Non-targeted analysis based on quantitative prediction and toxicity assessment for emerging contaminants in tire particle leachates.

Non-targeted analysis (NTA) has great potential to screen emerging contaminants in the environment, and some studies have conducted in-depth investigation on environmental samples. Here, we used a NTA workflow to identify emerging contaminants in used tire particle (TP) leachates, followed by quantitative prediction and toxicity assessment based on hazard scores. Tire particles were obtained from four different types of automobiles, representing the most common tires during daily transportation. With the instrumental analysis of TP leachates, a total of 244 positive and 104 negative molecular features were extracted from the mass data. After filtering by a specialized emerging contaminants list and matching by spectral databases, a total of 51 molecular features were tentatively identified as contaminants, including benzothiazole, hexaethylene glycol, 2-hydroxybenzaldehyde, etc. Given that these contaminants have different mass spectral responses in the mass spectrometry, models for predicting the response of contaminants were constructed based on machine learning algorithms, in this case random forest and artificial neural networks. After five-fold cross-validation, the random forest algorithm model had better prediction performance (MAECV = 0.12, Q2 = 0.90), and thus it was chosen to predict the contaminant concentrations. The prediction results showed that the contaminant at the highest concentration was benzothiazole, with 4,875 µg/L in the winter tire sample. In addition, the joint toxicity assessment of four types of tires was conducted in this study. According to different hazard levels, hazard scores increasing by a factor 10 were developed, and hazard scores of all the contaminants identified in each TP leachate were summed to obtain the total hazard score. All four tires were calculated to have relatively high risks, with winter tires having the highest total hazard score of 40,751. This study extended the application of NTA research and led to the direction of subsequent targeting studies on highly concentrated and toxic contaminants.

Current Knowledge and Future Perspectives of Buttock Augmentation: A Bibliometric Analysis from 1999 to 2021.

BACKGROUND: The number of patients undergoing buttock augmentation surgery has increased rapidly with time, changes in people's aesthetic perceptions, and the increased concern for their shape. The number of publications regarding buttock augmentation has also continued to increase. However, no bibliometric analysis concerning buttock augmentation has been published. This study aimed to provide a qualitative and quantitative evaluation of buttock augmentation-related publications using bibliometric analysis and information on research hotspots and trends in this field. METHODS: The buttock augmentation-related publications published between 1999 and 2021 were extracted from the Web of Science Core Collection (WOSCC) database for analysis. The data were analysed and presented using VOSviewer and Microsoft Excel. RESULTS: There were 492 articles in the (WOSCC) database, including 442 (89.84%) original research articles, with the number of publications increasing each year. The USA (208 publications, 42.28%) is the leading contributor in this field and has a high academic reputation. The most productive and co-cited journal on this subject is "Plastic and Reconstructive Surgery" (66 publications, 13.41%, 2200 citations). Cardenas-Camarena (9 publications, 1.83%, 158 citations) was the most published and co-cited author. Research hotspots include the following three topics: experience and technology of buttock augmentation, autologous fat buttock augmentation and its safety, and buttock aesthetics study. There will be more publications in the future, and research trends will focus on silicone implants, safety, satisfaction, and autologous fat grafting. CONCLUSION: Buttock augmentation research is rapidly evolving, and this study provides a perspective view of buttock augmentation research in Plastic and Reconstructive Surgery. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Buccal Fat Pad Transplantation for Correction of Asian Upper Eyelid Depression: A Clinical Study.

