Short Half-life Time Research Articles

New Chitosan-Based Co-Delivery Nanosystem for Diabetes Mellitus Therapy.

Type 2 diabetes mellitus (T2DM) is one of the most common metabolic disorders, with a major involvement of oxidative stress in its onset and progression. Pioglitazone (Pio) is an antidiabetic drug that mainly works by reducing insulin resistance, while curcumin (Cur) is a powerful antioxidant with an important hypoglycemic effect. Both drugs are associated with several drawbacks, such as reduced bioavailability and a short half-life time (Pio), as well as instability and poor water solubility (Cur), which limit their therapeutic use. In order to overcome these disadvantages, new co-delivery (Pio and Cur) chitosan-based nanoparticles (CS-Pio-Cur NPs) were developed and compared with simple NPs (CS-Pio/CS-Cur NPs). The NPs were characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). In addition, the entrapment efficiency (EE) and loading capacity (LC), as well as the release profile, of the APIs (Pio and Cur) from the CS-APIs NPs in simulated fluids (SGF, SIF, and SCF) were also assessed. All the CS-APIs NPs presented a small particle size (PS) (211.6-337.4 nm), a proper polydispersity index (PI) (0.104 and 0.289), and a positive zeta potential (ZP) (21.83 mV-32.64 mV). Based on the TEM results, an amorphous state could be attributed to the CA-APIs NPs, and the TEM analysis showed a spherical shape with a nanometric size for the CS-Pio-Cur NPs. The FT-IR spectroscopy supported the successful loading of the APIs into the CS matrix and proved some interactions between the APIs and CS. The CS-Pio-Cur NPs presented increased or similar EE (85.76% ± 4.89 for Cur; 92.16% ± 3.79 for Pio) and LC% (23.40% ± 1.62 for Cur; 10.14% ± 0.98 for Pio) values in comparison with simple NPs, CS-Cur NPs (EE = 82.46% ± 1.74; LC = 22.31% ± 0.94), and CS-Pio NPs (EE = 93.67% ± 0.89; LC = 11.24% ± 0.17), respectively. Finally, based on the release profile results, it can be appreciated that the developed co-delivery nanosystem, CS-Pio-Cur NPs, assures a controlled and prolonged release of Pio and Cur from the polymer matrix along the GI tract.

Toxicokinetics of selenate in earthworm sub-tissues and potential bio-accessibility assessment of earthworm-derived selenium

Selenium (Se) pollution is mainly caused by anthropogenic activities, and the resulting biosecurity concerns have garnered significant attention in recent years. Using one-compartmental toxicokinetic (TK) modelling, this study explored the kinetic absorption, sub-tissue distribution, and elimination processes of the main Se species (selenate, Se(VI)) in the cultivated aerobic soil of the earthworm Eisenia fetida. The bio-accessibility of earthworm-derived Se was assessed using an in vitro simulated gastrointestinal digestion test to evaluate its potential trophic risk. The results demonstrated that Se accumulated in the pre-clitellum (PC) and total tissues (TT) of earthworms in a time- and dose-dependent manner. The highest Se levels in the PC, post-clitellum (PoC), and TT were 70.54, 57.93, and 64.26 mg/kg during the uptake phase, respectively. The kinetic Se contents in the earthworms PC and TT were consistent with the TK model but not with PoC. The earthworm TT exhibited a faster uptake (Kus = 0.83–1.02 mg/kg/day) and elimination rate of Se (Kee = 0.044–0.049 mg/kg/day), as well as a shorter half-life time (LT1/2 = 15.88–14.22 days) than PC at low soil Se levels (≤5 mg/kg). Conversely, the opposite trend was observed with higher Se concentrations (10 and 20 mg/kg). These results are likely attributable to the tissue specificity and concentration of the toxicant. Earthworms PC and TT exhibited a higher kinetic Se accumulation factor (BAFk) than steady-state BAF (BAFss), with values ranging from 8 to 24 and 3–13, respectively. Furthermore, the bio-accessibility of earthworm-derived Se to poultry ranged from 66.25 % to 84.35 %. As earthworms are at the bottom of the terrestrial food chain, the high bio-accessibility of earthworm-derived Se poses a potential risk to predators. This study offers data support and a theoretical foundation for understanding the biological footprint of soil Se and its toxicological impacts and ecological hazards.

