Ceftazidime-avibactam induced renal disorders: past and present.

With the increasing prevalence of multidrug-resistant Gram-negative bacterial pathogens worldwide, antimicrobial resistance has become a significant public health concern. Ceftazidime-avibactam (CAZ-AVI) exhibited excellent in vitro activity against many carbapenemase-producing pathogens, and was widely used for the treatment of various complicated infections. CAZ-AVI is well tolerated across all dosing regimens, and its associated acute kidney injury (AKI) in phase II/III clinical trials is rare. However, recent real-world studies have demonstrated that CAZ-AVI associated AKI was more frequent in real-world than in phase II and III clinical trials, particularly in patients receiving concomitant nephrotoxic agents, with critically ill patients being at a higher risk. Herein, we reviewed the safety data related to renal impairment of CAZ-AVI, and discussed its pharmacokinetic/pharmacodynamic targets and dosage adjustment in patients with impaired renal function. This review aimed to emphasize the importance for healthcare professionals to be aware of this adverse event of CAZ-AVI and provide practical insights into the dosage optimization in critically ill patients with renal dysfunction.

Preparation of hydroxyapatite nanofibers by using ionic liquids as template and application in enhancing hydrogel performance.

Introduction: Hydroxyapatite (HAP or HA) nanofibers are very attractive in the field of biomedical engineering. However, templates used for preparing HAP nanofibers are usually hydrophobic molecules, like fatty acids and/or surfactants, which are difficult to remove and potentially toxic. Therefore, it is important to develop a green approach to prepare HAP nanofibers. Methods: Imidazolium-based ionic liquids (ILs) were used as templates to control the crystallization of HAP. The obtained HAP nanofibers were composited into polyvinyl alcohol-sodium alginate (PVA-Alg) hydrogel (HAP@H). The rheological performance, stretching, and compression properties were tested. Scanning electron microscope (SEM), high resolution transmission electron microscope (HRTEM), X-ray diffraction (XRD), Fourier-transform infrared (FT-IR), and differential scanning calorimetry (DSC) were adopted to characterize the morphology, size, crystallographic orientations, and phase of HAP@H. Results: HAP nanofibers with a length of ∼50 µm were harvested. The DSC results proved that water loss temperature increased from 98°C (for pure hydrogel) to 107°C (for HAP@H). Also, HAP@H hydrogel presented much better porous structure, tensile performance, and compressive performance than that of pure hydrogel. Discussion: The morphology, size, and growth direction of HAP could be modulated easily by altering the alkyl chain length of ILs' cations. This is possibly due to face-specific adsorption of imidazolium moieties on HAP nanocrystals. The enhancing performance of HAP@H is probably due to the composited highly oriented HAP nanofibers.

Electrospinning of antibacterial and anti-inflammatory Ag@hesperidin core-shell nanoparticles into nanofibers used for promoting infected wound healing.

Bacterial infection and excessive inflammation are still the main obstacles to wound repair. Thus, antibacterial and anti-inflammation nanomaterials are always attracting for infected wound healing. In this work, ultra-uniform (∼20 nm) and colloidally stable Ag nanoparticles (Ag-Hes NPs) with core-shell structure were prepared by using hesperidin as reducing and capping agent. The obtained Ag-Hes NPs present effective antibacterial properties on both Staphylococcus aureus and Escherichia coli. Ag-Hes NPs also got high 1,1-diphenyl-1-picrylhydrazyl scavenging capability of 69%. Under the package of polyvinyl alcohol and sodium alginate, Ag-Hes NPs were encapsulated into electro spun nanofibers to form hydrogel (Ag-Hes@H). This strategy provides a moisture environment which could enrich and release Ag-Hes NPs gradually. Cell experiments and animal wound healing investigation proved that Ag-Hes@H could promote the proliferation and migration of human umbilical vein endothelial cells and accelerate infected wound healing. Meanwhile, Ag-Hes@H significantly reduced the expression of inflammatory cytokines, including IL-6, MMP9 and TNF-α. Immunohistochemistry data further suggested that Ag-Hes@H accelerated wound closure by promoting collagen deposition and skin cell proliferation. The designed antibacterial and anti-inflammatory Ag-Hes@H has great potential for promoting infected wound healing.

Preparation of Photocatalytic and Antibacterial MOF Nanozyme Used for Infected Diabetic Wound Healing.

