Metal-Folded Single-Chain Nanoparticle: Nanoclusters and Self-Assembled Reduction-Responsive Sub-5-nm Discrete Subdomains.

Easy access to discrete nanoclusters in metal-folded single-chain nanoparticles (metal-SCNPs) and independent ultrafine sudomains in the assemblies via coordination-driven self-assembly of hydrophilic copolymer containing 9% imidazole groups is reported herein. 1 H NMR, dynamic light scattering, and NMR diffusion-ordered spectroscopy results demonstrate self-assembly into metal-SCNPs (>70% imidazole-units folded) by neutralization in the presence of Cu(II) in water to pH 4.6. Further neutralization induces self-assembly of metal-SCNPs (pH 4.6-5.0) and shrinkage (pH 5.0-5.6), with concurrent restraining residual imidazole motifs and hydrophilic segment, which organized into constant nanoparticles over pH 5.6-7.5. Atomic force microscopy results evidence discrete 1.2 nm nanoclusters and sub-5-nm subdomains in metal-SCNP and assembled nanoparticle. Reduction of metal center using sodium ascorbate induces structural rearrangement to one order lower than the precursor. Enzyme mimic catalysis required media-tunable discrete ultrafine interiors in metal-SCNPs and assemblies have hence been achieved.

Integrating transcriptomics and biochemical analysis to understand the interactive mechanisms of the coexisting exposure of nanoplastics and erythromycin on Chlorella pyrenoidosa.

Nanoplastics and antibiotics frequently co-exist in water polluted by algal blooms, but little information is available about interaction between substances. Erythromycin, as a representative of antibiotics, has been frequently detected in aquatic environments. This investigation attempted to reveal the interaction mechanism of nanoplastics and erythromycin on Chlorella pyrenoidosa. Results demonstrated that the joint toxicity of erythromycin and nanoplastics was dynamic and depended on nanoplastics concentration. Antagonistic effects of 1/2 or 1 EC50 erythromycin and nanoplastic concentration (10 mg/L) on the growth of C. pyrenoidosa was observed. The joint toxicity of 1/2 or 1 EC50 erythromycin and nanoplastic concentration (50 mg/L) was initially synergistic during 24-48 h and then turned to antagonistic during 72-96 h. Consequently, antagonistic effect was the endpoint for joint toxicity. Integration of transcriptomics and physiological biochemical analysis indicated that the co-existence of nanoplastics and erythromycin affected the signal transduction and molecular transport of algal cell membrane, induced intracellular oxidative stress, and hindered photosynthetic efficiency. Overall, this study provided a theoretical basis for evaluating the interactive mechanisms of nanoplastics and antibiotics.

Application of mesenchymal stem/stromal cells in periodontal regeneration: Opportunities and challenges.

Guided tissue regeneration (GTR) has been widely used in the periodontal treatment of intrabony and furcation defects for nearly four decades. The treatment outcomes have shown effectiveness in reducing pocket depth, improving attachment gain and bone filling in periodontal tissue. Although applying GTR could reconstruct the periodontal tissue, the surgical indications are relatively narrow, and some complications and race ethic problems bring new challenges. Therefore, it is challenging to achieve a consensus concerning the clinical benefits of GTR. With the appearance of stem cell-based regenerative medicine, mesenchymal stem/stromal cells (MSCs) have been considered a promising cell resource for periodontal regeneration. In this review, we highlight preclinical and clinical periodontal regeneration using MSCs derived from distinct origins, including non-odontogenic and odontogenic tissues and induced pluripotent stem cells, and discuss the transplantation procedures, therapeutic mechanisms, and concerns to evaluate the effectiveness of MSCs.

Micro/nano-plastics and microalgae in aquatic environment: Influence factor, interaction, and molecular mechanisms.

