Oral microbiota and gastrointestinal microbiota, the two largest microbiomes in the human body, are closely correlated and frequently interact through the oral-gut axis. Recent research has focused on the roles of these microbiomes in human health and diseases. Under normal conditions, probiotics and commensal bacteria can positively impact health. However, altered physiological states may induce dysbiosis, increasing the risk of pathogen colonization. Studies suggest that oral and gastrointestinal pathogens contribute not only to localized diseases at their respective colonized sites but also to the progression of systemic diseases. However, the mechanisms by which bacteria at these local sites are involved in systemic diseases remain elusive. In response to this gap, the focus has shifted to bacterial extracellular vesicles (BEVs), which act as mediators of communication between the microbiota and the host. Numerous studies have reported the targeted delivery of bacterial pathogenic substances from the oral cavity and the gastrointestinal tract to distant organs via BEVs. These pathogenic components subsequently elicit specific cellular responses in target organs, thereby mediating the progression of systemic diseases. This review aims to elucidate the extensive microbial communication via the oral-gut axis, summarize the types and biogenesis mechanisms of BEVs, and highlight the translocation pathways of oral and gastrointestinal BEVs in vivo, as well as the impacts of pathogens-derived BEVs on systemic diseases.
Background: Oral squamous cell carcinoma (OSCC) is one of the most prevalent kinds of cancers. Therefore, there is a pressing need to create a new risk scoring model to personalize the prognosis of OSCC patients and screen for patient-specific therapeutic agents and molecular targets. Methods: Firstly, A series of bioinformatics was performed to construct a novel ferroptosis-related prognostic model; Further, drug sensitivity analysis was used to screen for specific therapeutic agents for OSCC; Single-cell analysis was employed to investigate the enrichment of FRDEGs (ferroptosis-related differentially expressed genes) in the OSCC microenvironment; Finally, various experiments were conducted to screen and validate molecular therapeutic targets for OSCC. Results: In this study, we constructed a novel 10-FRDEGs risk scoring model. Base on the risk scoring model, we founded three potential chemotherapeutic agents for OSCC: 5Z)-7-Oxozeaenol, AT-7519, KIN001-266; In addition, FRDEGs were enriched in the epithelial cells of OSCC. Finally, we found that CA9 and CAV1 could regulate OSCC proliferation, migration and ferroptosis in vitro. Conclusion: A novel 10-FRDEGs risk scoring model can predict the prognosis of patients with OSCC.Further,5Z)-7-Oxozeaenol, AT-7519, KIN001-266 are potential chemotherapeutic agents for OSCC.Moreover, we identified CA9ãCAV1 as potential molecular target for the treatment of OSCC.Our findings provide new directions for prognostic assessment and precise treatment of oral cell squamous carcinoma.
Purpose: This study aimed to analyze the expression and prognosis of SRY-box transcription factor 11 (SOX11) in neuroblastoma (NB), as well as the biological function and potential regulatory mechanism of SOX11 in NB. Methods: Public RNA sequencing was used to detect the expression level of SOX11. The Kaplan-Meier curve and hazard ratios (HR) were used to determine the prognostic value of SOX11 in NB. Functional analyses were performed using CCK8, wound healing assay, and transwell invasion assay. Finally, the potential target genes of SOX11 were predicted by Harmonizonme (Ma'ayan Laboratory) and Cistrome Data Browser (Cistrome Project) database to explore the potential molecular mechanism of SOX11 in NB. Results: Compared with normal adrenal tissue, the expression of SOX11 in NB tissue was significantly upregulated. The Kaplan-Meier curve showed that high expression of SOX11 was associated with poor prognosis in children with NB (HR, 1.719; P = 0.049). SOX11 knockdown suppressed the migration capacity of SK-N-SH cells but did not affect proliferation and invasion capacity. Enhancer of zeste homolog 2 (EZH2) may be a potential downstream target gene for the transcription factor SOX11 to play a role in NB. Conclusion: The transcription factor SOX11 was significantly upregulated in NB. SOX11 knockdown suppressed the migration capacity of NB cell SK-N-SH. SOX11 may promote the progression of NB by targeting EZH2.