Bacterial infection has been a considerable obstacle for diabetic wound healing. A multifunctional nanoplatform used as nanozyme for bacterial infected diabetic wound is extremely attractive. Therefore, gold nanoclusters modified zirconium-based porphyrin metal-organic frameworks (Au NCs@PCN) were constructed by an in situ growth method. Through SEM, TEM, and EDS mapping, the surface of ellipsoid-shaped particles around 190 nm was observed to be evenly interspersed with 5-8 nm gold nanoclusters. Notably, Au NCs@PCN exhibits excellent performance in exciting ROS generation and photothermal effects. Under near-infrared (NIR) laser irradiation, Au NCs@PCN can be heated to 56.2 °C and produce ROS, showing an effective killing effect on bacteria. Antibacterial studies showed that Au NCs@PCN inhibited MRSA and Ampr E. coli by destroying membrane structure and inducing protein leakage up to 95.3% and 90.6%, respectively. Animal experiments showed that Au NCs@PCN treated diabetic rats had reduced wound coverage to 2.7% within 21 days. The immunoblot analysis showed that proangiogenic and proepithelial cell proliferation factors were expressed significantly up-regulated. These results prove that Au NCs@PCN with photocatalytic and nanozyme activity has a broad application prospect for promoting diabetic infected wound healing.

Preparation of epigallocatechin gallate decorated Au-Ag nano-heterostructures as NIR-sensitive nano-enzymes for the treatment of osteoarthritis through mitochondrial repair and cartilage protection.

Osteoarthritis (OA), a widespread degenerative disease characterized by cartilage destruction, has emerged as a public health challenge in the current aging society. In addition to applied steroids and surgery, near-infrared (NIR) sensitive nano-enzyme for the treatment of osteoarthritis through mitochondrial repair and cartilage protection is attractive and promising. In this study, a NIR sensitive multifunctional heterostructure (EGCG (Epigallocatechin gallate) decorated Au-Ag nano-jars (E@Au-Ag)) was introduced as an enzyme-sensitive active nanoplatform for the treatment of osteoarthritis. Molecular biology results indicated that E@Au-Ag possesses intrinsic properties of anti-oxidative stress and was able to reduce the apoptosis rate of chondrocytes by 83.3%. The area of the intra-articular joint cavity injected with E@Au-Ag can be elevated to 46.6 °C under NIR to promote the release of EGCG further to induce cartilage regeneration. X-ray radiography and section staining showed that E@Au-Ag reduced cartilage damage and decreased OARSI scores by approximately 52% after 8 weeks of treatment in a surgically induced OA model. The results demonstrated that this multifunctional enzyme-like nanoplatform with a synergistic NIR sensitive property to facilitate cartilage migration and regeneration repair provides a promising OA treatment strategy. STATEMENT OF SIGNIFICANCE: 1. NIR-sensitive nano-enzyme is gaining much attention in the field of biomedical materials. 2. EGCG decorated Au-Ag nano-heterostructures were utilized as NIR-sensitive nano-enzymes for the treatment of osteoarthritis through mitochondrial repair and cartilage protection. 3. The obtained multifunctional Au-Ag nano-heterostructures are promising for osteoarthritis treatment.

Preparation of EGCG decorated, injectable extracellular vesicles for cartilage repair in rat arthritis.

Arthritis is a kind of chronic inflammatory autoimmune disease, which can destroy joint cartilage and bone, leading to joint pain, joint swelling, and limited mobility. Traditional therapies have many side effects or focus too much on anti-inflammation while neglecting joint repair. In this experiment, we combined Epigallocatechin gallate (EGCG) with extracellular vesicles derived from macrophages to treat rheumatoid arthritis. Sustained-release resulted in a significant decrease in chondrocyte expression of hypoxia-inducible factor 1-alpha, a decrease in apoptosis-related proteins Cytochrome C, Caspase-3, Caspase-9, and Bax. Molecular biological analysis showed that extracellular vesicles-encapsulated EGCG (EVs-EGCG) more significantly upregulated type II collagen expression by about 1.8-fold than EGCG alone, which was more beneficial for arthritis repair. Animal experiments revealed that these EGCG-coated extracellular vesicles significantly reduced swelling, decreased synovial hyperplasia, repaired cartilage, and attenuated arthritis-related pathology scores in arthritic rats. Measurement data showed that EVs-EGCG treatment reduced joint swelling by approximately 39.5% in rheumatoid rats. In vitro studies have shown that this EVs-EGCG can increase the expression of cartilage type II collagen and reduce apoptosis of chondrocytes. Moreover, it was demonstrated in vivo experiments to reduce cartilage destruction in rheumatoid arthritis rats, providing a solution for the treatment of rheumatoid arthritis.