Effective delivery of miR-150-5p with nucleus pulposus cell-specific nanoparticles attenuates intervertebral disc degeneration.

The use of gene therapy to deliver microRNAs (miRNAs) has gradually translated to preclinical application for the treatment of intervertebral disc degeneration (IDD). However, the effects of miRNAs are hindered by the short half-life time and the poor cellular uptake, owing to the lack of efficient delivery systems. Here, we investigated nucleus pulposus cell (NPC) specific aptamer-decorated polymeric nanoparticles that can load miR-150-5p for IDD treatment. The role of miR-150-5p during disc development and degeneration was examined by miR-150-5p knockout (KO) mice. Histological analysis was undertaken in disc specimens. The functional mechanism of miR-150-5p in IDD development was investigated by qRT-PCR assay, Western blot, coimmunoprecipitation and immunofluorescence. NPC specific aptamer-decorated nanoparticles was designed, and its penetration, stability and safety were evaluated. IDD progression was assessed by radiological analysis including X-ray and MRI, after the annulus fibrosus needle puncture surgery with miR-150-5p manipulation by intradiscal injection of nanoparticles. The investigations into the interaction between aptamer and receptor were conducted using mass spectrometry, molecular docking and molecular dynamics simulations. We investigated NPC-specific aptamer-decorated polymeric nanoparticles that can bind to miR-150-5p for IDD treatment. Furthermore, we detected that nanoparticle-loaded miR-150-5p inhibitors alleviated NPC senescence in vitro, and the effects of the nanoparticles were sustained for more than 3months in vivo. The microenvironment of NPCs improves the endo/lysosomal escape of miRNAs, greatly inhibiting the secretion of senescence-associated factors and the subsequent degeneration of NPCs. Importantly, nanoparticles delivering miR-150-5p inhibitors attenuated needle puncture-induced IDD in mouse models by targeting FBXW11 and inhibiting TAK1 ubiquitination, resulting in the downregulation of NF-kB signaling pathway activity. NPC-targeting nanoparticles delivering miR-150-5p show favorable therapeutic efficacy and safety and may constitute a promising treatment for IDD.

Multifunctional Deep Eutectic Solvent-Based Microemulsion for Transdermal Delivery of Artemisinin.

As a serious public health issue, malaria threatens the health of millions of people. Artemisinin, a gift from traditional Chinese medicine, has been used in the treatment of malaria and has shown good therapeutic efficiency. However, due to its low solubility, poor bioavailability, and short half-life time, some smart delivery strategies are still required. Herein, a multifunctional DES prepared from ibuprofen and menthol was prepared. This DES was shown to efficiently promote the solubility of artemisinin up to 400-fold. Then, it was further applied as the oil phase to construct an O/W microemulsion with the help of Tween-80 + Span-20 mixed surfactants. The prepared microemulsion displayed high efficiency in improving the permeability of artemisinin, which can be ascribed to the presence of the permeation enhancer menthol in DES and the microstructure of the O/W microemulsion. Moreover, the simultaneous permeation of artemisinin and ibuprofen further indicated the potential benefits of the presented formulation in the treatment of malaria. To sum up, the microemulsion based on multifunctional DES presented herein provided an effective method for transdermal delivery of artemisinin.

Revolutionizing cancer treatment: the power of bi- and tri-specific T-cell engagers in oncolytic virotherapy.

Bi- or tri-specific T cell engagers (BiTE or TriTE) are recombinant bispecific proteins designed to stimulate T-cell immunity directly, bypassing antigen presentation by antigen-presenting cells (APCs). However, these molecules suffer from limitations such as short biological half-life and poor residence time in the tumor microenvironment (TME). Fortunately, these challenges can be overcome when combined with OVs. Various strategies have been developed, such as encoding secretory BiTEs within OV vectors, resulting in improved targeting and activation of T cells, secretion of key cytokines, and bystander killing of tumor cells. Additionally, oncolytic viruses armed with BiTEs have shown promising outcomes in enhancing major histocompatibility complex I antigen (MHC-I) presentation, T-cell proliferation, activation, and cytotoxicity against tumor cells. These combined approaches address tumor heterogeneity, drug delivery, and T-cell infiltration, offering a comprehensive and effective solution. This review article aims to provide a comprehensive overview of Bi- or TriTEs and OVs as promising therapeutic approaches in the field of cancer treatment. We summarize the cutting-edge advancements in oncolytic virotherapy immune-related genetic engineering, focusing on the innovative combination of BiTE or TriTE with OVs.