INTRODUCTION: Aging of hematopoietic stem cells (HSCs) has emerged as an important challenge to human health. Recent advances have raised the prospect of rejuvenating aging HSCs via specific medical interventions, including pharmacological treatments. Nonetheless, efforts to develop such drugs are still in infancy until now. OBJECTIVES: We aimed to screen the prospective agents that can rejuvenate aging HSCs and explore the potential mechanisms. METHODS: We screened a set of natural anti-aging compounds through oral administration to sub-lethally irradiated mice, and identified 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (TSG) as a potent rejuvenating agent for aging HSCs. Then naturally aged mice were used for the follow-up assessment to determine the HSC rejuvenating potential of TSG. Finally, based on the transcriptome and DNA methylation analysis, we validated the role of the AMP-activated protein kinase (AMPK)-ten-eleven-translocation 2 (Tet2) axis (the AMPK-Tet2 axis) as the underlying mechanisms of TSG for ameliorating HSCs aging. RESULTS: TSG treatment not only significantly increased the absolute number of common lymphoid progenitors (CLPs) along with B lymphocytes, but also boosted the HSCs/CLPs repopulation potential of aging mice. Further elaborated mechanism research demonstrated that TSG supplementation restored the stemness of aging HSCs, as well as promoted an epigenetic reprograming that was associated with an improved regenerative capacity and an increased rate of lymphopoiesis. Such effects were diminished when the mice were co-treated with an AMPK inhibitor, or when it was performed in Tet2 knockout mice as well as senescent cells assay. CONCLUSION: TSG is effective in rejuvenating aging HSCs by modulating the AMPK- Tet2 axis and thus represents a potential candidate for developing effective HSC rejuvenating therapies.
Mid-infrared (MIR) Si-based optoelectronics has wide potential applications, and its design requires simultaneous consideration of device performance optimization and the feasibility of heterogeneous integration. The emerging interest in all-dielectric metasurfaces for optoelectronic applications stems from their exceptional ability to manipulate light. In this Letter, we present our research on an InSb all-dielectric metasurface designed to achieve ultrahigh absorptivity within the 5-5.5â µm wavelength range. By integrating an InSb nanodisk array layer on a Si platform using wafer bonding and heteroepitaxial growth, we demonstrate three kinds of metasurface with high absorptivity of 98.36%, 99.28%, and 99.18%. The enhanced absorption is mainly contributed by the Kerker effect and the anapole state and the peak, with the added flexibility of tuning both the peak and bandwidth of absorption by altering the metasurface parameters. Our findings provide an alternative scheme to develop high-performance detectors and absorbers for MIR silicon photonics.
Healing of fractures or bone defects is significantly hindered by overactivated osteoclasts and inhibited osteogenesis in patients with abnormal bone metabolism. Current clinical approaches using titanium alloys or stainless steel provide mechanical support but have no biological effects on bone regeneration. Therefore, designing and fabricating degradable metal materials with sufficient mechanical strength and bidirectional regulation of both osteoblasts and osteoclasts is a substantial challenge. Here, this study first reported an adaptive biodegradable Zn-0.8 Mg alloy with bidirectional regulation of bone homeostasis, which promotes osteogenic differentiation by activating the Pi3k/Akt pathway and inhibits osteoclast differentiation by inhibiting the GRB2/ERK pathway. The anti-osteolytic ability of the Zn-0.8 Mg alloy was verified in a mouse calvarial osteolysis model and its suitability for internal fracture fixation with high-strength screws was confirmed in the rabbit femoral condyle fracture model. Furthermore, in an aged postmenopausal rat femoral condyle defect model, 3D printed Zn-0.8 Mg scaffolds promoted excellent bone regeneration through adaptive structures with good mechanical properties and bidirectionally regulated bone metabolism, enabling personalized bone defect repair. These findings demonstrate the substantial potential of the Zn-0.8 Mg alloy for treating fractures or bone defects in patients with aberrant bone metabolism.