Tea polyphenol modified, photothermal responsive and ROS generative black phosphorus quantum dots as nanoplatforms for promoting MRSA infected wounds healing in diabetic rats.

BACKGROUND: Healing of MRSA (methicillin-resistant Staphylococcus aureus) infected deep burn wounds (MIDBW) in diabetic patients remains an obstacle but is a cutting-edge research problem in clinical science. Surgical debridement and continuous antibiotic use remain the primary clinical treatment for MIDBW. However, suboptimal pharmacokinetics and high doses of antibiotics often cause serious side effects such as fatal complications of drug-resistant bacterial infections. MRSA, which causes wound infection, is currently a bacterium of concern in diabetic wound healing. In more severe cases, it can even lead to amputation of the patient's limb. The development of bioactive nanomaterials that can promote infected wound healing is significant. RESULTS: The present work proposed a strategy of using EGCG (Epigallocatechin gallate) modified black phosphorus quantum dots (BPQDs) as therapeutic nanoplatforms for MIDBW to achieve the synergistic functions of NIR (near-infrared)-response, ROS-generation, sterilization, and promoting wound healing. The electron spin resonance results revealed that EGCG-BPQDs@H had a more vital photocatalytic ability to produce singlet oxygen than BPQDs@H. The inhibition results indicated an effective bactericidal rate of 88.6% against MRSA. Molecular biology analysis demonstrated that EGCG-BPQDs significantly upregulated CD31 nearly fourfold and basic fibroblast growth factor (bFGF) nearly twofold, which were beneficial for promoting the proliferation of vascular endothelial cells and skin epidermal cells. Under NIR irradiation, EGCG-BPQDs hydrogel (EGCG-BPQDs@H) treated MIDBW area could rapidly raise temperature up to 55 °C for sterilization. The MIBDW closure rate of rats after 21 days of treatment was 92.4%, much better than that of 61.1% of the control group. The engineered EGCG-BPQDs@H were found to promote MIDBW healing by triggering the PI3K/AKT and ERK1/2 signaling pathways, which could enhance cell proliferation and differentiation. In addition, intravenous circulation experiment showed good biocompatibility of EGCG-BPQDs@H. No significant damage to major organs was observed in rats. CONCLUSIONS: The obtained results demonstrated that EGCG-BPQDs@H achieved the synergistic functions of photocatalytic property, photothermal effects and promoted wound healing, and are promising multifunctional nanoplatforms for MIDBW healing in diabetics.

A fluorinated chitosan-based QuEChERS method for simultaneous determination of 20 organophosphorus pesticide residues in ginseng using GC-MS/MS.

In this study, a new fluorinated methacrylamide (MACF) was synthesized and evaluated as an adsorbent in the dispersive solid-phase extraction for the effective determination and extraction of 20 organophosphorus pesticides (OPPs) from ginseng samples using the QuEChERS (quick, easy, cheap, effective, rugged, safe) method coupled with GC-MS/MS. The properties of MACF were characterized using Fourier-transform infrared spectroscopy, elemental analysis, and high-resolution 19 F NMR. MACF, chitosan, primary and secondary amine, octadecylsilane, graphitized carbon black, Z-Sep, Z-Sep+ , and EMR-Lipid were compared in terms of extraction efficiency. The best results were obtained when MACF was used. Matrix-matched calibration was employed for quantification. All the OPPs exhibited good linearity (r2 > 0.9969) with the concentration at their respective concentration ranges. The limits of detection were 1.5-3.0 µg/kg, and the limits of quantification were 5.0-10.0 µg/kg. The trueness of the 20 pesticides at four spiked levels ranged from 86.1 to 111.1%, and the relative standard deviation was less than 11.3%. The modified QuEChERS method using MACF as the adsorbent was sensitive, reliable, and cost-effective and could be used for the determination of 20 OPP residues in ginseng.

