Drug-loaded nanoparticles conjugated with genetically engineered bacteria for cancer therapy.

Drug-loaded nanoparticles have been widely used as synergists in high-intensity focused ultrasound (HIFU) tumor ablation therapy. However, these synergists have certain limitations, such as poor tumor targeting and low accumulation at the tumor site, that restrict the therapeutic efficacy of HIFU. In this study, we utilized drug-loaded nanoparticles conjugated with genetically engineered bacteria which can selectively colonize the hypoxic areas of tumor to facilitate HIFU ablation. Genetically modified Escherichia coli carrying gas vesicles (GVs-E. coli), which were gas-filled protein nanostructures, had a negatively charged surface and could specifically target into the tumor. In contrast, paclitaxel (PTX) and perfluorohexane (PFH) co-loaded cationic lipid nanoparticles (PTX-CLs) had a positively charged surface, hence, GVs-E. coli was used as a vehicle by conjugating with PTX-CLs via electrostatic adsorption and subsequently attracting more PTX-CLs to the tumor site. To improve the therapeutic efficiency of HIFU, the GVs in GVs-E. coli and PFH encapsulated in PTX-CLs could act as cavitation nuclei to enhance the HIFU cavitation effect, while PTX entrapped in PTX-CLs was released at the tumor site under HIFU irradiation, enhancing the therapeutic efficacy of HIFU and chemo-synergistic therapy. This novel combination strategy has great potential for cancer treatment.

Clinical efficacy of melatonin as adjunctive therapy to non-surgical treatment of periodontitis: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to evaluate the effect of adjunctive melatonin supplementation on clinical outcomes after non-surgical periodontal treatment. METHODS: PubMed, Embase, and Web of Science databases were systematically searched for randomised controlled trials (RCTs) of melatonin adjuvant therapy for periodontitis from inception until May 2021. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and registered on The International Prospective Register of Systematic Reviews (PROSPERO) (CRD42021250630). The risk of bias of included studies was assessed according to the Cochrane Handbook for Systematic Reviews of Interventions. The pooled effect estimates were calculated by a random-effects model, and results were expressed as weighted mean differences (WMD). RESULTS: Seven RCTs comprising 412 participants were included in the meta-analysis. The pooled results showed that adjuvant use of melatonin for non-surgical periodontal treatment significantly improved the probing depth (PD) [WMD = - 1.18, 95% CI (- 1.75, - 0.62) I2 = 85.7%], clinical attachment loss (CAL) [WMD = - 1.16, 95% CI (- 1.60, - 0.72) I2 = 76.7%] and gingival index (WMD = - 0.29, 95%CI [- 0.48, - 0.11], I2 = 63.6%) compared with non-surgical treatment alone. In addition, subgroup analysis showed that higher doses of melatonin (3-10 mg) significantly improved PD [WMD = - 1.32, 95%CI (- 2.31, - 0.15) I2 = 93%] and CAL [WMD = - 1.30, 95%CI (- 1.80, - 0.81) I2 = 73.7%] compared with lower doses of melatonin (< 3 mg). CONCLUSIONS: We found that adjunctive melatonin supplementation can significantly improve the periodontal status after non-surgical treatment, suggesting that melatonin may be a new adjuvant therapy for periodontitis when non-surgical periodontal treatment alone cannot achieve the desired improvement.

[Research progress on liposome and nanomicelle targeted drug delivery system across blood-brain barrier].

The blood-brain barrier(BBB), a protective barrier between brain tissues and brain capillaries, can prevent drugs from entering the brain tissues to exert the effect, which greatly increases the difficulty in treating brain diseases. The drug delivery system across the BBB can allow efficient drug delivery across the BBB by virtue of carriers and formulations, thereby enhancing the therapeutic effect of drugs on brain tissue diseases. Liposomes and micelles have been extensively studied with advances in the targeted therapy across the BBB for the brain due to their unique structures and drug delivery advantages. This study summarized the research status of liposome and micelle drug delivery systems across the BBB based on the literature in recent years and analyzed their application advantages and mechanism in terms of trans-BBB capability, targeting, and safety. Moreover, the problems and possible countermeasures in the research on trans-BBB liposomes and micelles were discussed according to the current clinical translation, which may provide refe-rences and ideas for the development of trans-BBB targeted nano-drugs.