BACKGROUND: Differentiation therapy, a highly regarded treatment method in tumor research, aims to induce tumor cells to differentiate back to normal cells, deviating from the malignant pathway and returning to a benign state. Its development relies on the continuous discovery of efficient and low-toxic differentiation inducers, including plant-derived active components that offer significant biological utilization and therapeutic potential. For this reason, the exploration of plant-derived inducers, particularly in their application in differentiation therapy, holds great promise in advancing cancer treatment strategies toward more effective and safer alternatives. PURPOSE: This paper aims to provide a valuable reference for researchers seeking to identify natural, efficient, and low-toxic differentiation inducers from plants and highlights a promising research direction for the application of differentiation therapy in malignant tumor treatment. METHODS: For the collection of pertinent information, an extensive search was conducted across diverse literature and electronic databases, including PubMed, ScienceDirect, Wiley, ACS, CNKI, Springer, Taylor & Francis, Web of Science, Google Scholar, and Baidu Scholar. This comprehensive approach aimed to retrieve and include all relevant literature from 1985 to 2023. Primary keywords such as "Natural medicinal plant," "Differentiation therapy," and "Differentiation inducer" were utilized, supplemented by secondary search terms including "Cancer," "Tumor," "Herbal medicine," "Induced differentiation," and "Cancer treatment." RESULTS: This study systematically evaluated the application of plant-derived inducers in tumor-induced differentiation therapy. Through extensive literature review, specific plant components with confirmed differentiation-inducing properties were identified. Furthermore, potential molecular mechanisms underlying this process were outlined, shedding light on the future development of differentiation therapy in cancer treatment. CONCLUSION: Plant-derived active components exhibit substantial biological utility and therapeutic potential. Delving deeper into the research on these components as differentiation inducers holds promise for the selection of novel cancer drugs and the unveiling of novel pathways for cancer treatment. These results emphasize the importance of continued exploration and in-depth research into natural, efficient, and low-toxic differentiation inducers from plants, which could significantly advance cancer treatment strategies. Moreover, the highlighted research direction underscores the relevance of differentiation therapy in the context of malignant tumor treatment, indicating its potential as a safer and more effective alternative in cancer therapy.
Groundwater contamination with arsenic and nitrate poses a pressing concern for the safety of local communities. Bioremediation, utilizing Fe(II)-oxidizing nitrate reducing bacteria, shows promise as a solution to this problem. However, the relatively weak environmental adaptability of a single bacterium hampers practical application. Therefore, this study explored the feasibility and characteristics of a mixed iron-dependent autotrophic denitrifying (IDAD) culture for effectively removing arsenic and nitrate from synthetic groundwater. The IDAD biosystem exhibited stable performace and arsenic resistance, even at a high As(III) concentration of 800 µg/L. Although the nitrogen removal efficiency of the IDAD biosystem decreased from 71.4% to 64.7% in this case, the arsenic concentration in the effluent remained below the standard (10 µg/L) set by WHO. The crystallinity of the lepidocrocite produced by the IDAD culture decreased with increasing arsenic concentration, but the relative abundance of the key iron-oxidizing bacteria norank_f_Gallionellaceae in the culture showed an opposite trend. Metagenomic analysis revealed that the IDAD culture possess arsenic detoxification pathways, including redox, methylation, and efflux of arsenic, which enable it to mitigate the adverse impact of arsenic stress. This study provides theoretical understanding and technical support for the remediation of arsenic and nitrate-contaminated groundwater using the IDAD culture.
The Crumbs protein (CRB) family plays a crucial role in maintaining the apical-basal polarity and integrity of embryonic epithelia. The family comprises different isoforms in different animals and possesses diverse structural, localization, and functional characteristics. Mutations in the human CRB1 or CRB2 gene may lead to a broad spectrum of retinal dystrophies. Various CRB-associated experimental models have recently provided mechanistic insights into human CRB-associated retinopathies. The knowledge obtained from these models corroborates the importance of CRB in retinal development and maintenance. Therefore, complete elucidation of these models can provide excellent therapeutic prospects for human CRB-associated retinopathies. In this review, we summarize the current animal models and human-derived models of different CRB family members and describe the main characteristics of their retinal phenotypes.