Micro/nano-plastics, as emerging persistent pollutant, are frequently detected in aquatic environments together with other environmental pollutants. Microalgae are the major primary producers and bear an important responsibility for maintaining the balance of aquatic ecosystems. Numerous studies have been conducted on the influence of micro/nano-plastics on the growth, photosynthesis, oxidative stress, gene expression and metabolites of microalgae in laboratory studies. However, it is difficult to comprehensively evaluate the toxic effects of micro/nano-plastics on microalgae due to different experimental designs. Moreover, there is a lack of effective analysis of the aforementioned multi-omics data and reports on shared biological patterns. Therefore, the purpose of this review is to compare the acute, chronic, pulsed, and combined effect of micro/nano-plastics on microalgae and explore hidden rules in the molecular mechanisms of the interaction between them. Results showed that the effect of micro/nano-plastics on microalgae was related to exposure mode, exposure duration, exposure size, concentration, and type of micro/nano-plastics. Meanwhile, the phenomenon of poisoning and detoxification between micro/nano-plastics and microalgae was found. The inhibitory mechanism of micro/nano-plastics on algal growth was due to the micro/nano-plastics affected the photosynthesis, oxidative phosphorylation, and ribosome pathways of algal cells. This brought the disruption of the functions of chloroplasts, mitochondria, and ribosome, as well as impacted on energy metabolism and translation pathways, eventually leading to impairment of cell function. Besides, algae resisted this inhibitory effect by regulating the alanine, aspartate, and glutamate metabolism and purine metabolism pathways, thereby increasing the chlorophyll synthesis, inhibiting the increase of reactive oxygen species, delaying the process of lipid peroxidation, balancing the osmotic pressure of cell membrane.

N-Nitrosodimethylamine formation in metformin hydrochloride sustained-release tablets: Effects of metformin and hypromellose used in drug product formulation.

In recent years, nitrosamines have been discovered in some types of drug products that becomes a current regulatory hotspot, and have attracted a lot attention from both regulatory authorities and industry. This manuscript provided an industry perspective on the nitrosamines research. A liquid chromatography coupled with tandem mass spectrometry（LC-MS/MS）method was developed and applied for the quantification of N-nitrosodimethylamine (NDMA) in metformin hydrochloride sustained-release tablets (MET). The key factors resulting in the NDMA formation in MET were identified through forced degradation and drug-excipient studies, which included high temperature, dimethylamine, strong alkali and oxidation conditions, peroxide and alkaline components contained in the formulation as well as the nitrite and nitrate impurities that might be presented in certain excipients. Further, API particle size and water content of the drug product would also affect the growth rate of NDMA. Therefore, the following mitigation strategies to reduce the risk of nitrosamines in the finished drug product are proposed in this manuscript: 1) avoid the use of excipients containing nitrite, nitrate and peroxide impurities; 2) avoid high temperature and strong alkaline environment in the production and storage condition; 3) maintain an appropriate water content level in the formulation. Based on the above principles, it was recommended to add antioxidant or incorporate excipient such as Na2CO3 to modify the formulation pH to weak basic environment in the formulation of MET, which can could effectively prevent formation of NDMA in the stability process.

Dental applications of induced pluripotent stem cells and their derivatives.

Periodontal tissue regeneration is the ideal tactic for treating periodontitis. Tooth regeneration is the potential strategy to restore the lost teeth. With infinite self-renewal, broad differentiation potential, and less ethical issues than embryonic stem cells, induced pluripotent stem cells (iPSCs) are promising cell resource for periodontal and tooth regeneration. This review summarized the optimized technologies of generating iPSC lines and application of iPSC derivatives, which reduce the risk of tumorigenicity. Given that iPSCs may have epigenetic memory from the donor tissue and tend to differentiate into lineages along with the donor cells, iPSCs derived from dental tissues may benefit for personalized dental application. Neural crest cells (NCCs) and mesenchymal stem or stomal cells (MSCs) are lineage-specific progenitor cells derived from iPSCs and can differentiate into multilineage cell types. This review introduced the updated technologies of inducing iPSC-derived NCCs and iPSC-derived MSCs and their application in periodontal and tooth regeneration. Given the complexity of periodontal tissues and teeth, it is crucial to elucidate the integrated mechanisms of all constitutive cells and the spatio-temporal interactions among them to generate structural periodontal tissues and functional teeth. Thus, more sophisticated studies in vitro and in vivo and even preclinical investigations need to be conducted.

Mechanism of the inhibition and detoxification effects of the interaction between nanoplastics and microalgae Chlorella pyrenoidosa.