OBJECTIVES: To investigate the effect of buccal fat pad transplantation in front of the aponeurosis to correct Asian upper eyelid depression. METHODS: Eighty-five individuals who were treated with buccal fat pad transplantation were recruited for this study. The upper eyelid depression data were collected before and after treatment, and the aesthetic outcomes were assessed using the Global Aesthetic Improvement Scale (GAIS) and the Likert scale. RESULTS: All patients obtained natural-looking eyelids, and the sunken contour deformity improved. The mean preoperative sunken depth was 6.7±1.0 mm (4-12 mm), and the mean sunken depth at the last follow-up was 4.2±0.9 mm (2-6 mm) (P <0.05). The visual analogue scale score was 2.12±1.75 (1-4) in the immediate postoperative period. The GAIS scores were satisfactory (very much improved, 89.4%; much improved, 7.1%; and improved, 3.5%). According to the Likert scale scores, all patients were satisfied with the clinical outcomes (excellent, 87.1%; very good, 9.4%; and good, 3.5%). A 'fair' or 'poor' result was not reported by any patient. CONCLUSION: Buccal fat pad transplantation corrects upper eyelid depression in a simple, safe, and effective manner and can efficiently fill the depressed portion and restore a beautiful double eyelid. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Identification of novel Aß-LilrB2 inhibitors as potential therapeutic agents for Alzheimer's disease.

LilrB2 is an Aß receptor with high affinity, which not only contributes to memory deficits but also mediates the loss of synaptic plasticity. Thus, Aß-LilrB2 interaction inhibitors (ALIs) might be a potential therapeutic strategy for Alzheimer's disease. In this study, an ELISA-based interaction assay was established as a novel approach to identify ALIs and was used to screen 110 compounds from a compound library. Among the 110 compounds, four compounds presented IC50 values lower than the positive control flusipirilene. The two phenyl-1,3,5-triazine derivatives (compound 103 and 104) displayed inhibitory activities with the IC50 of 0.23 µM and 0.05 µM respectively. The neuroprotection activities of the hit compounds were evaluated in SH-SY5Y cell line. Compound 104 presented good safety and neuroprotective effects against Aß. Further study of its effect on the downstream pathway of Aß indicated that compound 104 was able to reverse the Aß induced cofilin dephosphorylation, tau hyperphosphorylation and neurite outgrowth inhibition. The docking study showed that fluspirilene and compound 104 were favorably positioned into the Ben 3 and 4 binding pockets via their aromatic ring, which was similar to that reported for Aß. Based on these facts, compound 104 can be identified as a potential ALI which might be of therapeutic importance for AD treatment.

Exploring the role of potassium ferrate and straw fiber in enhancing the strength of cement-based solidified municipal sludge.

The effect of potassium ferrate (PF) and straw fiber (SF) on the strength of cement-based solidified municipal sludge, including the influence of reducing the organic matter in the sludge on the efficiency of the hydration of the cement, was studied. Single-factor tests, orthogonal tests, and linear weighted optimization methods were used to obtain suitable ratios to meet practical requirements, and then SEM and XRD analyses were used to explore the solidification mechanism. The results showed that PF and SF had significant influence on the strength, with SF having the greatest influence and the strength increasing with the amount of both admixtures, and cement had no significant influence on the strength. After linear weighting optimization, the ideal dosage was found to be 20% cement, 20% PF, and 5% SF, which produced a solidified sludge that had an strength of 126.87 kPa, far higher than the 50 kPa required to qualify for disposal in landfills. Analysis of the mineral content and microstructure showed that PF and SF could promote cement hydration and produce more hydration products, and the density of the optimized sample was much higher than that of the raw sludge and a sludge sample mixed with 20% cement alone.

Postmodulation of the Metal-Organic Framework Precursor toward the Vacancy-Rich CuxO Transducer for Sensitivity Boost: Synthesis, Catalysis, and H2O2 Sensing.

Metal-organic frameworks (MOFs) act as versatile coordinators for the subsequent synthesis of high-performance catalysts by providing dispersed metal-ion distribution, initial coordination condition, dopant atom ratios, and so on. In this work, a crystalline MOF trans-[Cu(NO3)2(Him)4] was synthesized as the novel precursor of a redox-alternating CuxO electrochemical catalyst. Through simple temperature modulation, the gradual transformation toward a highly active nanocomposite was characterized to ascertain the signal enhancing mechanism in H2O2 reduction. Owing to the proprietary structure of the transducer material and its ensuing high activity, a proof-of-principle sensor was able to provide an amplified sensitivity of 2330 µA mM-1 cm-2. The facile one-pot preparation and intrinsic nonenzymatic nature also suggests its wide potentials in medical settings.