Membrane Proteins , Retinal Diseases , Humans , Animals , Membrane Proteins/genetics , Membrane Proteins/metabolism , Retinal Diseases/genetics , Retinal Diseases/pathology , Retinal Diseases/metabolism , Retina/metabolism , Retina/pathology , Eye Proteins/genetics , Eye Proteins/metabolism , Disease Models, Animal , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Mutation
Seawater-drowning-induced acute lung injury (SD-ALI) is a life-threatening disorder characterized by increased alveolar-capillary permeability, an excessive inflammatory response, and refractory hypoxemia. Perfluorocarbons (PFCs) are biocompatible compounds that are chemically and biologically inert and lack toxicity as oxygen carriers, which could reduce lung injury in vitro and in vivo. The aim of our study was to explore whether the vaporization of PFCs could reduce the severity of SD-ALI in canines and investigate the underlying mechanisms. Eighteen beagle dogs were randomly divided into three groups: the seawater drowning (SW), perfluorocarbon (PFC), and control groups. The dogs in the SW group were intratracheally administered seawater to establish the animal model. The dogs in the PFC group were treated with vaporized PFCs. Probe-based confocal laser endomicroscopy (pCLE) was performed at 3 h. The blood gas, volume air index (VAI), pathological changes, and wet-to-dry (W/D) lung tissue ratios were assessed. The expression of heme oxygenase-1 (HO-1), nuclear respiratory factor-1 (NRF1), and NOD-like receptor family pyrin domain containing-3 (NLRP3) inflammasomes was determined by means of quantitative real-time polymerase chain reaction (qRT-PCR) and immunological histological chemistry. The SW group showed higher lung injury scores and W/D ratios, and lower VAI compared to the control group, and treatment with PFCs could reverse the change of lung injury score, W/D ratio and VAI. PFCs deactivated NLRP3 inflammasomes and reduced the release of caspase-1, interleukin-1ß (IL-1ß), and interleukin-18 (IL-18) by enhancing the expression of HO-1 and NRF1. Our results suggest that the vaporization of PFCs could attenuate SD-ALI by deactivating NLRP3 inflammasomes via the HO-1/NRF1 pathway.
Acute Lung Injury , Fluorocarbons , Inflammasomes , NLR Family, Pyrin Domain-Containing 3 Protein , Animals , Fluorocarbons/pharmacology , Dogs , Acute Lung Injury/metabolism , Acute Lung Injury/drug therapy , Acute Lung Injury/pathology , Inflammasomes/metabolism , Inflammasomes/drug effects , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Seawater , Male , Drowning/metabolism , Disease Models, Animal , Lung/pathology , Lung/metabolism , Lung/drug effects
BACKGROUND: Neutrophils are traditionally viewed as first responders but have a short onset of action in response to traumatic brain injury (TBI). However, the heterogeneity, multifunctionality, and time-dependent modulation of brain damage and outcome mediated by neutrophils after TBI remain poorly understood. METHODS: Using the combined single-cell transcriptomics, metabolomics, and proteomics analysis from TBI patients and the TBI mouse model, we investigate a novel neutrophil phenotype and its associated effects on TBI outcome by neurological deficit scoring and behavioral tests. We also characterized the underlying mechanisms both in vitro and in vivo through molecular simulations, signaling detections, gene expression regulation assessments [including dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays], primary cultures or co-cultures of neutrophils and oligodendrocytes, intracellular iron, and lipid hydroperoxide concentration measurements, as well as forkhead box protein O1 (FOXO1) conditional knockout mice. RESULTS: We identified that high expression of the FOXO1 protein was induced in neutrophils after TBI both in TBI patients and the TBI mouse model. Infiltration of these FOXO1high neutrophils in the brain was detected not only in the acute phase but also in the chronic phase post-TBI, aggravating acute brain inflammatory damage and promoting late TBI-induced depression. In the acute stage, FOXO1 upregulated cytoplasmic Versican (VCAN) to interact with the apoptosis regulator B-cell lymphoma-2 (BCL-2)-associated X protein (BAX), suppressing the mitochondrial translocation of BAX, which mediated the antiapoptotic effect companied with enhancing interleukin-6 (IL-6) production of FOXO1high neutrophils. In the chronic stage, the "FOXO1-transferrin receptor (TFRC)" mechanism contributes to FOXO1high neutrophil ferroptosis, disturbing the iron homeostasis of oligodendrocytes and inducing a reduction in myelin basic protein, which contributes to the progression of late depression after TBI. CONCLUSIONS: FOXO1high neutrophils represent a novel neutrophil phenotype that emerges in response to acute and chronic TBI, which provides insight into the heterogeneity, reprogramming activity, and versatility of neutrophils in TBI.