Basic Reproduction Number of Enterovirus 71 and Coxsackievirus A16 and A6: Evidence From Outbreaks of Hand, Foot, and Mouth Disease in China Between 2011 and 2018.

BACKGROUND: Enterovirus 71 (EV-A71), coxsackievirus A16 (CV-A16), and coxsackievirus A6 (CV-A6) are common serotypes causing hand, foot, and mouth disease (HFMD). Analyses on the basic reproduction number (R0) of common pathogens causing HFMD are limited and there are no related studies using field data from outbreaks in mainland China. METHODS: We estimated the pathogen-specific basic reproduction number based on laboratory-confirmed HFMD outbreaks (clusters of ≥10 HFMD cases) reported to the national surveillance system between 2011 and 2018. The reproduction numbers were calculated using a mathematical model and the cumulative cases during the initial growth periods. RESULTS: This study included 539 outbreaks, of which 198 were caused by EV-A71, 316 by CV-A16, and 25 by CV-A6. All 10 417 cases involved were children. Assuming the outbreaks occurred in closed systems and the incubation period is 5 days, the median (interquartile range [IQR]) R0 estimates of EV-A71, CV-A16, and CV-A6 were 5.06 (2.81, 10.20), 4.84 (3.00, 9.00), and 5.94 (3.27, 10.00). After adjusting for seroprevalences, the R0 (IQR) estimates for EV-A71, CV-A16 (optimistic and conservative scenarios), and CV-A6 were 12.60 (7.35, 25.40), 9.29 (6.01, 19.20), 15.50 (9.77, 30.40), and 25.80 (14.20, 43.50), respectively. We did not observe changes in the R0 of EV-A71 after vaccine licensure (P = .67). CONCLUSIONS: HFMD is highly transmissible when caused by the 3 most common serotypes. In mainland China, it primarily affects young children. Although a vaccine became available in 2016, we have not yet observed any related changes in the disease dynamics.

Polyethylenimine (PEI)-modified poly (lactic-co-glycolic) acid (PLGA) nanoparticles conjugated with tumor-homing bacteria facilitate high intensity focused ultrasound-mediated tumor ablation.

The acoustic propagation characteristic of ultrasound determines that the energy of ultrasound beam will decrease with the increase of its propagation depth in the body. Similarly, the energy of High Intensity Focused Ultrasound (HIFU) will be attenuated with the increase of HIFU propagation depth in the body. Ensuring sufficient ultrasound energy deposition in the HIFU ablation region for tumor ablation is usually achieved by increasing the ultrasound irradiation power or prolonging the ultrasound ablation time. However, these two methods may damage the normal tissue adjacent to the HIFU ablation region. Herein, we constructed the nanoparticles conjugated with tumor-homing bacteria as the biological tumor-homing synergist to facilitate HIFU-mediated tumor ablation avoiding the potential safety risk. In our strategy, Bifidobacterium bifidum (B.bifidum) was selectively colonized in the hypoxic region of solid tumors after been injected into 4T1 breast cancer bearing-BALB/c mice via the tail vein due to its anaerobic growth characteristic. The amount of B. bifidum with negative surface potential in the hypoxic region of solid tumors was increased by its anaerobic proliferation. Polyethylenimine (PEI) -modified Poly (lactic-co-glycolic) acid nanoparticles loaded sodium bicarbonate (PEI-PLGA-NaHCO3-NPs) with positive surface potential injected into 4T1 breast cancer bearing-BALB/c mice via the tail vein displayed the tumor-homing ability by the electrostatic adsorption with B. bifidum colonized solid tumors. PEI-PLGA-NaHCO3-NPs could release NaHCO3 to produce carbon dioxide (CO2) as cavitation nuclei inside the acidic microenvironment of solid tumors. When HIFU irradiated solid tumors contained with more cavitation nuclei, the ultrasound energy deposition at the tumor region was increased to destroy the tumors more effectively. Meanwhile, the improved efficiency of HIFU-mediated tumor ablation reduced the dependence of the tumor ablation on the ultrasound energy dose, which improved the safety of HIFU-mediated tumor ablation to the non-targeted ablation tissue. This tumor-homing synergist shows the potential application value on the HIFU-mediated tumor ablation in the clinical.