Most previous studies have focused on the toxicity of microplastics on aquatic organisms. However, research on nanoplastics is still limited and poses significant threat to aquatic organisms than microplastics. Therefore, this study investigated the effects of nanoplastics (80 nm) on the microalgae Chlorella pyrenoidosa. One unanticipated finding was that inhibition and detoxification effects existed in the interaction between nanoplastics and C. pyrenoidosa. Nanoplastics contributed the maximum inhibition rates of 27.73%, 29.64%, and 11.76% on algal growth, chlorophyll a, and Fv/Fm, respectively, which were much higher than those of microplastics. However, the inhibitory effect of nanoplastics gradually decreased with prolonged exposure time after reaching a maximum. The transcriptomic analysis explained that the inhibition effect of nanoplastics was due to the blockage of the gene expression of aminoacyl tRNA synthetase and the synthesis of related enzymes and proteins at low concentrations (10 mg·L-1). Moreover, it affected DNA damage repair and hindered photosynthesis at high concentrations (50 mg·L-1). The detoxification phenomenon is attributed to the promotion of cell proliferation, the acceleration of the degradation of damaged proteins and organs, and the regulation of intracellular osmotic pressure in algae. The results of this study provide an understanding of the mechanism underlying the interaction between nanoplastics and microalgae.

Multiple congenital granular cell tumours of the maxilla and mandible: a rare case report and review of the literature.

Congenital granular cell tumour (CGCT) is a benign lesion that predominantly arises from the alveolar ridges of neonates, especially the maxilla. However, it's only 10 percent of multiple lesions in all reported cases, in which simultaneously mandibular and maxillary involvements are more extremely rare. For treatments of multiple CGCTs, few standard procedures were reported. In addition to surgical excision, which refers to a preferred method, conservative treatment is an available choice. Here, a case of multiple CGCTs using different therapeutic strategies was reported because of its rarity and innovation. A five-day-old female newborn presented two congenital masses attached to the right mandibular and maxillary alveolar ridge. The size of the mandibular lesion causing difficulty in feeding was 3 cm in diameter and 0.5 cm in the maxilla. Based on different manifestations, surgical excision and conservative treatment were adopted respectively. The mandibular mass was excised while that in the maxilla underwent spontaneous regression. Satisfactory results were achieved for this patient. There was no evidence of recurrence after a 6-month follow-up. Microscopic examination and immunohistochemistry analysis confirmed the diagnosis and differential diagnosis of CGCT and even proposed the possibility of histogenesis from neural crest. Moreover, we reviewed the literature and summarized the characteristics to provide new ideas for the treatment of multiple CGCTs.

Comparison of the effects of continuous and accumulative exposure to nanoplastics on microalga Chlorella pyrenoidosa during chronic toxicity.

Most previous studies have focused on the continuous exposure of aquatic organisms to nanoplastics. However, persistent pollutants in natural aquatic surroundings are a threat, and their concentrations are continuously increasing. The discussion and research into the effects of accumulative exposure to these materials are limited. Therefore, this study aimed to compare the effects of continuous and accumulative exposure to polystyrene (PS) nanoplastics (80 nm) on Chlorella pyrenoidosa during chronic toxicity. The results indicated that under conditions of continuous exposure, this alga exhibited self-recovery to defend against the negative effects of PS nanoplastics during 15-21 days of exposure (the 21-d inhibitory rate was 1.41%). However, one unanticipated finding was that during the same period of accumulative exposure, nanoplastics retained a substantial and stable inhibitory effect on the algal growth (the 21-d inhibitory rate was 6.79% in accumulative exposure for twice), indicating the invalid self-recovery of algae. The results of scanning electron microscopy demonstrated that on day 21, the degree of damage to the algal cells under accumulative exposure was more severe than that under continuous exposure. Hence, nanoplastics exerted an irreversibly negative effect on aquatic organisms depending on the pattern, frequency, concentration, and duration of exposure. This project evaluated the practical significance of nanoplastics in aquatic ecosystems.

Transcriptome analysis of the toxic mechanism of nanoplastics on growth, photosynthesis and oxidative stress of microalga Chlorella pyrenoidosa during chronic exposure.