Pharmacokinetics of intravenous and topical lidocaine in patients undergoing thoracoscopic pulmonary resection: a comparative study.

Lidocaine was the commonly used local anesthetic. The present study aimed to compare the pharmacokinetics of intravenous and topical lidocaine in patients undergoing thoracoscopic pulmonary resection. Sixty patients who were scheduled for thoracoscopic pulmonary resection were screened and randomly assigned to the intravenous lidocaine group and topical lidocaine group. After induction, the patient in the intravenous group was given an intravenous bolus of 1.5 mg/kg lidocaine, while the patient in the topical group was given 3.0 mg/kg lidocaine via the "spray-as-you-go" method. Arterial blood was sampled at preset intervals, and plasma concentrations of lidocaine and its metabolites [monoethylglycinexylidide (MEGX) and glycinexylidide (GX)] were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Following intravenous administration, plasma lidocaine concentration reached its peak with a time to reach Cmax (Tmax) of 0.05 h and then decreased in a biphasic manner with a very short half-life time (T1/2) of 1.85 h. After topical administration, lidocaine was well absorbed, with Tmax of 0.21 h and bioavailability of 71.02%. The mean Tmax, Cmax, and area under the curve from the time (AUC0-t) of MEGX and GX were higher in the topical group than in the intravenous group. There were no obvious differences in the Cmax, T1/2, clearance, or apparent volume of distribution of lidocaine between the two groups. No obvious adverse events were observed. Topical administration of 3 mg/kg lidocaine via the "spray-as-you-go" method is an effective and safe technology for patients undergoing thoracoscopic pulmonary resection.

Relevance of Sulfate Functionalization and Porous Structure of TiO2 Ceramic Foams in Photocatalytic Degradation of Dye Molecules

A one-step route was developed for sulfate functionalization of titania foam, consisting of integrating the sol-gel process with an emulsion template. The resulting material was used to evaluate the relevance of the porous structure and surface sulfate groups in the photocatalytic degradation of Rhodamine B molecules in water under UV irradiation. X-ray diffraction (XRD) analysis showed that the anatase crystalline phase was metastabilized by functionalization of the surface with sulfate species, which caused the crystallite size to decrease from 21 to 10 nm, while the specific surface area increased from 4 to 42 cm2 g-1. Small-angle X-ray scattering (SAXS) measurements during heating of the non-sulfated (E-TiO2) and sulfated (E-TiO2/SO42-) sols emulsified with sodium dodecyl sulfate (SDS) as surfactant and isopropyl myristate as the nonpolar phase, revealed formation of the liquid crystalline structure. Elimination of this mesophase template allowed the preparation of ceramic foams with hierarchical structure formed by meso- and macropore families. The kinetics of photodegradation reaction of Rhodamine B followed a pseudofirst order mechanism. The most efficient photocatalytic activity (higher rate constant and shorter half-life time) was obtained for the foam templated using 20% of SDS (E-TiO2/SO42- 20SDS), which exhibited the highest values for porosity (93%) and specific surface area (80 m3 g-1).