Quinic Acid-Conjugated Nanoparticles Enhance Drug Delivery to Solid Tumors via Interactions with Endothelial Selectins.

Current nanoparticle (NP) drug carriers mostly depend on the enhanced permeability and retention (EPR) effect for selective drug delivery to solid tumors. However, in the absence of a persistent EPR effect, the peritumoral endothelium can function as an access barrier to tumors and negatively affect the effectiveness of NPs. In recognition of the peritumoral endothelium as a potential barrier in drug delivery to tumors, poly(lactic-co-glycolic acid) (PLGA) NPs are modified with a quinic acid (QA) derivative, synthetic mimic of selectin ligands. QA-decorated NPs (QA-NP) interact with human umbilical vein endothelial cells expressing E-/P-selectins and induce transient increase in endothelial permeability to translocate across the layer. QA-NP reach selectin-upregulated tumors, achieving greater tumor accumulation and paclitaxel (PTX) delivery than polyethylene glycol-decorated NPs (PEG-NP). PTX-loaded QA-NP show greater anticancer efficacy than Taxol or PTX-loaded PEG-NP at the equivalent PTX dose in different animal models and dosing regimens. Repeated dosing of PTX-loaded QA-NP for two weeks results in complete tumor remission in 40-60% of MDA-MB-231 tumor-bearing mice, while those receiving control treatments succumb to death. QA-NP can exploit the interaction with selectin-expressing peritumoral endothelium and deliver anticancer drugs to tumors to a greater extent than the level currently possible with the EPR effect.

Construction and biocompatibility of a thin type I/II collagen composite scaffold.

Articular cartilage injury is a common type of damage observed in clinical practice. A matrix-induced autologous chondrocyte implant was developed to repair articular cartilage as an advancement on the autologous chondrocyte implant procedure. Here, we establish a thin double layer of collagen as a novel and effective bioscaffold for the regeneration of cartilaginous lesions. We created a collagen membrane with double layers using a cover slip, a cover slip, and the collagen was then freeze-dried under vacuum. Carbodiimide as a crosslinking agent was used to obtain a relatively stable collagen construction. The thickness of the knee joint cartilage from grown rabbits was measured from a frozen section. Both type I and type II collagens were characterized using Sodium dodecylsulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and ultraviolet absorption peaks. The aperture size of the scaffold was observed using a scanning electron microscope (SEM). The degradation of the scaffolds in vitro was tested through digestion using collagenase solution. The mechanical capacity of the scaffolds was assessed under dynamic compression. The influence of the scaffold on chondrocyte proliferation was assessed using the methyl thiazolyl tetrazolium (MTT) colourimetric assay and scanning electron microscopy. The frozen sections of the rabbit femoral condyle showed that the thickness of the weight-bearing area of the articular cartilage was less than 1 mm. The results of the SDS-PAGE and ultraviolet absorption peaks of the collagens were in agreement with the standard photographs in the references. SEM showed that the aperture size of the cross-linked scaffold was 82.14 ± 15.70 µm. The in vitro degradation studies indicated that Carbodiimide cross-linking can effectively enhance the biostability of the scaffolds. The Carbodiimide cross-linking protocol resulted in a mean value for the samples that ranged from 8.72 to 15.95 MPa for the compressive strength. The results of the MTT demonstrated that the scaffold had promoted chondrocyte proliferation and SEM observations showed that the scaffold was a good adhesive and growth material for chondrocytes. Thin type I/II collagen composite scaffold can meet the demands of cartilage tissue engineering and have good biocompatibility.

Polydopamine-functionalized nanographene oxide: a versatile nanocarrier for chemotherapy and photothermal therapy.