Preparation of ROS active and photothermal responsive hydroxyapatite nanoplatforms for anticancer therapy.

Photothermal responsive nanoplatforms are attracting for photothermal therapy (PTT) of cancer. Herein, we propose a strategy to prepare IR-780 modified hydroxyapatite (HAP) nanorods as photothermic agents (HAP@IR-780). The results demonstrated that the obtained HAP@IR-780 was photothermal responsive under near-infrared laser irradiation the photothermal conversion efficiency was 69.3%, and it remained photostability after 4 cycles of irradiation. This advantage overcomes the optical instability of IR780. MTT and cellular uptake research proved that HAP@IR-780 was biocompatible in appropriate concentration range (0-20 µg/mL) without laser irradiation. Concentration-dependent internalization and reactive oxygen species (ROS) related apoptosis of HAP@IR-780 for MCF-7 cells were observed. Animal experiments showed that the gathered HAP@IR-780 at the tumor site reached a photothermal responsive temperature up to 57.9 °C, which could almost ablate the tumor with volumes as large as 1500 mm3. In general, our photothermal material has good photothermal conversion characteristics, and may have the least safety problems while showing excellent therapeutic effects. Therefore, HAP@IR-780 has a brilliant prospect in the field of tumor photothermal therapy.

Preparation of Ag Nanoclusters-Modified Non-Sintered Silica Ceramic-Like Nanosheet for Removing Dyes and Bacteria from Water.

PURPOSE: Worldwide water contamination treatment and water security are essential for all living organisms. Among various water contaminants, dye, and bacteria pollution needs to be solved urgently. METHODS AND RESULTS: In this work, a ceramic sheet from monodisperse, porous silica nanospheres (SiO2 NSs) with an average diameter of 220 was prepared. The prepared SiO2 ceramic sheets were investigated as a "filtration" material in removing dyes (alcian blue, AB; and methylene blue, MB) and bacteria (E. coli and S. aureus). The obtained sheets had efficient adsorption efficiency of 98.72% (for AB) and 97.35% (for MB), and a high adsorption capacity for AB is 220 (mg/g), for MB is 176 (mg/g). Furthermore, these SiO2 ceramic sheets had a high recycling capability for removing dyes by calcination. Being modified by Ag nanoclusters, the ceramic sheets present a strong bactericidal function. CONCLUSION: Our results demonstrated that the obtained SiO2 non-sintered ceramic sheets is rapid and efficient in the filtration of dyes and bacteria from polluted water.

Modulation of Rat Kidney Stone Crystallization and the Relative Oxidative Stress Pathway by Green Tea Polyphenol.

The role of tea polyphenol (TP) in modulating kidney stone crystallization and regulating the relative nephropathy pathway of rats was investigated. Calcium oxalate (CaOx) crystallization and oxidative stress are essential for kidney stone diseases. The kidney stone model in a rat was established by using ethylene glycol to affect the oxalic acid metabolism. The crystallization process of CaOx in the rat kidney was modulated by different TP intakes. At the same time, the effects of different types of CaOx, extracted from the rat kidney, on the proliferation and differentiation of HK-2 cells were also studied. The results showed that calcium oxalate monohydrate crystals were obtained in the blank control and the low-dose TP groups. However, CaOx crystals extracted from higher-TP-intake groups were mainly calcium oxalate dihydrate. Moreover, the size of the CaOx crystals produced in TP intake groups was much smaller than that of the blank control group. Cell experiment results show that TP can effectively reduce the damage of CaOx crystals to HK-2 cells. Further research found that TP can significantly improve oxidative stress in cases of kidney stones. TP has been proven to control CaOx crystallization in vitro, but the in vivo research results obtained through the rat stone model in this paper are novel and originally important for researching the relationship between tea drinking and preventive treatment of kidney stone diseases.

Encapsulation of green tea polyphenol nanospheres in PVA/alginate hydrogel for promoting wound healing of diabetic rats by regulating PI3K/AKT pathway.