Synthesis and Characterization of Carboxymethylated Locust Bean Gum‐co‐poly(SA)‐cl‐poly(MBA) pH Responsive Hydrogel for Controlled Drug Delivery of Metformin Hydrochloride

AbstractThe development of hydrophilic carriers with dual stimuli‐ responsiveness for the drug encapsulation and controlled release is one of the biggest challenges for the modern medicinal chemist. In this context, the current study explores the application of locust bean gum (LB), to develop a pH and temperature responsive matrix for controlled delivery of an anti‐diabetic drug, Metformin HCl (MFH) for the first time. LB gum was first structurally modified to carboxymethylated locust bean gum (CMLB). It was copolymerized with sodium acrylate (SA) and cross‐linked by using N,N‐methylene bisacrylamide (MBA) to form hydrogel (CMLB‐co‐poly(SA)‐cl‐poly(MBA)). The model hydrogel was examined using FTIR, TGA, SEM, XRD, and 13C‐NMR to determine structural changes, thermal behaviour and surface morphology. Network parameters confirm the porous nature of the hydrogel and support their swelling behaviour. The drug loaded CMLB‐co‐poly(SA)‐cl‐poly(MBA) hydrogel follows the non‐Fickian diffusion of the anti‐diabetic drug, Metformin HCl (MFH), which is having short and biological half life time. The MFH release profile was analysed by fitting data in the Korsmeyer‐Peppas kinetic model with high rate of release in pH 7.4 compared to Distilled Water (DW) and pH 2.2. Thus we can explore the bio‐compatible synthesized hydrogel as a carrier for sustained drug delivery.

Revealing degradation of organic constituents of urine during the electrochemical oxidation of ciprofloxacin via boron-doped diamond anode

Ciprofloxacin (CIP) is a widely prescribed fluoroquinolone antibiotic used to treat various types of infections, including respiratory and digestive diseases. However, after uptake, unmetabolized CIP is excreted through both urine and feces and persists in the aquatic environment due to its inefficient removal in municipal wastewater facilities. This accumulation causes potential risks to the health of living organisms. The present work reports a study on the remediation of CIP in synthetic urine by electrochemical oxidation (ECO) using an undivided cell with a boron-doped diamond (BDD) anode and a stainless-steel cathode. The heterogeneous hydroxyl radical BDD(OH) formed at the anode surface from water discharge, remaining adjacent to it due to its short half-life time, and the powerful free chlorine formed from Cl− oxidation were the pre-eminent oxidants. The influence of pH and current density (j) on CIP abatement was analyzed, rapidly attaining its overall removal at j ≥ 40 mA cm−2 within the pH range 3.0–9.0 thanks to the action of free chlorine. The CIP decay always obeyed a pseudo-first-order reaction. The uric acid contained in the synthetic urine was completely oxidized, whereas a partial destruction was found for the major component urea and a smaller destruction of creatinine. A moderate TOC reduction slightly ≥ 40% was determined at pH 3.0 and 7.0 for j = 100 mA cm−2. The main nitrogenated species released was NH3 and small contents of residual free chlorine were finally detected. The present study reveals a good oxidation power of the ECO process with a BDD anode to remediate synthetic urine contaminated with CIP.

Evaluation of ceftriaxone pharmacokinetics in hospitalized Egyptian pediatric patients

This study aimed to evaluate ceftriaxone pharmacokinetics that affects the achievement of targets in the treatment of critically ill children (meningitis, pneumonia, urinary tract infection, peritonitis, and infective endocarditis( who were admitted to Zagazig University Pediatric hospital in Egypt to monitor for the drug adverse effects.Blood samples were obtained from 24 hospitalized pediatric patients (ages ranging from 2.5 months to 12 years) after administering the calculated dose of ceftriaxone via intravenous bolus route. Then, ceftriaxone plasma concentrations were measured using a validated HPLC method with ultraviolet detection. The pharmacokinetic analysis was conducted using Phoenix Winnonlin Program® software.Data for total and free ceftriaxone best fitted on a one-compartment model with the first-order elimination process. Clearance of ceftriaxone is reduced for patients with reduced kidney function and increased with those with augmented renal clearance. The volume of distribution and the free fraction are increased in these patients, especially those with hypoalbuminemia with a shorter half-life time were detected. A slight increase in total bilirubin and liver enzymes has been observed after treatment with ceftriaxone in these patients. Conclusion: In most critically ill pediatric patients, the current ceftriaxone treatment regimen (50 to 100 mg/kg) offers adequate pathogenic coverage. The clearance of free ceftriaxone in all patients correlates well with their renal function (eGFR), with r2 = 0.7252. During therapy with ceftriaxone at all doses ranging from 50 to 100 mg/kg, a rise in total bilirubin was observed in these patients. Moreover, liver enzymes (ALT and AST) increased moderately (p 0.0001). So, it is recommended to monitor total bilirubin and liver enzymes during the treatment with ceftriaxone, especially for a long duration (more than 5 days) or use another agent in patients with high baseline values.What is Known:• The dosing regimen of ceftriaxone (50 to 100 mg/kg) provided optimum therapeutic outcomes.• Some studies show data for total and free Ceftriaxone best fitted on a one-compartment model while other studies show data for total and free Ceftriaxone best fitted on a two-compartment model.What is New:• Up to my knowledge this is the first study ,considering individual pharmacokinetic analysis, conducted on hospitalized Egyptian pediatric population most of them with reduced kidney function with ages ranging from 2.5 months to 12 years. Data for total and free Ceftriaxone best fitted on a one-compartment model with linear clearance of the free ceftriaxone.• In all patients, total bilirubin and liver function tests were mildly increased, making them at risk for cholestasis or ceftriaxone-induced cholestatic hepatitis.