For releasing both drug and heat to selected sites, a combination of chemotherapy and photothermal therapy in one system is a more effective way to destroy cancer cells than monotherapy. Graphene oxide (GO) with high drug-loading efficiency and near-infrared (NIR) absorbance has great potential in drug delivery and photothermal therapy, but it is difficult to load drugs with high solubility. Herein, we develop a versatile drug delivery nanoplatform based on GO for integrated chemotherapy and photothermal therapy by a facile method of simultaneous reduction and surface functionalization of GO with poly(dopamine) (PDA). Due to the excellent adhesion of PDA, both low and high solubility drugs can be encapsulated in the PDA-functionalized GO nanocomposite (rGO-PDA). The fabricated nanocomposite exhibits good biocompatibility, excellent photothermal performance, high drug loading capacity, an outstanding sustained release property, and efficient endocytosis. Moreover, NIR laser irradiation facilitates the release of loaded drugs from rGO-PDA. These features make the rGO-PDA nanocomposite achieve excellent in vivo synergistic antitumor therapeutic efficacy.

Thermoresponsive Delivery of Paclitaxel by ß-Cyclodextrin-Based Poly(N-isopropylacrylamide) Star Polymer via Inclusion Complexation.

Paclitaxel (PTX), a hydrophobic anticancer drug, is facing several clinical limitations such as low bioavailability and drug resistance. To solve the problems, a well-defined ß-cyclodextrin-poly(N-isopropylacrylamide) star polymer was synthesized and used as a nanocarrier to improve the water solubility and aim to thermoresponsive delivery of PTX to cancer cells. The star polymer was able to form supramolecular self-assembled inclusion complex with PTX via host-guest interaction at room temperature, which is below the low critical solution temperature (LCST) of the star polymer, significantly improving the solubilization of PTX. At body temperature (above LCST), the phase transition of poly(N-isopropylacrylamide) segments induced the formation of nanoparticles, which greatly enhanced the cellular uptake of the polymer-drug complex, resulting in efficient thermoresponsive delivery of PTX. In particular, the polymer-drug complex exhibited better antitumor effects than the commercial formulation of PTX in overcoming the multi-drug resistance in AT3B-1 cells.

Relationships between actual and desired workplace characteristics and job satisfaction for community health workers in China: a cross-sectional study.

BACKGROUND: Community health workers are the main providers of community health services in China and have been important in the process of health system reform that has been in place since 2009. Therefore, it is critical that healthcare managers and policy decision makers motivate current staff and improve their job satisfaction. This study examined workplace characteristics and their contribution to job satisfaction in community health workers in Heilongjiang Province, China. METHODS: A cross-sectional survey of 448 community health workers, from three cities in Heilongjiang province, was conducted between October 1, 2012 and December 31, 2012. Multistage sampling procedures were used to measure socioeconomic and demographic status, job satisfaction, and both actual and desired workplace characteristics. Factor analysis was conducted to determine the main factors contributing to workplace characteristics, and multiple linear regression analysis was performed to assess the key determinants of job satisfaction. RESULTS: Eight groups of factors were identified as the most important workplace characteristics. These comprised system and policy; fringe benefits; work itself; work relationships; professional development; recognition; work environment; and remuneration. In all cases, all desired workplace characteristics were higher than the associated actual workplace characteristics. The main determinants of job satisfaction were occupation, years worked in health service institution, and five subscales representing the gap between desired and actual workplace characteristics, which were system and policy; fringe benefits; working relationship; professional development; and remuneration. CONCLUSIONS: These findings suggested that managers wishing to enhance job satisfaction should assess workplace characteristics comprehensively and design mechanisms that reduce the gap between actual and desired workplace characteristics.

Design of health information management model for elderly care using an advanced higher-order hybrid clustering algorithm from the perspective of sports and medicine integration.