Rapid fabrication of precise high-throughput filters from membrane protein nanosheets.

Biological membranes are ideal for separations as they provide high permeability while maintaining high solute selectivity due to the presence of specialized membrane protein (MP) channels. However, successful integration of MPs into manufactured membranes has remained a significant challenge. Here, we demonstrate a two-hour organic solvent method to develop 2D crystals and nanosheets of highly packed pore-forming MPs in block copolymers (BCPs). We then integrate these hybrid materials into scalable MP-BCP biomimetic membranes. These MP-BCP nanosheet membranes maintain the molecular selectivity of the three types of ß-barrel MP channels used, with pore sizes of 0.8 nm, 1.3 nm, and 1.5 nm. These biomimetic membranes demonstrate water permeability that is 20-1,000 times greater than that of commercial membranes and 1.5-45 times greater than that of the latest research membranes with comparable molecular exclusion ratings. This approach could provide high performance alternatives in the challenging sub-nanometre to few-nanometre size range.

Nitrated and parent PAHs in the surface water of Lake Taihu, China: Occurrence, distribution, source, and human health risk assessment.

Nitrated polycyclic aromatic hydrocarbons (NPAHs) have toxic potentials that are higher than those of their corresponding parent polycyclic aromatic hydrocarbons (PAHs) and thus have received increasing attention in recent years. In this study, the occurrence, distribution, source, and human health risk assessment of 15 NPAHs and 16 PAHs were investigated in the surface water from 20 sampling sites of Lake Taihu during the dry, normal, and flood seasons of 2018. The ΣPAH concentrations ranged from 255 to 7298 ng/L and the ΣNPAH concentrations ranged from not-detected (ND) to 212 ng/L. Among the target analytes, 2-nitrofluorene (2-nFlu) was the predominant NPAH, with a detection frequency ranging from 85% to 90% and a maximum concentration of 56.2 ng/L. The three-ringed and four-ringed NPAHs and PAHs comprised the majority of the detected compounds. In terms of seasonal variation, the highest levels of the ΣNPAHs and ΣPAHs were in the dry season and flood season, respectively. Diagnostic ratio analysis indicated that the prime source of NPAHs was direct combustion, whereas in the case of PAHs the contribution was predominantly from a mixed pattern including pollution from unburned petroleum and petroleum combustion. The human health risk of NPAHs and PAHs was evaluated using a lifetime carcinogenic risk assessment model. The carcinogenic risk level of the targets ranged from 2.09 × 10-7 to 5.75 × 10-5 and some surface water samples posed a potential health risk.

Novel glucagon- and OXM-based peptides acting through glucagon and GLP-1 receptors with body weight reduction and anti-diabetic properties.

Oxyntomodulin (OXM) is an endogenous gastrointestinal hormone, which activates both the Glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR). However, OXM has shortcomings including poor GLP-1R agonism to control glycemia, short half-life and others. Inspired from the sequence relationship between OXM and glucagon, in this study, we introduced different C-terminus residues of GLP-1, exenatide and OXM to glucagon to get a series of hybrid peptides with enhanced GLP-1R activation. The formed glucagon-exenatide hybrid peptide shows higher GLP-1R activation properties than OXM. Then the peptides based on the glucagon-exenatide hybrid peptide were coupled with fatty acid side chains to prolong their half-lives. As a result, the most potent compound 16a could stimulate insulin secretion and maintain blood glucose in normal level for ~42.6 h in diabetic mice. 16a exhibited reduced HbA1c level in diabetic mice, lowered body weight significantly in obesity mice on chronic treatment assay. 16a, combined efficient GCGR/GLP-1R activity, is potential as novel treatment for obesity and diabetes. This finding provides new insights into balancing GLP-1/GCGR potency of glucagon-exenatide hybrid peptide and is helpful for discovery of novel anti-diabetic and bodyweight-reducing drugs.