Difficult healing of skin wounds is one of the serious complications of diabetes mellitus. Green tea polyphenols (TP) have been found to have good therapeutic effects on wounds healing. However, TP that is soluble in water and easily been oxidized requires a gel material that provides moisture retention, oxidation prevention, and sustained release of TP to achieve better wound healing effect. Therefore, in this work, novel tea polyphenol nanospheres (TPN) were synthesized and encapsulated in a PVA /alginate hydrogel (TPN@H). The prepared TPN@H was characterized and applicated in model diabetic rats for promoting wound healing and regulating immune response. Fourier-transform infrared spectroscopy (FT-IR), UV spectroscopy, scanning electron microscopy (SEM), atomic force microscope (AFM), confocal laser scanning microscopy (CLSM), dynamic light scattering (DLS) and differential scanning calorimetry (DSC) were used for characterization. Animal experiments and molecular mechanism research proved that TPN@H could promote wound healing of diabetic rats by regulating PI3K/AKT signaling pathway.

Dialysis Preparation of Smart Redox and Acidity Dual Responsive Tea Polyphenol Functionalized Calcium Phosphate Nanospheres as Anticancer Drug Carriers.

Large-scale preparation of biocompatible drug delivery systems with targeted recognition and controlled release properties has always been attractive. However, this strategy has been constrained by a lot of design challenges, such as complicated steps and premature drug release. Herein, in this paper, we address these problems by a facile in situ mineralization method, which synthesizes biodegradable tea polyphenol coated monodisperse calcium phosphate nanospheres using for targeted and controlled delivery of doxorubicin. Dialysis diffusion method was used to control ion release to form mineralized nanospheres. The polyphenol coatings and calcium phosphate used in this work could be biodegraded by intracellular glutathione and acidic microenvironment, respectively, resulting the release of encapsulated drug. According to confocal fluorescence microscopy, and cytotoxicity experiments, the prepared tea polyphenol functionalized, doxorubicin loaded calcium phosphate nanospheres were confirmed to have highly efficient internalization and obvious cell killing effect on target tumor cells, but not normal cells. Our results suggest that these tea polyphenols functionalized calcium phosphate nanospheres are promising vehicles for controlled release of an anticancer drug in cancer therapy.

pH and folic acid dual responsive polysaccharide nanospheres used for nuclear targeted cancer chemotherapy.

Ideal nanoscale drug delivery system (DDS) should be biocompatible, having targeted recognition and controlled release properties. In this work, monodispersed, doxorubicin (Dox) loaded chitosan (Cts) nanospheres functionalized by mesoporous SiO2 and folic acid (FA) were prepared, briefly named as DCSF NSs. The prepared raspberry-like DCSF NSs had an average size of 440 nm and drug loading efficiency (DLE) of 42.61%. The drug release results confirmed that the release of Dox could be controlled by pH change. Cell apoptosis results indicated that the obtained DCSF NSs could kill 90% of MCF-7 cells in 48 h. Confocal laser scanning microscopy (CLSM) results further revealed that folic acid could mediate the cellular uptake of DCSF NSs. These results demonstrated that the obtained DCSF NSs were pH-responsive, folic acid-triggered nuclear targeted, which can be used as ideal DDS for tumor chemotherapy.

Toxicity of food sweetener-sodium cyclamate on osteoblasts cells.

In this paper, the effect of commonly used food sweetener (sodium cyclamate) on the proliferation and differentiation of osteoblasts has been researched. The morophology change of osteoblasts was investigated by confocal laser scanning microscopy. Cell viability was studied by MTT analysis. BMP2 expression was analyzed by western blot and immunofluorescence. Mineralization ability of osteoblasts was researched by using alizarin red staining method. The results indicate that a very low concentration (0.06 µM) of sodium cyclamate can curle and fold microfilament and microtubule of osteoblasts. The increase addition of sodium cyclamate resulted significantly decrease of cells viability. The expression of bone morphogenetic protein-2 (BMP2) was seriously suppressed by sodium cyclamate. Alizarin Red staining experiment revealed that sodium cyclamate decreased the mineralization ability of osteoblasts. The present results suggest that sodium cyclamate can seriously inhibit the proliferation and differentiation of osteoblasts.

GSH and enzyme responsive nanospheres based on self-assembly of green tea polyphenols and BSA used for target cancer chemotherapy.