Brain Injuries, Traumatic , Neutrophils , Animals , Humans , Mice , bcl-2-Associated X Protein/metabolism , Brain , Brain Injuries, Traumatic/complications , Depression , Forkhead Box Protein O1/metabolism , Iron
This research addressed the drawbacks of the conventional hybrid structure and processing technique by presenting a novel distributed fiber optic sensor based on a hybrid Michelson and Mach-Zehnder interferometer. The sensor can achieve blind spot free positioning and has a wide response frequency, additionally its structure is not complex. It can obtain two phase signals from each of the two interferometers by using a demodulation method that uses a 3 × 3 optical coupler. To determine the position of the disturbance, we computed cross-correlations on the two signals following basic mathematical techniques. Markov Transition Field was used to transform the phase signals-which had been filtered by a band pass filter-into two-dimensional images. Tagged photos built a dataset, which is then fed into a neural network to identify patterns. Experiments have shown that the frequency response capacity of the structure was verified, and it was able to achieve location within 0-30â km with location errors of ±85 m. In a six-category pattern recognition, the testing set accuracy was 98.74%.
Reconciling the dilemma between rapid degradation and overdose toxicity is challenging in biodegradable materials when shifting from bulk to porous materials. Here, we achieve significant bone ingrowth into Zn-based porous scaffolds with 90% porosity via osteoinmunomodulation. At microscale, an alloy incorporating 0.8 wt% Li is employed to create a eutectoid lamellar structure featuring the LiZn4 and Zn phases. This microstructure optimally balances high strength with immunomodulation effects. At mesoscale, surface pattern with nanoscale roughness facilitates filopodia formation and macrophage spreading. At macroscale, the isotropic minimal surface G unit exhibits a proper degradation rate with more uniform feature compared to the anisotropic BCC unit. In vivo, the G scaffold demonstrates a heightened efficiency in promoting macrophage polarization toward an anti-inflammatory phenotype, subsequently leading to significantly elevated osteogenic markers, increased collagen deposition, and enhanced new bone formation. In vitro, transcriptomic analysis reveals the activation of JAK/STAT pathways in macrophages via up regulating the expression of Il-4, Il-10, subsequently promoting osteogenesis.
Osteogenesis , Tissue Scaffolds , Osteogenesis/physiology , Tissue Scaffolds/chemistry , Porosity , Printing, Three-Dimensional , Zinc/pharmacology
Accurate prediction of the efficacy of immunotherapy for cancer patients through the characterization of both genetic and phenotypic heterogeneity in individual patient cells holds great promise in informing targeted treatments, and ultimately in improving care pathways and clinical outcomes. Here, we describe the nanoplatform for interrogating living cell host-gene and (micro-)environment (NICHE) relationships, that integrates micro- and nanofluidics to enable highly efficient capture of circulating tumor cells (CTCs) from blood samples. The platform uses a unique nanopore-enhanced electrodelivery system that efficiently and rapidly integrates stable multichannel fluorescence probes into living CTCs for in situ quantification of target gene expression, while on-chip coculturing of CTCs with immune cells allows for the real-time correlative quantification of their phenotypic heterogeneities in response to immune checkpoint inhibitors (ICI). The NICHE microfluidic device provides a unique ability to perform both gene expression and phenotypic analysis on the same single cells in situ, allowing us to generate a predictive index for screening patients who could benefit from ICI. This index, which simultaneously integrates the heterogeneity of single cellular responses for both gene expression and phenotype, was validated by clinically tracing 80 non-small cell lung cancer patients, demonstrating significantly higher AUC (area under the curve) (0.906) than current clinical reference for immunotherapy prediction.