Constraining dark matter decay with cosmic microwave background and weak-lensing shear observations

From observations at low and high redshifts, it is well known that the bulk of dark matter (DM) has to be stable or at least very long-lived. However, the possibility that a small fraction of DM is unstable or that all DM decays with a half-life time (τ) significantly longer than the age of the Universe is not ruled out. One-body decaying dark matter (DDM) consists of a minimal extension to the ΛCDM model. It causes a modification of the cosmic growth history as well as a suppression of the small-scale clustering signal, providing interesting consequences regarding theS8tension, which is the observed difference in the clustering amplitude between weak-lensing (WL) and cosmic microwave background (CMB) observations. In this paper, we investigate models in which a fraction or all DM decays into radiation, focusing on the long-lived regime, that is,τ ≳ H0−1(H0−1being the Hubble time). We used WL data from the Kilo-Degree Survey (KiDS) and CMB data fromPlanck. First, we confirm that this DDM model cannot alleviate theS8difference. We then show that the most constraining power for DM decay does not come from the nonlinear WL data, but from CMB via the integrated Sachs-Wolfe effect. From the CMB data alone, we obtain constraints ofτ ≥ 288 Gyr if all DM is assumed to be unstable, and we show that a maximum fraction off = 0.07 is allowed to decay assuming the half-life time to be comparable to (or shorter than) one Hubble time. The constraints from the KiDS-1000 WL data are significantly weaker,τ ≥ 60 Gyr andf < 0.34. Combining the CMB and WL data does not yield tighter constraints than the CMB alone, except for short half-life times, for which the maximum allowed fraction becomesf = 0.03. All limits are provided at the 95% confidence level.

Light-Triggered Nitric Oxide Nanogenerator with High l-Arginine Loading for Synergistic Photodynamic/Gas/Photothermal Therapy.

The development of nanomedicines that combine photothermal therapy (PTT) with photodynamic therapy (PDT) is considered promising for cancer treatment, but still faces the challenge of enhancing tumoricidal efficiency. Fortunately, apart from the well-acknowledged effect on direct tumor cell-killing, nitric oxide (NO) is also considered to be effective for the enhancement of both PTT and PDT. However, both the low loading efficiency of NO precursor and the short half-life time and diffusion distance of NO hamper the synergistic therapeutic efficacy of NO. Taking the aforementioned factors into account, a mitochondria-targeted nitric oxide nanogenerator, EArgFe@Ce6, is constructed to achieve high loading of the NO donor l-Arginine (l-Arg) for synergistic photodynamic/gas/photothermal therapy upon single 660nm light irradiation. The coordination of epigallocatechin gallate (EGCG) and ferric ions (Fe3+ ) provides EArgFe@Ce6 supreme photothermal capability to perform low-temperature PTT (mPTT). EGCG endows EArgFe@Ce6 with mitochondria-targeting capability and meanwhile favors hypoxia alleviation for enhanced PDT. The PDT-produced massive reactive oxygen species (ROS) further catalyzes l-Arg to generate a considerable amount of NO to perform gas therapy and sensitize both mPTT and PDT. In vitro and in vivo studies demonstrate that the synergistic photodynamic/gas/photothermal therapy triggered by single 660nm light irradiation is highly effective for tumor treatments.