In the context of integrating sports and medicine domains, the urgent resolution of elderly health supervision requires effective data clustering algorithms. This paper introduces a novel higher-order hybrid clustering algorithm that combines density values and the particle swarm optimization (PSO) algorithm. Initially, the traditional PSO algorithm is enhanced by integrating the Global Evolution Dynamic Model (GEDM) into the Distribution Estimation Algorithm (EDA), constructing a weighted covariance matrix-based GEDM. This adapted PSO algorithm dynamically selects between the Global Evolution Dynamic Model and the standard PSO algorithm to update population information, significantly enhancing convergence speed while mitigating the risk of local optima entrapment. Subsequently, the higher-order hybrid clustering algorithm is formulated based on the density value and the refined PSO algorithm. The PSO clustering algorithm is adopted in the initial clustering phase, culminating in class clusters after a finite number of iterations. These clusters then undergo the application of the density peak search algorithm to identify candidate centroids. The final centroids are determined through a fusion of the initial class clusters and the identified candidate centroids. Results showcase remarkable improvements: achieving 99.13%, 82.22%, and 99.22% for F-measure, recall, and precision on dataset S1, and 75.22%, 64.0%, and 64.4% on dataset CMC. Notably, the proposed algorithm yields a 75.22%, 64.4%, and 64.6% rate on dataset S, significantly surpassing the comparative schemes' performance. Moreover, employing the text vector representation of the LDA topic vector model underscores the efficacy of the higher-order hybrid clustering algorithm in efficiently clustering text information. This innovative approach facilitates swift and accurate clustering of elderly health data from the perspective of sports and medicine integration. It enables the identification of patterns and regularities within the data, facilitating the formulation of personalized health management strategies and addressing latent health concerns among the elderly population.

Double synergic chitosan-coated poly (lactic-co-glycolic) acid nanospheres loaded with nucleic acids as an intranasally administered vaccine delivery system to control the infection of foot-and-mouth disease virus.

BACKGROUND & AIMS: The spread of foot-and-mouth disease virus (FMDV) through aerosol droplets among cloven-hoofed ungulates in close contact is a major obstacle for successful animal husbandry. Therefore, the development of suitable mucosal vaccines, especially nasal vaccines, to block the virus at the initial site of infection is crucial. PATIENTS AND METHODS: Here, we constructed eukaryotic expression plasmids containing the T and B-cell epitopes (pTB) of FMDV in tandem with the molecular mucosal adjuvant Fms-like tyrosine kinase receptor 3 ligand (Flt3 ligand, FL) (pTB-FL). Then, the constructed plasmid was electrostatically attached to mannose-modified chitosan-coated poly(lactic-co-glycolic) acid (PLGA) nanospheres (MCS-PLGA-NPs) to obtain an active nasal vaccine targeting the mannose-receptor on the surface of antigen-presenting cells (APCs). RESULTS: The MCS-PLGA-NPs loaded with pTB-FL not only induced a local mucosal immune response, but also induced a systemic immune response in mice. More importantly, the nasal vaccine afforded an 80% protection rate against a highly virulent FMDV strain (AF72) when it was subcutaneously injected into the soles of the feet of guinea pigs. CONCLUSIONS: The nasal vaccine prepared in this study can effectively induce a cross-protective immune response against the challenge with FMDV of same serotype in animals and is promising as a potential FMDV vaccine.

Tailoring biomaterials for monitoring and evoking tertiary lymphoid structures.

Despite the remarkable clinical success of immune checkpoint blockade (ICB) in the treatment of cancer, the response rate to ICB therapy remains suboptimal. Recent studies have strongly demonstrated that intratumoral tertiary lymphoid structures (TLSs) are associated with a good prognosis and a successful clinical response to immunotherapy. However, there is still a shortage of efficient and wieldy approaches to image and induce intratumoral TLSs in vivo. Biomaterials have made great strides in overcoming the deficiencies of conventional diagnosis and therapies for cancer, and antitumor therapy has also benefited from biomaterial-based drug delivery models. In this review, we summarize the reported methods for TLS imaging and induction based on biomaterials and provide potential strategies that can further enhance the effectiveness of imaging and stimulating intratumoral TLSs to predict and promote the response rates of ICB therapies for patients. STATEMENT OF SIGNIFICANCE: In this review, we focused on the promising of biomaterials for imaging and induction of TLSs. We reviewed the applications of biomaterials in molecular imaging and immunotherapy, identified the biomaterials that may be suitable for TLS imaging and induction, and provided outlooks for further research. Accurate imaging and effective induction of TLSs are of great significance for understanding the mechanism and clinical application. We highlighted the need for multidisciplinary coordination and cooperation in this field, and proposed the possible future direction of noninvasive imaging and artificial induction of TLSs based on biomaterials. We believe that it can facilitate collaboration and galvanize a broader effort.