Neoplastic Cells, Circulating , Humans , Neoplastic Cells, Circulating/pathology , Neoplastic Cells, Circulating/metabolism , Microfluidics/methods , Single-Cell Analysis/methods , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/blood , Phenotype , Cell Line, Tumor , Immunotherapy/methods , Gene Expression Profiling/methods , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/blood , Microfluidic Analytical Techniques/methods , Microfluidic Analytical Techniques/instrumentation
Based on Sima and Lu's system of the family Magnoliaceae, the genus Lirianthe Spach s. l. includes approximately 25 species, each with exceptional landscaping and horticultural or medical worth. Many of these plants are considered rare and are protected due to their endangered status. The limited knowledge of species within this genus and the absence of research on its chloroplast genome have greatly impeded studies on the relationship between its evolution and systematics. In this study, the chloroplast genomes of eight species from the genus Lirianthe were sequenced and analyzed, and their phylogenetic relationships with other genera of the family Magnoliaceae were also elucidated. The results showed that the chloroplast genome sizes of the eight Lirianthe species ranged from 159,548 to 159,833 bp. The genomes consisted of a large single-copy region, a small single-copy region, and a pair of inverted repeat sequences. The GC content was very similar across species. Gene annotation revealed that the chloroplast genomes contained 85 protein-coding genes, 37 tRNA genes, and 8 rRNA genes, totaling 130 genes. Codon usage analysis indicated that codon usage was highly conserved among the eight Lirianthe species. Repeat sequence analysis identified 42-49 microsatellite sequences, 16-18 tandem repeats, and 50 dispersed repeats, with microsatellite sequences being predominantly single-nucleotide repeats. DNA polymorphism analysis revealed 10 highly variable regions located in the large single-copy and small single-copy regions, among which rpl32-trnL, petA-psbJ, and trnH-psbA were the recommended candidate DNA barcodes for the genus Lirianthe species. The inverted repeat boundary regions show little variation between species and are generally conserved. The result of phylogenetic analysis confirmed that the genus Lirianthe s. l. is a monophyletic taxon and the most affinal to the genera, Talauma and Dugandiodendron, in Sima and Lu's system and revealed that the genus Lirianthe s. s. is paraphyletic and the genus Talauma s. l. polyphyletic in Xia's system, while Magnolia subsection Gwillimia is paraphyletic and subsection Blumiana polyphyletic in Figlar and Nooteboom's system. Morphological studies found noticeable differences between Lirianthe species in aspects including leaf indumentum, stipule scars, floral orientation, tepal number, tepal texture, and fruit dehiscence. In summary, this study elucidated the chloroplast genome evolution within Lirianthe and laid a foundation for further systematic and taxonomic research on this genus.
Genome, Chloroplast , Magnolia , Phylogeny , Molecular Sequence Annotation , Plants/genetics
In order to mitigate the risk of roof-dominated coal burst in underground coal mining, horizontal long borehole staged hydraulic fracturing technology has been prevailingly employed to facilitate the weakening treatment of the hard roof in advance. Such weakening effect, however, can hardly be evaluated, which leads to a lack of a basis in which to design the schemes and parameters of hydraulic fracturing. In this study, a combined underground-ground integrated microseismic monitoring and transient electromagnetic detection method was utilized to carry out simultaneous evaluations of the seismic responses to each staged fracturing and the apparent resistivity changes before and after all finished fracturing. On this basis, the comparable and applicable fracturing effects on coal burst prevention were evaluated and validated by the distribution of microseismic events and their energy magnitude during the mining process. Results show that the observed mining-induced seismic events are consistent with the evaluation results obtained from the combined seismic-electromagnetic detection method. However, there is a limited reduction effect on resistivity near the fractured section that induces far-field seismic events. Mining-induced seismic events are concentrated primarily within specific areas, while microseismic events in the fractured area exhibit high frequency but low energy overall. This study validates the rationality of combined seismic-electromagnetic detection results and provides valuable insights for optimizing fracturing construction schemes as well as comprehensively evaluating outcomes associated with underground directional long borehole staged hydraulic fracturing.