Ultrathin ZnIn2 S4 Nanosheets Anchored on Ti3 C2 TX MXene for Photocatalytic H2 Evolution.

Photocatalysts derived from semiconductor heterojunctions that harvest solar energy and catalyze reactions still suffer from low solar-to-hydrogen conversion efficiency. Now, MXene (Ti3 C2 TX ) nanosheets (MNs) are used to support the in situ growth of ultrathin ZnIn2 S4 nanosheets (UZNs), producing sandwich-like hierarchical heterostructures (UZNs-MNs-UZNs) for efficient photocatalytic H2 evolution. Opportune lateral epitaxy of UZNs on the surface of MNs improves specific surface area, pore diameter, and hydrophilicity of the resulting materials, all of which could be beneficial to the photocatalytic activity. Owing to the Schottky junction and ultrathin 2D structures of UZNs and MNs, the heterostructures could effectively suppress photoexcited electron-hole recombination and boost photoexcited charge transfer and separation. The heterostructure photocatalyst exhibits improved photocatalytic H2 evolution performance (6.6 times higher than pristine ZnIn2 S4 ) and excellent stability.

Design, synthesis and biological evaluation of novel 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as potential BRD4 inhibitors.

Recently, diverse kinase inhibitors were reported having interaction with BRD4. It provided a strategy for developing a new structural framework for the next-generation BRD4-selective inhibitors. Starting from PLK1 kinase inhibitor BI-2536, we designed 18 compounds by modifying dihydropteridine core. Compound 23 showed potent BRD4 inhibitory activities with IC50 of 79 nM and no inhibitory activities for PLK1. Cell antiproliferation assay was performed and potent inhibitory activity against MV4;11 with IC50 of 1.53 µM. Cell apoptosis and western blotting indicated compound 23 induced apoptosis by down-regulating c-Myc. These novel selective BRD4 inhibitors provided new lead compounds for further drug development.

Novel lipid side chain modified exenatide analogs emerged prolonged glucoregulatory activity and potential body weight management properties.

Exenatide is known as the first marketed GLP-1 agonist for antidiabetic treatment, but it need twice injection a day because of its fast clearance. This work aims to prolong the half-life of exenatide by modified with novel lipid chain. Four optimized exenatide analogs named as Cys12-Exenatide (1-39)-NH2, Cys40-Exenatide (1-39)-NH2, Cys12-Tyr22-Gln24-Glu28-Arg35-Exenatide (1-39)-NH2 and Tyr22-Gln24-Glu28-Arg35-Cys40-Exenatide (1-39)-NH2 were selected and applied for conjugation. Then a series of evaluations including GLP-1R activation assay were conducted, conjugation C2 was selected for further investigation. Glucoregulatory and insulin secretion assay and hypoglycemic duration test were accessed and showed that C2 was capable of comparable insulinotropic activities and glucose-lowering abilities with those of liraglutide and exenatide. Cell protective effects in INS-1 cells confirmed that C2 had relatively protection effects. Meanwhile, once daily injection of C2 to STZ-induced diabetic mice achieved long-term beneficial effects on glucose tolerance, body weight and blood chemistry. Acute feeding studies were evaluated in DIO mice. These results suggested that C2 is a promising agent for further investigation of its potential to treat diabetes patients with obese.

Synthesis and evaluation of redox-sensitive gonadotropin-releasing hormone receptor-targeting peptide conjugates.