The toxicity of nanoplastics to aquatic organisms has been widely studied in terms of biochemical indicators. However, there is little discussion about the underlying toxic mechanism of nanoplastics on microalgae. Therefore, the chronic effect of polystyrene (PS) nanoplastics (80 nm) on Chlorella pyrenoidosa was investigated, in terms of responses at the biochemical and molecular/omic level. It was surprising that both inhibitory and promoting effects of nanoplastcis on C. pyrenoidosa were found during chronic exposure. Before 13 days, the maximum growth inhibition rate was 7.55% during 10 mg/L PS nanoplastics treatment at 9 d. However, the inhibitory effect gradually weakened with the prolongation of exposure time. Interestingly, algal growth was promoted for 1-5 mg/L nanoplastics during 15-21 d exposure. Transcriptomic analysis explained that the inhibitory effect of nanoplastics could be attributed to suppressed gene expression of aminoacyl-tRNA synthetase that resulted in the reduced synthesis of related enzymes. The promotion phenomenon may be due to that C. pyrenoidosa defended against nanoplastics stress by promoting cell proliferation, regulating intracellular osmotic pressure, and accelerating the degradation of damaged proteins and organs. This study is conducive to provide theoretical basis for evaluating the actual hazard of nanoplastics to aquatic organisms.

Sequentially Triggered Delivery System of Black Phosphorus Quantum Dots with Surface Charge-Switching Ability for Precise Tumor Radiosensitization.

Cancer radiotherapy suffers from drawbacks such as radiation resistance of hypoxic cells, excessive radiation that causes damage of adjacent healthy tissues, and concomitant side effects. Hence, radiotherapy sensitizers with improved radiotherapeutic performance and requiring a relatively small radiation dose are highly desirable. In this study, a nanosystem based on poly(lactic- co-glycolic acid) (PLGA) and ultrasmall black phosphorus quantum dots (BPQDs) is designed and prepared to accomplish precise tumor radiosensitization. The PLGA nanoparticles act as carriers to package the BPQDs to avoid off-target release and rapid degradation during blood circulation. The nanosystem that targets the polypeptide peptide motif Arg-Gly-Asp-Gys actively accumulates in tumor tissues. The 2,3-dimethylmaleic anhydride shell decomposes in an acidic microenvironment, and the nanoparticles become positively charged, thereby favoring cellular uptake. Furthermore, glutathione (GSH) deoxidizes the disulfide bond of cystamine and sequentially triggers release of BPQDs, rendering tumor cells sensitive to radiotherapy. The treatment utilizing the PLGA-SS-D@BPQDs nanosystem and X-ray induces cell apoptosis triggered by overproduction of reactive oxygen species. In the in vivo study, the nanosystem shows excellent radiotherapy sensitization efficiency but negligible histological damage of the major organs. This study provides insights into the design and fabrication of surface-charge-switching and pH-responsive nanosystems as potent radiosensitizers to achieve excellent radiotherapy sensitization efficacy and negligible toxic side effects.

[Garrè's osteomyelitis with bilateral mandible: a case report].

Garrès osteomyelitis is a specific type of chronic osteomyelitis that most commonly occurs in young patients, secondary to dental infection, and affects the unilateral side of the mandible. Bilateral mandibular Garrè's osteomyelitis is rare. In this article, a case of Garrè's osteomyelitis with bilateral mandible is reported. Its etiology, clinical pathologic features, diagnosis, differential diagnosis, and treatment methods are discussed by reviewing relevant literature.

Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma.

BACKGROUND: Oral cancer is 1 of the 6 most common human cancers, with an annual incidence of >300,000 cases worldwide. This study aimed to investigate potential biomarkers in human saliva to facilitate the early diagnosis of oral squamous cell carcinoma (OSCC). METHODS: Unstimulated whole saliva obtained from OSCC patients (n=30) and apparently healthy individuals (n=30) were assayed with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) in hydrophilic interaction chromatography mode. The data were analyzed using a nonparametric Mann-Whitney U test, logistic regression, and the receiver operating characteristic (ROC) to evaluate the predictive power of each of 4 biomarkers, or combinations of biomarkers, for OSCC screening. RESULTS: Four potential salivary biomarkers demonstrated significant differences (P<0.05) in concentrations between patients at stages I-II and the healthy individuals. The area under the curve (AUC) values in control vs OSCC I-II mode based on choline, betaine, pipecolinic acid, and l-carnitine were 0.926, 0.759, 0.994, and 0.708, respectively. Four salivary biomarkers in combination yielded satisfactory accuracy (0.997), sensitivity (100%), and specificity (96.7%) in distinguishing OSCC I-II from control. CONCLUSIONS: Salivary metabolite biomarkers for the early diagnosis of OSCC were verified in this study. The proposed approach is expected to be applied as a potential technique of preclinical screening of OSCC.