Structure-based virtual screening and fragment replacement to design novel inhibitors of Coxsackievirus A16 (CVA16).

Numerous studies have shown that hand, foot and mouth disease (HFMD) pathogen Coxsackievirus A16 (CVA16) can also cause severe neurological complications and even death. Currently, there is no effective drugs and vaccines for CVA16. Therefore, developing a drug against CVA16 has become critical. In this study, we conducted two strategies-virtual screening (VS) and fragment replacement to obtain better candidates than the known drug GPP3. Through VS, 37 candidate drugs were screened (exhibiting a lower binding energy than GPP3). After toxicity evaluations, we obtained five candidates, analysed their binding modes and found that four candidates could enter the binding pocket of the GPP3. In another strategy, we analysed the four positions in GPP3 structures by the FragRep webserver and obtained a large number of candidates after replacing different functional groups, we obtained eight candidates (that target the four positions above) with the combined binding score and synthetic accessibility evaluations. AMDock software was uniformly utilized to perform molecular docking evaluation of the candidates with binding activity superior to that of GPP3. Finally, the selected top three molecules (Lapatinib, B001 and C001) and its interaction with CAV16 were validated by molecular dynamics (MD) simulation. The results indicated that all three molecules retain inside the pocket of CAV16 receptor throughout the simulation process, and he binding energy calculated from the MD simulation trajectories also support the strong affinity of the top three molecules towards the CVA16. These results will provide new ideas and technical guidance for designing and applying CVA16 therapeutics.Communicated by Ramaswamy H. Sarma.

HIGHLIGHTSThe dual strategies of computer-aided VS and fragment replacement were first used to obtain candidate small molecules with stronger binding activity than the hand-foot-mouth COV16 viral drug molecule GPP3.The binding patterns of GPP3 and several candidate molecules obtained by VS were analyzed, and a new and interesting binding pattern was found ­ binding at the entrance of the pocket instead of inside the pocket.The Top3 candidate molecules were verified by MD simulations.Through molecular docking, a comprehensive comparative analysis was conducted between all candidate molecules obtained in this study and anti-hand-foot-mouth virus drugs used in clinic.

Improved pH stability, heat stability, and functionality of phycocyanin after PEGylation.

Phycocyanin (PC), a spirulina-derived protein-chromophore complex, suffers from poor techno-functional properties and is highly susceptible to aggregation and color changes upon heating and pH fluctuations. We tackled these issues by modifying PC via PEGylation. Electrophoresis and Fourier transform infrared spectroscopy proved successful conjugation of methoxy PEG (mPEG) chains on PC after PEGylation. Circular dichroism indicated highly ordered folding states adopted by PEGylated PC, which we attributed to the mPEG chains on the protein surface that sterically stabilized the protein structure. Consequently, the mPEG-PC conjugates exhibited high blue color intensity and improved thermodynamic stability. Further, benefit from an electrostatic shielding effect of mPEG chains, surface charges of PEGylated PC were neutralized over pH 2-9 and the blue hue of PC was stabilized against pH variations. Additionally, the flexible and hydrophilic mPEG polymers on the PC surface promoted protein-protein and protein-water interactions. PEGylated PC thus gained increased protein solubility, techno-functionality (emulsifying, foaming, and gelling performance), and antioxidant activities, when compared to unmodified PC. Heat-induced gels formed by mPEG-PC conjugates exhibited increased stiffness, higher water retention, and weak gel-type rheological properties. After PEGylation, the improved functional properties, bioactivity, and color stability against heat and pH fluctuations will facilitate food and pharmaceutical applications of PC.

Inhibition of Biofilm Formation and Virulence Factors of Cariogenic Oral Pathogen Streptococcus mutans by Shikimic Acid.