One Thrombin Generation Method Can Monitor Both Standard and Extended Half Life FVIII Products in Haemophilia a Patients with or without Emicizumab

Introduction Severe haemophilia A (SHA) is a bleeding disorder characterized by absent Factor VIII (FVIII). Traditionally, these patients are treated with intravenous prophylactic FVIII replacement concentrates to prevent spontaneous bleeding episodes. As an alternative, various extended half-life (EHL) FVIII products were introduced, since conventional standard factor FVIII (SHL) concentrates have a short half life time. Recently, a non-factor product, emicizumab, was introduced that mimics FVIII activity. Subcutaneous administration of this drug may clinically resemble a mild haemophilia. Conventional laboratory tests are unreliable for these new agents. However, techniques are needed for monitoring in emergency situations and in case of surgery. Global coagulation assays, like thrombin generation (TG), may be promising as an universal laboratory test to measure the full coagulation product spectrum in order to monitor the effectiveness of various FVIII and non-FVIII replacement products. Aim The aim of this pilot study was to assess FVIII and/or emicizumab activity levels by a commercially available thrombin generation assay (TGA), using plasma samples of patients treated with conventional or EHL FVIII products in presence or absence of emicizumab were tested. Methods Blood was collected in standard citrated tubes (0,109 M BD) used for routine coagulation testing, without adding a contact activator inhibitor. Platelet poor plasma was prepared by double centrifugation. In total, plasma samples were obtained from 10 healthy volunteers and 18 patients. Four samples were taken from 4 patients with trough levels FVIII, 10 samples from 6 patients on prophylactic replacement therapy using SHL or EHL FVIII products, 22 samples from 12 patients on emicizumab and 10 samples of 3 patients on emicuzimab plus EHL FVIII. FVIII One Stage Clotting Assay (OSA), emicizumab levels and bovine FVIII chromogenic substrate assay (CSA) were determined using Siemens reagents on CS2500. TG was measured using PPP Reagent LOW by Calibrated Automated Thrombogram (CAT) method (Stago). TG is represented by both normalized Endogenous Thrombin Potential (ETP%) and Peakheight (Peak%) as a percentage of a normal pooled plasma composed of more than 120 healthy volunteers. Results FVIII levels by OSA showed the best correlation with TG ETP% and Peak% with Spearman correlation coefficients (r) of both 0,8. Emicuzimab had a moderate correlation with ETP% (r=0,42) and Peak % (r=0,58). In patients with emicuzimab and SHL the correlation between FVIII by bovine CSA was also moderate, 0,47 (ETP%) and 0,50 (Peak%). Lowest ETP% and Peak% were suggested in de patients in their through levels (Figure 1, red bars). Patients on emicizumab have higher ETP% and Peak%, although the median levels are not within the normal range (Figure 1, green bars). Patients on SHL or EHL replacement therapy with or without emicizumab give the impression that their ETP% and Peak% are approaching normal values (Figure 1, blue bars and yellow bars, respectively). Conclusion The commercial available TG assay (PPP Reagent LOW) may be used to test different Haemophilia A replacement therapies in double centrifuged, plasma samples collected without a contact activator inhibitor. Since one reliable uniform test is clinically needed, future applicability for this assay in monitoring SHA patients has to be studied in larger cohorts. Furthermore, the relevance of ETP% and Peak% has to be related to clinical outcomes such as severity of bleeding. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

New composite membranes based on PVDF fibers loaded with TiO2: Sm nanostructures and reinforced with graphene/graphene oxide for photocatalytic applications