Lytic peptides have been demonstrated to exhibit obvious advantages in cancer therapy with binding ability toward tumor cells via electrostatic attractions, which are lack of active targeting and aggregation to tumor tissue. In the present study, five conjugated lytic peptides were redesigned and constructed to target gonadotropin releasing hormone receptors (GnRHr), meanwhile, the disulfide bridge was introduced to achieve redox sensitive delivery based on the experience from the preliminary work of lytic peptides P3 and P7. YX-1, was considered to be the most promising for in-depth study. YX-1 possessed high potency (IC50 = 3.16 ±â€¯0.3 µM), low hemolytic effect, and cell membrane permeability in human A2780 ovarian cancer cells. Moreover, YX-1 had prominent pro-apoptotic activity by activating the mitochondria-cytochrome c-caspase apoptotic pathway. The study yielded the conjugate YX-1 with superior properties for antineoplastic activity, which makes it a promising potential candidate for targeting cancer therapy.

Identification of highly potent and orally available free fatty acid receptor 1 agonists bearing isoxazole scaffold.

The free fatty acid receptor 1 (FFA1) is being considered to be a novel anti-diabetic target based on its role in amplifying insulin secretion. We have previously identified several series of FFA1 agonists with different heterocyclic scaffolds. Herein, we describe the structural exploration of other heterocyclic scaffolds directed by drug-like physicochemical properties. Further structure-based design and chiral resolution provided the most potent compound 11 (EC50 = 7.9 nM), which exhibited improved lipophilicity (LogD7.4: 1.93), ligand efficiency (LE = 0.32) and ligand lipophilicity efficiency (LLE = 6.2). Moreover, compound 11 revealed an even better pharmacokinetic property than that of TAK-875 in terms of plasma clearance, maximum concentration, and plasma exposure. Although robust agonistic activity and PK profiles for compound 11, the glucose-lowering effects in vivo is not ideal, and the exact reason for in vitro/in vivo difference was worthy for further exploration.

Novel fatty acid chain modified GLP-1 derivatives with prolonged in vivo glucose-lowering ability and balanced glucoregulatory activity.

Glucagon-like peptide-1 is a potent hypoglycemic hormone with beneficial properties for the treatment of diabetes. However, its half-life is short because the rapid metabolic degradation. This study aims to prolong the half-life of glucagon-like peptide-1 through conjugation with the fatty acid side chain which helps the conjugates to interact with the albumin. Firstly, we chose two optimized polypeptide chains which have tremendous hypoglycemic effect named Cys17-Gly8-GLP-1(7-36)-NH2 and Cys37-Gly8-GLP-1(7-37)-NH2, and various fatty acid chains were modified. All conjugates preserved relatively strong GLP-1R activation and I-6 behaved best in glucose-lowering ability. The prolonged antidiabetic effects of I-6 were further confirmed by hypoglycemic efficacy test in vivo. Meanwhile, once daily injection of I-6 to diabetic mice achieved long-term beneficial effects on glucose tolerance, body weight and blood chemistry. It is concluded that I-6 is a promising agent for further investigation of its potential to treat obese patients with diabetes.

Design, synthesis, and biological evaluation of deuterated phenylpropionic acid derivatives as potent and long-acting free fatty acid receptor 1 agonists.

The free fatty acid receptor 1 (FFA1) is a potential target due to its function in enhancement of glucose-stimulated insulin secretion. Takeda's compound 1 has robustly in vitro activity for FFA1, but it has been suffered from poor pharmacokinetic (PK) profiles because the phenylpropanoic acid is vulnerable to ß-oxidation. To identify orally available agonists, we tried to interdict the metabolically labile group by incorporating two deuterium atoms at the α-position of phenylpropionic acid. Interestingly, the differences of physicochemical properties between hydrogen and deuterium are quite small, but there are many differences in the structure-activity relationship between phenylpropionic acid series and present deuterated series. Further optimizations of deuterated series led to the discovery of compound 18, which exhibited a superior balance in terms of in vitro activity, lipophilicity, and solubility. Better still, compound 18 revealed a lower clearance (CL = 0.44 L/h/kg), higher maximum concentration (Cmax = 7584.27 µg/L), and longer half-life (T1/2 = 4.16 h), resulting in a >23-fold exposure than compound 1. In subsequent in vivo pharmacodynamic studies, compound 18 showed a robustly glucose-lowering effect in rodent without the risk of hypoglycemia.