Oral diseases are prevalent but challenging diseases owing to the highly movable and wet, microbial and inflammatory environment. Polymeric materials are regarded as one of the most promising biomaterials due to their good compatibility, facile preparation, and flexible design to obtain multifunctionality. Therefore, a variety of strategies have been employed to develop materials with improved therapeutic efficacy by overcoming physicobiological barriers in oral diseases. In this review, we summarize the design strategies of polymeric biomaterials for the treatment of oral diseases. First, we present the unique oral environment including highly movable and wet, microbial and inflammatory environment, which hinders the effective treatment of oral diseases. Second, a series of strategies for designing polymeric materials towards such a unique oral environment are highlighted. For example, multifunctional polymeric materials are armed with wet-adhesive, antimicrobial, and anti-inflammatory functions through advanced chemistry and nanotechnology to effectively treat oral diseases. These are achieved by designing wet-adhesive polymers modified with hydroxy, amine, quinone, and aldehyde groups to provide strong wet-adhesion through hydrogen and covalent bonding, and electrostatic and hydrophobic interactions, by developing antimicrobial polymers including cationic polymers, antimicrobial peptides, and antibiotic-conjugated polymers, and by synthesizing anti-inflammatory polymers with phenolic hydroxy and cysteine groups that function as immunomodulators and electron donors to reactive oxygen species to reduce inflammation. Third, various delivery systems with strong wet-adhesion and enhanced mucosa and biofilm penetration capabilities, such as nanoparticles, hydrogels, patches, and microneedles, are constructed for delivery of antibiotics, immunomodulators, and antioxidants to achieve therapeutic efficacy. Finally, we provide insights into challenges and future development of polymeric materials for oral diseases with promise for clinical translation.
Anti-Infective Agents , Polymers , Polymers/chemistry , Biocompatible Materials/chemistry , Anti-Inflammatory Agents , Immunologic Factors
Background: Aildenafil citrate is a potent and selective inhibitor of cyclic guanosine monophosphate-specific phosphodiesterase type 5, developed for the treatment of erectile dysfunction (ED). Aim: This study aimed to assess the pharmacokinetics, safety, and tolerability of aildenafil citrate tablets after multiple doses in healthy Chinese males. Methods: Twenty participants were divided into 2 groups, 10 participants each. Participants were administered multiple doses of aildenafil citrate tablets at 30 and 60 mg. Outcomes: The safety evaluation was based on clinical symptoms and adverse events. Concentrations of aildenafil and its key metabolites (M1, M5, and M12) in human serum were measured by liquid chromatography-tandem mass spectrometry. Results: Pharmacokinetic analysis showed rapid absorption and elimination of aildenafil, with a median time to maximum serum concentration of 1 hour and mean terminal half-lives of 2.75 and 3.26 hours in the respective dose groups. The mean maximum concentration was proportional to the aildenafil dose in the range of 30 to 60 mg, although the area under the curve was not proportional for serum concentration vs time 0 to the last measurable time point (24 hours). Multiple doses of aildenafil were well tolerated, with 60.0% of men experiencing treatment-emergent adverse events, notably myalgia and fatigue, particularly in the 60-mg group. Clinical Implications: Aildenafil citrate tablets demonstrated favorable tolerability with once-daily administration over the clinical dose range. The occurrence of myalgia and fatigue was more prevalent in the 60-mg group. From a pharmacokinetic perspective, optimal administration of aildenafil citrate tablets appears to be 1 hour before sexual intercourse in men with ED. Strengths and Limitations: This study presents robust safety and pharmacokinetic data at expected therapeutic doses, unaffected by clinical factors. The efficacy of aildenafil citrate tablets warrants further validation in individuals with ED. Conclusion: Aildenafil citrate tablets exhibited good tolerability in healthy Chinese males following multiple doses at 30 and 60 mg. The 60-mg group showed an increased incidence of myalgia and fatigue, suggesting the need for heightened clinical vigilance. The mean maximum concentration, but not the area under the curve, displayed dose proportionality within the 30- to 60-mg dose range, and no significant drug accumulation was observed with repeated daily administration. Clinical Trial Registration: CTR20192473 (http://www.chinadrugtrials.org.cn).