Developing safe and effective stimuli-responsive nanocarriers is very important for tumor chemotherapy. In this work, bovine serum albumin (BSA) and green tea polyphenol (TP) were used to prepare glutathione (GSH) and enzyme (trypsin) responsive nanocarriers for doxorubicin (DOX). These nanocarriers were further modified with folate, briefly named as DOX@BSA-TP-FA NSs. The diameter of nanocarriers was about 220 nm. The DOX loading efficiency and loading amount were 86.4% and 23.5 wt%, respectively. The cellular uptake, apoptosis, and GSH and trypsin responsive release properties of these nanocarriers were investigated.

Encapsulation of green tea polyphenol by pH responsive, antibacterial, alginate microgels used for minimally invasive treatment of bone infection.

The treatment of bone infection requires drug carriers take large number of cargo, be antibacterial, promote proliferation and differentiation of osteoblasts. Herein, we proposed a strategy of preparing pH responsive, antibacterial, multistage structured microspheres encapsulated with green tea polyphenol used for minimally invasive treatment of bone infection. Tea polyphenol (TP) were encapsulated by porous silica nanospheres (SiO2 NSs). Then, sodium alginate (SA) microgel spheres (MSs) were prepared to encapsulate a lot of TP loaded SiO2 NSs. The outer layer of obtained TP@SiO2@SA microgel spheres were further wrapped by pH sensitive CaCO3. Mineral out-layer of the composite microspheres is used to neutralize the acidic environment caused by bacterial infection. At the same time, encapsulated TP is released pH sensitively to resist oxidative stress. Our results exhibited excellent drug delivery properties including drug loading efficiency (DLE) of 92.96% and drug loading content (DLC) of 19.62%. Besides, results demonstrated that TP@SiO2@SA@CaCO3 MSs can effectively kill Staphylococcus aureus and promote proliferation and differentiation of osteoblasts under stimulation of H2O2 at pH = 5.5.

Construction of injectable, pH sensitive, antibacterial, mineralized amino acid yolk-shell microspheres for potential minimally invasive treatment of bone infection.

INTRODUCTION: Treatment of infection within bone is difficult, and conventional surgical treatment brings intense pain to the patients physically and mentally. There is an urgent need to develop injectable nano- and/or micro-medicine for minimally invasive treatment of osteomyelitis. METHODS: In this paper, amino acid (L-lysine [Lys]) was mineralized into yolk-shell structured CaCO3 microspheres (MSs). The morphologies of the obtained MSs were investigated by scanning electron microscopy and transmission electron microscopy. The composition of CaCO3 MSs was identified by using Fourier transform infrared spectroscopy. The as-prepared CaCO3 MSs were examined with power X-ray diffraction analysis to obtain the crystallographic structure of the MSs. RESULTS: The as prepared Lys encapsulated CaCO3 MSs (Lys@CaCO3 MSs) were used as micro-drug to improve acidic environment of osteomyelitis caused by bacterial infection and promote osteoblast proliferation under oxidative stress. These pH responsive Lys@CaCO3 MSs have a drug loading efficiency of 89.8 wt % and drug loading content (DLC) of 22.3 wt %. CONCLUSION: Our results demonstrated that Lys@CaCO3 MSs can effectively kill Staphylococcus aureus and promote proliferation and differentiation of osteoblasts under stimulation of H2O2 at pH = 5.5.

Preparation of anticancer micro-medicine based on quinoline and chitosan with pH responsive release performance.

N-(2-(3-fluorobenzyl)-2H-indazol-5-yl)-2-phenyl-2H-pyrazolo[4,3-c]qui- nolin-4-amine (LZC-2b) with a quinoline structure was synthesized as an anticancer prodrug. The pH sensitive anticancer drugs obtained by a simple hydrothermal method. The interaction of chitosan (Cts) and LZC-2b is used to complete the encapsulation without any cross-linking. The obtained micromedicine (LZC-2b@Cts-MSs) has an average size of ∼980 nm. The drug loading efficiency (DLE) of LZC-2b@Cts-MSs was about 79%. In addition, drug release from LZC-2b@Cts-MSs was pH depended. At pH = 7.4, only 5.1% of loaded LZC-2b was released, while 90.3% of loaded LZC-2b was released at pH = 5.0. Cell culture results indicate that LZC-2b@Cts-MSs can be easily uptaken by KB cells. Cell viability results show that KB cells can be effectively killed by LZC-2b@Cts-MSs. Our strategy of synthesis and preparation of pH responsive LZC-2b@Cts-MSs has promising prospect in chemotherapy of oral cancer.