Pro-apoptotic cationic host defense peptides rich in lysine or arginine to reverse drug resistance by disrupting tumor cell membrane.

Host defense peptides have been demonstrated to exhibit prominent advantages in cancer therapy with selective binding ability toward tumor cells via electrostatic attractions, which can overcome the limitations of traditional chemotherapy drugs, such as toxicity on non-malignant cells and the emergence of drug resistance. In this work, we redesigned and constructed a series of cationic peptides by inserting hydrophobic residues into hydrophilic surface or replacing lysine (K) with arginine (R), based on the experience from the preliminary work of host defense peptide B1. In-depth studies demonstrated that the engineered peptides exhibited more potent anti-cancer activity against various cancer cell lines and much lower toxicity to normal cells compared with B1. Further investigation revealed that compounds I-3 and I-7 could act on cancer cell membranes and subsequently alter the permeability, which facilitated obvious pro-apoptotic activity in paclitaxel-resistant cell line (MCF-7/Taxol). The result of mitochondrial membrane potential assay (ΔΨm) demonstrated that the peptides induced ΔΨm dissipation and mitochondrial depolarization. The caspase-3 cellular activity assay showed that the anti-cancer activity of peptides functioned via caspase-3-dependent apoptosis. The study yielded compound I-7 with superior properties for antineoplastic activity in comparison to B1, which makes it a promising potential candidate for cancer therapy.

Discovery of novel 2-substituted-4-(2-fluorophenoxy) pyridine derivatives possessing pyrazolone and triazole moieties as dual c-Met/VEGFR-2 receptor tyrosine kinase inhibitors.

In our efforts to develop novel dual c-Met/VEGFR-2 inhibitors as potential anticancer agents, a series of 2-substituted-4-(2-fluorophenoxy) pyridine derivatives bearing pyrazolone scaffold were designed and synthesized. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2, especially compound 9h, 12b and 12d. Based on the further enzyme assay in vitro, compound 12d was considered as the most promising one, the IC50 values of which were 0.11µM and 0.19µM for c-Met and VEGFR-2, respectively. Further molecular docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, indicating that 12d was a potential compound for cancer therapy deserving further study.

Reversal of P-glycoprotein-mediated multidrug resistance and pharmacokinetics study in rats by WYX-5.

Multidrug resistance (MDR) is one of the major obstacles confronted in cancer chemotherapy; this obstacle is mainly due to the overexpression of P-glycoprotein (P-gp). Co-administration of anticancer drugs and P-gp inhibitors is a promising approach to overcome MDR. WYX-5, a novel P-gp inhibitor, shows a notable reversal effect with low cytotoxicity in vitro. In this paper, the reversal mechanism and safety of the MDR modulator WYX-5 were explored in vitro, and evaluated for its pharmacokinetics and effects on adriamycin (ADM) metabolism in vivo. The results suggest that WYX-5 is a potent P-gp inhibitor with EC50 in nanomole range (EC50 = 204.3 ± 20.2 nmol·L-1), relative safety (therapeutic index = 446.4), which performs as a substrate of P-gp and retrains its function. Further, WYX-5 (5 mg·kg-1) had relatively ideal pharmacokinetic properties (T1/2 = 6.448 h, F = 96.05%) without interactions with ADM metabolism in vivo. In conclusion, WYX-5 may be a promising candidate for MDR cancer combined-chemotherapy research.

Design, synthesis and biological evaluation of LBM-A5 derivatives as potent P-glycoprotein-mediated multidrug resistance inhibitors.

A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors with triazol-N-phenethyl-tetrahydroisoquinoline or triazol-N-ethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 4 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity toward K562 cells (IC50>100µM). Compared with VRP, compound 4 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 4 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 4 could remarkably increase the intracellular accumulation of Adriamycin (ADM) in K562/A02 cells as well as inhibit rhodamine-123 (Rh123) efflux from the cells. These results suggested that compound 4 may represent a promising candidate for developing P-gp-mediated MDR inhibitors.