New composite membranes based on PVDF fibers loaded with Sm doped TiO2 (TiO2:Sm) nanostructures and graphene-based nanoparticles obtained by the electrospinning technique are reported. The addition of the inorganic nanostructures induced photocatalytic properties, while the graphene-based nanoparticles (G - graphene or GO - graphene oxide) improved the mechanical properties. Advanced instrumental methods for material analysis (e.g., XRD, SEM, mechanical, and DVS) were employed to characterize the structure and surface properties. The membranes were used in photocatalytic assays for the degradation of methylene blue (MB) under visible light irradiation. To intensify the photocatalytic processes, the effect of hydrogen peroxide addition was also investigated. The results revealed that the PVDF-based membrane containing 15% TiO2:Sm and 2.5% GO showed an optimal photocatalytic activity due to its high porosity, relevant adsorption capacity, and improved mechanical properties. The response surface methodology was employed to optimize the experimental conditions of the photocatalytic process. The addition of H2O2 significantly increased the rate constant of photodegradation reaction (k = 6.624× 10−1 min−1), disclosing a half-life of the reaction of about 1 min. This short half-life time represents a remarkable outcome for a photocatalytic process conducted under visible light irradiation. Good recycling capacity was observed for the optimal (TiO2:Sm)[15%]/PVDF/GO[2.5%] composite membrane.

Improving Both the Thermostability and Catalytic Efficiency of Phospholipase D from Moritella sp. JT01 through Disulfide Bond Engineering Strategy.

Mining of Phospholipase D (PLD) with high activity and stability has attracted strong interest for investigation. A novel PLD from marine Moritella sp. JT01 (MsPLD) was biochemically and structurally characterized in our previous study; however, the short half-life time (t1/2) under its optimum reaction temperature seriously hampered its further applications. Herein, the disulfide bond engineering strategy was applied to improve its thermostability. Compared with wild-type MsPLD, mutant S148C-T206C/D225C-A328C with the addition of two disulfide bonds exhibited a 3.1-fold t1/2 at 35 °C and a 5.7 °C increase in melting temperature (Tm). Unexpectedly, its specific activity and catalytic efficiency (kcat/Km) also increased by 22.7% and 36.5%, respectively. The enhanced activity might be attributed to an increase in the activation entropy by displacing more water molecules by the transition state. The results of molecular dynamics simulations (MD) revealed that the introduction of double disulfide bonds rigidified the global structure of the mutant, which might cause the enhanced thermostability. Finally, the synthesis capacity of the mutant to synthesize phosphatidic acid (PA) was evaluated. The conversion rate of PA reached about 80% after 6 h reaction with wild-type MsPLD but reached 78% after 2 h with mutant S148C-T206C/D225C-A328C, which significantly reduced the time needed for the reaction to reach equilibrium. The present results pave the way for further application of MsPLD in the food and pharmaceutical industries.

ACEing premature codon termination using anticodon-engineered sup-tRNA-based therapy

ACEing premature codon termination using anticodon-engineered sup-tRNA-based therapy

Protocatechuic Acid-Based Supramolecular Hydrogel Targets SerpinB9 to Achieve Local Chemotherapy for OSCC.

Protocatechuic acid (PCA) is a natural phenolic acid present in daily vegetables and fruits. Notably, PCA was demonstrated to inhibit the biological function of SerpinB9 (Sb9) and exhibit an excellent antitumor effect, showing great potential in cancer treatment. However, the short half-life time limits PCA's wide application against cancers. To overcome this shortage of PCA, we integrated PCA and another natural product with strong self-assembling properties, isoguanosine (isoG), to develop a novel multifunctional supramolecular hydrogel with good biocompatibility and injectability, which remarkably lengthens the releasing time of PCA and exerts considerable anticancer effects in vitro and in vivo. Besides, we surprisingly found that PCA could not only target Sb9 but also restrain cancer development through activating the JNK/P38 pathway, decreasing the ROS level, and repairing cancer stemness. In all, our results demonstrate that this PCA-based hydrogel could act as a multifunctional hydrogel system equipped with considerable anticancer effects, providing potential local administration integrating with targeted therapy and chemotherapy in one simple modality.