The early diagnosis and monitoring of squamous cell carcinoma via saliva metabolomics.

Early diagnosis of oral squamous cell carcinoma (OSCC) is an attractive strategy to increase survival rate of patient. An integrated separation approach of reversed phase liquid chromatography and hydrophilic interaction chromatography combining with time of flight mass spectrometer has been firstly developed for performing global saliva metabonomics analysis for early diagnosis of OSCC. This approach was designed to overcome the limitations of a single chromatographic method due to different polarity of endogenous metabolites. As a result, 14 potential salivary metabolites were identified. Eight biomarkers up-regulated in OSCC patients are compared with control and six down-regulated groups. Receiver operating characteristic analysis was exploited to evaluate the diagnostic power of the candidate biomarkers, and related metabolic pathways have also been studied. Five salivary biomarkers (propionylcholine, N-Acetyl-L-phenylalanine, sphinganine, phytosphingosine, and S-carboxymethyl-L-cysteine) in combination yielded satisfactory accuracy (AUC = 0.997), sensitivity (100%), and specificity (96.7%) in distinguishing early stage of OSCC from the control. In this study, a comprehensive saliva metabonomics analysis for identifying potential biomarkers to early diagnose OSCC is successfully demonstrated, which has the advantages of non-invasive, simple, reliable, and low-cost. These novel metabolic biomarkers have obvious clinical utility that will help to diagnose OSCC at its early stage.

Measurement of salivary metabolite biomarkers for early monitoring of oral cancer with ultra performance liquid chromatography-mass spectrometry.

This study aimed to set-up an ultra performance liquid chromatography-electrospray ionization-mass spectrometry (UPLC-ESI-MS) method for the determination of salivary L-phenylalanine and L-leucine for early diagnosis of oral squamous cell carcinoma (OSCC). In addition, the diagnostic accuracy for both biomarkers was established by using receiver operating characteristic (ROC) analysis. Mean recoveries of l-phenylalanine and L-leucine ranged from 88.9 to 108.6% were obtained. Intra- and inter-day precision for both amino acids was less than 7%, with acceptable accuracy. Linear regression coefficients of both biomarkers were greater than 0.99. The diagnostic accuracy for both biomarkers was established by analyzing 60 samples from apparently healthy individuals and 30 samples from OSCC patients. Both potential biomarkers demonstrated significant differences in concentrations in distinguishing OSCC from control (P<0.05). As a single biomarker, L-leucine might have better predictive power in OSCC with T1-2 (early stage of OSCC including stage I and II), and L-phenylalanine might be used for screening and diagnosis of OSCC with T3-4 (advanced stage of OSCC including stage III and IV). The combination of L-phenylalanine and L-leucine will improve the sensitivity (92.3%) and specificity (91.7%) for early diagnosis of OSCC. The possibility of salivary metabolite biomarkers for OSCC diagnosis is successfully demonstrated in this study. This developed method shows advantages with non-invasive, simple, reliable, and also provides lower detection limits and excellent precision and accuracy. These non-invasive salivary biomarkers may lead to a simple clinical tool for the early diagnosis of OSCC.

Fluorescence ratiometric pH sensor prepared from covalently immobilized porphyrin and benzothioxanthene.

A fluorescence ratiometric sensor for pH determination is described in this paper. The sensor incorporated the pH-sensitive dye meso-5,10,15,20-tetra-(4-allyloxyphenyl)porphyrin (TAPP) as an indicator and a pH-insensitive dye N-(2-methacryloxyethyl)benzo[k,l]thioxanthene-3,4-dicarboximide (MBTD), a benzothioxanthene derivative, as a reference for fluorescence ratiometric measurement. To prevent leakage of the dyes, both were photocopolymerized with acrylamide, hydroxyethyl methacrylate, and triethylene glycol dimethacrylate on the silanized glass surface. The reproducibility and response time of the prepared sensor were sufficient. Most common coexisting inorganic ions and organic compounds did not interfere with pH sensing. In the acidic pH range from 1.5 to 5.0 the fluorescence intensity ratio of the two dyes varied linearly as a function of pH. The sensing membrane was found to have a lifetime of at least one month. The sensor was applied to the analysis of waste water and artificial samples.