Streptococcus mutans is known as an important oral pathogen causing dental caries, a widespread oral infectious disease. S. mutans synthesize exopolysaccharide (EPS) using glucosyltransferases (Gtfs), resulting in biofilm formation on the tooth surface. Bacterial cells in the biofilms become strongly resistant to a harsh environment, such as antibiotics and host defense mechanisms, making biofilm-based infections difficult to eliminate. Discovering novel antibiofilm agents, especially from natural products, helps to develop effective strategies against this kind of diseases. The present study investigated the inhibitory effect of shikimic acid (SA), one abundant compound derived from Illicium verum extract, on the biofilm formation of S. mutans. We found SA can reduce the EPS synthesized by this oral pathogen and modulate the transcription of biofilm formation related genes, leading to fewer bacterial cells in its biofilm. SA also interacted with cell membrane and membrane proteins, causing damage to bacterial cells. Ex vivo testing of biofilm formation on bovine teeth showed SA strongly decreased the number of S. mutans cells and the number of EPS accumulated on dental enamel surfaces. Moreover, SA exhibits almost no toxicity to human oral cells evaluated by in vitro biocompatibility assay. In conclusion, shikimic acid exhibits remarkable antibiofilm activity against S. mutans and has the potential to be further developed as a novel anticaries agent. IMPORTANCE Natural products are an important and cost-effective source for screening antimicrobial agents. Here, we identified one compound, shikimic acid, from Illicium verum extract, exhibiting antimicrobial activity against S. mutans proliferation. It also inhibits biofilm formation of this bacteria through decreasing Gtf expression and EPS synthesis. Furthermore, this compound exhibits no significant cytotoxicity at its MIC against S. mutans, providing evidence for its clinical application.

Caffeic Acid Phenethyl Ester (CAPE) Inhibits Cross-Kingdom Biofilm Formation of Streptococcus mutans and Candida albicans.

Streptococcus mutans and Candida albicans exhibit strong cariogenicity through cross-kingdom biofilm formation during the pathogenesis of dental caries. Caffeic acid phenethyl ester (CAPE), a natural compound, has potential antimicrobial effects on each species individually, but there are no reports of its effect on this dual-species biofilm. This study aimed to explore the effects of CAPE on cariogenic biofilm formation by S. mutans and C. albicans and the related mechanisms. The effect of CAPE on planktonic cell growth was investigated, and crystal violet staining, the anthrone-sulfuric acid assay and confocal laser scanning microscopy were used to evaluate biofilm formation. The structures of the formed biofilms were observed using scanning electron microscopy. To explain the antimicrobial effect of CAPE, quantitative real-time PCR (qRT-PCR) was applied to monitor the relative expression levels of cariogenic genes. Finally, the biocompatibility of CAPE in human oral keratinocytes (HOKs) was evaluated using the CCK-8 assay. The results showed that CAPE suppressed the growth, biofilm formation and extracellular polysaccharides (EPS) synthesis of C. albicans and S. mutans in the coculture system of the two species. The expression of the gtf gene was also suppressed by CAPE. The efficacy of CAPE was concentration dependent, and the compound exhibited acceptable biocompatibility. Our research lays the foundation for further study of the application of the natural compound CAPE as a potential antimicrobial agent to control dental caries-associated cross-kingdom biofilms. IMPORTANCE Severe dental caries is a multimicrobial infectious disease that is strongly induced by the cross-kingdom biofilm formed by S. mutans and C. albicans. This study aimed to investigate the potential of caffeic acid phenethyl ester (CAPE) as a natural product in the prevention of severe caries. This study clarified the inhibitory effect of CAPE on cariogenic biofilm formation and the control of cariogenic genes. It deepens our understanding of the synergistic cariogenic effect of S. mutans and C. albicans and provides a new perspective for the prevention and control of dental caries with CAPE. These findings may contribute to the development of CAPE as a promising antimicrobial agent targeting this caries-related cross-kingdom biofilm.

Auto-fluorescence of cellulose paper with spatial solid phrase dispersion-induced fluorescence enhancement behavior for three heavy metal ions detection.

Auto-fluorescence of cellulose paper is often considered as an interfering fluorescence, which directly impedes the cellulose paper as a substrate material. This paper creatively explored the composition and properties of auto-fluorescence, and lignosulfonate was primarily speculated as the main source of auto-fluorescence. Surprisingly, its spatial solid phrase dispersion-induced fluorescence enhancement behavior was found. Then, cellulose paper was modified with Mn-doped ZnS quantum dots, and the prepared ratiometric fluorescent paper chip has good performances on morphology, stability, and fluorescence properties. Besides, the paper chip exhibited different fluorescence responses to three heavy metal ions in water sample. The limit of detection for Cd2+, Hg2+ and Pb2+ reached 1.61 nM, 0.01 nM, and 0.02 nM, respectively. In short, the molecular simulation results theoretically proved that heavy metal ions owned substitution affinity with lignosulfonate. Ultimately, this study was the first attempt to utilize paper-based auto-fluorescence, which could better accelerate the development of paper-based chips.