Novel deuterated Mnk1/2 protein degrader VNLG-152R analogs: Synthesis, In vitro Anti-TNBC activities and pharmacokinetics in mice

A new and improved synthesis of lead Mnk1/2 protein degrader, VNLG-152R, 4-(±)-(1H-imidazole-1-yl)-N-(4-fluorophenyl)-(E)-retinamide (1) has been developed from commercially available 4-oxo-ATRA (8). This procedure was also utilized to synthesize the seven possible deuterated analogs of compound 1 (11–17). The deuterated analogs were either better or equipotent to 1 in in vitro antiproliferative activities against MDA-MB-231 and MDA-MB-468 human TNBC cells. The Mnk1/2 degraders were equally effective as a standard TNBC therapy (paclitaxel). Importantly, the expression of Mnk1, peIF4E and their associated downstream targets, including cyclin D1 and Bcl2, were strongly decreased in compound 1/analogs (11–17)-treated TNBC cells signifying inhibition of Mnk1-eIF4E signaling. More importantly, we showed that deuterated analogs, 12, 16 and 17 possess improved pharmacokinetics parameters following oral administration to CD-1 female mice compared to the parent non-deuterated compound 1, thus addressing the rapid clearance (short half-life and short residence time) pharmacokinetic inadequacy of compound 1.

Erythrocyte-biomimetic nanosystems to improve antitumor effects of paclitaxel on epithelial cancers.

Chemotherapy is a difficult treatment for cancer patients because of the low effective accumulation of chemo-drugs and their detrimental side effects. Nanoparticles have shown promise as a solution to these problems. However, the known differences in the porosity and vascularization of tumor vessels, and other factors, including the potential formation of a "protein crown," the short half-life time in circulation, and the low drug distribution, often limit their application. To address these problems, biomimetic nanoparticles coated with cell membranes have been developed and shown to have advantages such as prolonged circulation, high biocompatibility, and enhanced targeting abilities in drugs and nanoparticles, thus exhibiting good application prospects in cancer therapy for liver, lung, and melanoma cancers. Accordingly, we designed a PH-sensitive biomimetic nanodrug delivery system with a delicate "core-shell" structure based on red blood cell membranes. Briefly, core nanoparticles were synthesized by the self-assembly of natural amphoteric polymers, including hydrophilic carboxymethylcellulose sodium and hydrophobic stearic acid. For the shell structure, red blood cell membranes were modified using folic acid by a lipid tether (1,2-distearoyl-sn-glycero-3-phosphoethanolamine) to increase tumor-targeting ability, whereas polyethylene glycol was inserted to decrease lipid tether modification-induced potential sequestration by either the mononuclear phagocyte system or the reticuloendothelial system. Via a series of formulation optimizations, paclitaxel was packaged into the red blood membrane-based core-shell nanoparticles with an average size of 226.9±2.75nm and a negative Zeta potential of -14.5±0.3mV. More importantly, the examinations focusing on CD47, a representative red blood cell membrane protein, revealed not only the successful establishment of the membrane shell but also the right-side-out membrane orientation on our core-shell nanoparticles. Our nanodrug delivery system showed good biocompatibility and sensitivity to acidic tumor microenvironments while effectively prolonging the circulation time of paclitaxel and further enhancing its antitumor effects on epithelial malignancies, including liver, lung, and melanoma cancers. In particular, our nanodrug delivery system significantly alleviated paclitaxel-induced renal toxicity. Taken together, our findings highlight that the red blood membrane-based core-shell nanoparticle is a promising biomimetic nanodrug delivery system for functionally delivering chemotherapeutic drugs, and it has promise in clinical applications.

Defect induced enhanced catalytic activity of Lu doped titanium dioxide (TiO2) thin films

In this article, we report the property evaluation of Lu doped TiO2 thin films suitable for catalytic activity. The detailed investigation on the film's structural, optical, and chemical properties was carried out. The structural study using XRD and Raman reveal presence of dominant crystalline anatase phase for Lu doped samples. The spherical grains were observed on the surface of Lu doped films and these act as active centres during catalytic activity. XPS analysis confirm the chemical states of basic elements including Ti, O, and Lu, and a brief discussion on enhanced defects on doping using anion and cation core level spectra is described. Moreover, modified Auger parameter and change in chemical bonding interaction energy also strongly supports enhanced defects in the material. These defect centres may act as a trapping core, extending carrier recombination and increasing photocatalytic activity. Under UV irradiation, sample's photocatalytic performance was tested for methyl orange and methylene blue target dyes. Among the samples deposited, 0.4 at% Lu doped films perform better as a photocatalyst, with high degradation efficiency, high reaction rate, and short half-life time.