of apoptosis. The anticancer potential of methanol fruit endocarp extract of Nephelium lappaceum than other extracts and could be used successfully in future drug delivery systems and other biomedical concerns.

Facilitating GL13K Peptide Grafting on Polyetheretherketone via 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide: Surface Properties and Antibacterial Activity.

In the present work, the antimicrobial peptide (AMP) of GL13K was successfully coated onto a polyetheretherketone (PEEK) substrate to investigate its antibacterial activities against Staphylococcus aureus (S. aureus) bacteria. To improve the coating efficiency, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) was mixed with a GL13K solution and coated on the PEEK surface for comparison. Both energy-dispersive X-ray spectroscopy (EDX) and X-ray photoelectron spectroscopy (XPS) data confirmed 30% greater peptide coating on PEEK/GL13K-EDC than PEEK without EDC treatment. The GL13K graft levels are depicted in the micrograms per square centimeter range. The PEEK/GL13K-EDC sample showed a smoother and lower roughness (Rq of 0.530 µm) than the PEEK/GL13K (0.634 µm) and PEEK (0.697 µm) samples. The surface of the PEEK/GL13K-EDC was more hydrophilic (with a water contact angle of 24°) than the PEEK/GL13K (40°) and pure PEEK (89°) samples. The pure PEEK disc did not exhibit any inhibition zone against S. aureus. After peptide coating, the samples demonstrated significant zones of inhibition: 28 mm and 25 mm for the PEEK/GL13K-EDC and PEEK/GL13K samples, respectively. The bacteria-challenged PEEK sample showed numerous bacteria clusters, whereas PEEK/GL13K contained a little bacteria and PEEK/GL13K-EDC had no bacterial attachment. The results confirm that the GL13K peptide coating was able to induce antibacterial and biofilm-inhibitory effects. To the best of our knowledge, this is the first report of successful GL13K peptide grafting on a PEEK substrate via EDC coupling. The present work illustrates a facile and promising coating technique for a polymeric surface to provide bactericidal activity and biofilm resistance to medical implantable devices.

Size-Dependent Antibacterial Activity of Silver Nanoparticle-Loaded Graphene Oxide Nanosheets.

A series of graphene oxide (GO) suspensions with different particle sizes (<100 nm, ~100 nm, ~1 µm and >1 µm) were successfully fabricated after 0, 30, 60 and 120 min of sonication, respectively. The antibacterial properties of GO suspensions showed that >1 µm GO size resulted in a loss of nearly 50% of bacterial viability, which was higher than treatment by ~100 nm GO size (25%) towards Escherichia coli (E. coli). Complete entrapment of bacteria by the larger GO was observed in transmission electron microscopy (TEM). Silver nanoparticles (Ag NPs) were doped onto GO samples with different lateral sizes to form GO-Ag NP composites. Resulting larger GO-Ag NPs showed higher antibacterial activity than smaller GO-Ag NPs. As observed by Fourier transform infrared spectroscopy (FTIR), the interaction between E. coli and GO occurred mainly at the outer membrane, where membrane amino acids interact with hydroxyl and epoxy groups. The reactive oxygen species (ROS) and the considerable penetration of released Ag+ into the inner bacterial cell membrane result in loss of membrane integrity and damaged morphology. The present work improves the combined action of GO size effect with constant Ag loadings for potential antibacterial activity.

Synergistic Antibacterial Activity of Silver-Loaded Graphene Oxide towards Staphylococcus Aureus and Escherichia Coli.

In this study, the physicochemical and surface properties of the GO-Ag composite promote a synergistic antibacterial effect towards both Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. Aureus) bacteria. GO-Ag NPs have a better bactericidal effect on E. coli (73%) and S. Aureus (98.5%) than pristine samples (pure Ag or GO). Transmission electron microscopy (TEM) confirms that the GO layers folded entire bacteria by attaching to the membrane through functional groups, while the Ag NPs penetrated the inner cell, thus damaging the cell membrane and leading to cell death. Cyclic voltammetry (CV) tests showed significant redox activity in GO-Ag NPs, enabling good catalytic performance towards H2O2 reduction. Strong reactive oxygen species (ROS) in GO-Ag NPs suggests that ROS might be associated with bactericidal activity. Therefore, the synergy between the physicochemical effect and ROS production of this material is proposed as the mechanism of its antibacterial activity.

Synergetic effects of thymoquinone-loaded porous PVPylated Fe3O4 nanostructures for efficient pH-dependent drug release and anticancer potential against triple-negative cancer cells.