Disease burden in patients with severe hand, foot, and mouth disease in Jiangsu Province: a cross-sectional study.

This study aimed to estimate the disease burden and health-related quality of life (HRQOL) among patients with severe hand, foot, and mouth disease (HFMD) in Jiangsu Province, China. We analyzed the surveillance data of HFMD cases in Jiangsu Province from 2009 to 2020. Moreover, a cross-sectional study was conducted in Nanjing and Suzhou, China, between January 2017 and May 2018. Patients with severe HFMD and their parents were recruited from selected hospitals. Questionnaires and hospital management systems were used to collect data on direct economic burden. The HRQOL of children was assessed using the TNO-AZL Preschool Quality of Life (TAPQOL) scale. A total of 1,348,737 confirmed cases of HFMD were reported to the NNDRS in Jiangsu province during 2009-2020. Of these, 9,622 were severe cases, with 62 (.64%) of these being fatal. From January 2017 to May 2018, data was collected from 362 severe HFMD cases using a structured questionnaire. The median per capita direct economic burden was RMB 16142.88, and was associated with the region and length of hospital stay (P < .05). The direct economic burden for all cases of severe HFMD in Jiangsu province between 2017 and 2018 was approximately RMB 16.64 million. Finally, the median (IQR) of the TAPQOL scale for children with severe HFMD was 69.23 (56.20, 82.27). Severe HFMD infection is a relatively large burden for individuals, and the burden of EV-A71 infection was seen to be even greater for the population. Prevention of severe HFMD should strengthen hygiene habits and targeted measures for EV-A71 vaccination.

Platelet rich plasma enhanced neuro-regeneration of human dental pulp stem cells in vitro and in rat spinal cord.

Background: Human dental pulp stem cells (hDPSCs) exhibit excellent differentiation potential and are capable of differentiating into several different cellular phenotypes, including neurons. Platelet-rich plasma (PRP) contains numerous growth factors that can stimulate stem cell differentiation. In this study, we investigated the potential stimulatory effects of PRP on neurogenic differentiation and anti-apoptosis of hDPSCs in injured spinal cords. Methods: The unipotential differentiation capacity of hDPSCs was analyzed by cell surface antigen identification and cell cycle analysis. A spinal cord injury rat model composed of 40 Sprague-Dawley (SD) rats was used to facilitate an in vivo study. Rats were divided into four groups: a double-treatment group (receiving both neurogenic-induced hDPSCs and PRP), two single-treatment groups (receiving neurogenic-induced hDPSCs or PRP) and a sham group (receiving normal saline). The Basso, Beattie, Bresnahan Locomotor Rating Scale was subsequently used to evaluate the motor function of the spinal cord. Cell viability and differentiation of hDPSCs in the damaged spinal cords were analyzed and apoptosis of neural cells was evaluated using the terminal uridine nucleotide end labeling (TUNEL) assay. Results: Growth pattern, cell surface marker and cell cycle analyses revealed that hDPSCs have a high degree of multi-directional differentiation potential and can be induced into neurons in vitro. In the rat spinal cord injury model, double-treatment with hDPSC/PRP or single treatment with hDPSCs or PRP significantly improved motor function compared with the sham group (P<0.05). Apoptosis of neural cells was observed to be significantly higher in the sham group compared to any of the treatment groups. Double-treatment with hDPSCs and PRP resulted in the lowest apoptotic rate among the groups analyzed. Conclusions: hDPSCs exhibit differentiation potential and are capable of transforming into neural cells both in vitro and in vivo. Significantly increased inhibition of neuronal apoptosis and improved motor function recovery of the spinal cord were observed following double-treatment with hDPSCs and PRP compared with the single-treatment groups.