Porous iron oxide nanostructures have attracted increasing attention due to their potential biomedical applications as nanocarriers for cancer and many other therapies as well as minimal toxicity. Herbal anti-cancer agent thymoquinone loaded on Fe3O4 nanoparticles is envisaged to offer solution towards cancer treatment. The purpose of the present study was to investigate the efficacy of thymoquinone-loaded PVPylated Fe3O4 magnetic nanoparticles (TQ-PVP-Fe3O4 NPs) against triple-negative breast cancer (TNBC) cells. The porous PVPylated Fe3O4 NPs were prepared by a simple solvothermal process, whereas the thymoquinone drug was loaded via the nanoprecipitation method. Fourier transform infrared (FTIR) spectroscopic analysis confirmed the molecular drug loading, and surface morphological observation further confirmed this. The quantity of thymoquinone adsorbed onto the porous PVPylated Fe3O4 NPs was studied by thermogravimetric analysis (TGA). The positive surface charge of TQ-PVP-Fe3O4 NPs facilitates the interaction of the NPs with cancer (MDA-MB-231) cells to enhance the biological functions. In addition, the anticancer potential of NPs involving cytotoxicity, apoptosis induction, reactive oxygen species (ROS) generation, and changes in the mitochondrial membrane potential (ΔΨ m) of TNBC cells was evaluated. TQ-PVP-Fe3O4 NP-treated cells effectively increased the ROS levels leading to cellular apoptosis. The study shows that the synthesized TQ-PVP-Fe3O4 NPs display pH-dependent drug release in the cellular environment to induce apoptosis-related cell death in TNBC cells. Hence, the prepared TQ-PVP-Fe3O4 NPs may be a suitable drug formulation for anticancer therapy.

Highly Zeolite-Loaded Polyvinyl Alcohol Composite Membranes for Alkaline Fuel-Cell Electrolytes.

Having a secure and stable energy supply is a top priority for the global community. Fuel-cell technology is recognized as a promising electrical energy generation system for the twenty-first century. Polyvinyl alcohol/zeolitic imidazolate framework-8 (PVA/ZIF-8) composite membranes were successfully prepared in this work from direct ZIF-8 suspension solution (0⁻45.4 wt %) and PVA mixing to prevent filler aggregation for direct methanol alkaline fuel cells (DMAFCs). The ZIF-8 fillers were chosen for the appropriate cavity size as a screening aid to allow water and suppress methanol transport. Increased ionic conductivities and suppressed methanol permeabilities were achieved for the PVA/40.5% ZIF-8 composites, compared to other samples. A high power density of 173.2 mW cm-2 was achieved using a KOH-doped PVA/40.5% ZIF-8 membrane in a DMAFC at 60 °C with 1⁻2 mg cm-2 catalyst loads. As the filler content was raised beyond 45.4 wt %, adverse effects resulted and the DMAFC performance (144.9 mW cm-2) was not improved further. Therefore, the optimal ZIF-8 content was approximately 40.5 wt % in the polymeric matrix. The specific power output was higher (58 mW mg-1) than most membranes reported in the literature (3⁻18 mW mg-1).

HER2 Targeted Breast Cancer Therapy with Switchable "Off/On" Multifunctional "Smart" Magnetic Polymer Core-Shell Nanocomposites.

Multifunctional magnetic polymer nanocombinations are gaining importance in cancer nanotheranostics due to their safety and their potential in delivering targeted functions. Herein, we report a novel multifunctional core-shell magnetic polymer therapeutic nanocomposites (NCs) exhibiting pH dependent "Off-On" release of drug against breast cancer cells. The NCs are intact in blood circulation ("Off" state), i.e., at physiological pH, whereas activated ("On" state) at intracellular acidic pH environment of the targeted breast cancer cells. The NCs are prepared by coating the cannonball (iron nanocore) with hydrophobic nanopockets of pH-responsive poly(d,l-lactic-co-glycolic acid) (PLGA) polymer nanoshell that allows efficient loading of therapeutics. Further, the nanocore-polymer shell is stabilized by poly(vinylpyrrolidone) (PVP) and functionalized with a targeting HER2 ligand. The prepared Her-Fe3O4@PLGA-PVP nanocomposites facilitate packing of anticancer drug (Tamoxifen) without premature release in the bloodstream, recognizing the target cells through binding of Herceptin antibody to HER2, a cell surface receptor expressed by breast cancer cells to promote HER2 receptor mediated endocytosis and finally releasing the drug at the intracellular site of tumor cells ("On" state) to induce apoptosis. The therapeutic efficiency of hemo/cytocompatible NCs drug delivery system (DDS) in terms of targeted delivery and sustained release of therapeutic agent against breast cancer cells was substantiated by in vitro and in vivo studies. The multifunctional properties of Her-Tam-Fe3O4@PLGA-PVP NCs may open up new avenues in cancer therapy through overcoming the limitations of conventional cancer therapy.