A Simply Synthesized Shaking-induced Small Molecule System with Repeatableand Instantaneous Discoloration Response.

Force-related discoloration materials are highly valuable because of their characteristics of visualization, easy operation, and environment friendliness. Most force-related discoloration materials focus on polymers and depend on bond scission, which leads to insensitivity and unrecoverable. Small-molecule systems based on well-defined molecular structures and simple composition with high sensitivity would exhibit considerable mechanochromic potential. However, to date, researches about force-related discoloration materials based on small molecule solution remain limited and are rarely reported. In this study, we developed a repeatable and instantaneous discoloration small molecule solution system by simple one-pot synthesis method. It exhibited an instantaneous chromic change from yellowish to dark green under shaking and reverting back to yellow within 1 minute after removal of the shaking. Experimental results confirmed that the discoloration mechanism is attributed to the oscillation accelerating the production of unstable ortho-OH phenoxyl radical. The newly developed shaking-induced discoloration small molecule system (SDSMS) promises in field of mechanical force sensing and optical encryption.

Pemphigus oral lesions area index (POLAI): A new scoring scale for assessing oral pemphigus vulgaris.

OBJECTIVES: Current scales for Pemphigus vulgaris (PV) do not adequately represent the clinical variability of oral lesions. This study aimed to develop an independent scale, the Pemphigus Oral Lesions Area Index (POLAI), for assessment of oral PV exclusively, and compare POLAI, Pemphigus Disease Area Index (PDAI), Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and Oral Disease Severity Score (ODSS) regarding inter- and intra-observer reliability and validity. MATERIALS AND METHODS: Retrospective cohort included 209 sets of digital-photographs. Additional clinical cohort included 32 PV patients. All visits were assessed by four clinicians using the PDAI, ABSIS, ODSS and POLAI, and were rated by three specialists using the Physician's Global Assessment (PGA). RESULTS: The intraclass correlation coefficient showed the inter-observer reliability with 0.89 and 0.86 for PDAI, 0.87 for ABSIS, 0.93 for ODSS, 0.96 for POLAI, and 0.97 and 0.96 for PGA. Intra-observer agreements showed excellent reliability for all 4 scores. Highest correlation was observed between PGA and POLAI (correlation coefficients were 0.96). The mean time taken to complete each scale was within 1.5 min. CONCLUSION: POLAI is valid for the assessment of oral PV with superior inter- and intra-observer reliability to PDAI, ABSIS and ODSS, and is feasible in clinic.

Mutant Phosphodiesterase 3A Protects From Hypertension-Induced Cardiac Damage.

BACKGROUND: Phosphodiesterase 3A (PDE3A) gain-of-function mutations cause hypertension with brachydactyly (HTNB) and lead to stroke. Increased peripheral vascular resistance, rather than salt retention, is responsible. It is surprising that the few patients with HTNB examined so far did not develop cardiac hypertrophy or heart failure. We hypothesized that, in the heart, PDE3A mutations could be protective. METHODS: We studied new patients. CRISPR-Cas9-engineered rat HTNB models were phenotyped by telemetric blood pressure measurements, echocardiography, microcomputed tomography, RNA-sequencing, and single nuclei RNA-sequencing. Human induced pluripotent stem cells carrying PDE3A mutations were established, differentiated to cardiomyocytes, and analyzed by Ca2+ imaging. We used Förster resonance energy transfer and biochemical assays. RESULTS: We identified a new PDE3A mutation in a family with HTNB. It maps to exon 13 encoding the enzyme's catalytic domain. All hitherto identified HTNB PDE3A mutations cluster in exon 4 encoding a region N-terminally from the catalytic domain of the enzyme. The mutations were recapitulated in rat models. Both exon 4 and 13 mutations led to aberrant phosphorylation, hyperactivity, and increased PDE3A enzyme self-assembly. The left ventricles of our patients with HTNB and the rat models were normal despite preexisting hypertension. A catecholamine challenge elicited cardiac hypertrophy in HTNB rats only to the level of wild-type rats and improved the contractility of the mutant hearts, compared with wild-type rats. The ß-adrenergic system, phosphodiesterase activity, and cAMP levels in the mutant hearts resembled wild-type hearts, whereas phospholamban phosphorylation was decreased in the mutants. In our induced pluripotent stem cell cardiomyocyte models, the PDE3A mutations caused adaptive changes of Ca2+ cycling. RNA-sequencing and single nuclei RNA-sequencing identified differences in mRNA expression between wild-type and mutants, affecting, among others, metabolism and protein folding. CONCLUSIONS: Although in vascular smooth muscle, PDE3A mutations cause hypertension, they confer protection against hypertension-induced cardiac damage in hearts. Nonselective PDE3A inhibition is a final, short-term option in heart failure treatment to increase cardiac cAMP and improve contractility. Our data argue that mimicking the effect of PDE3A mutations in the heart rather than nonselective PDE3 inhibition is cardioprotective in the long term. Our findings could facilitate the search for new treatments to prevent hypertension-induced cardiac damage.

Identification of the causal relationship between sleep quality, insomnia, and oral ulcers.

BACKGROUND: Multiple epidemiological studies have posited a potential association between sleep quality and the risk of oral diseases, yet the resulting conclusions have remained contentious, and the presence of a causal link remains equivocal. In this study, we aimed to investigate the causal relationship between sleep duration, insomnia, and common oral diseases. METHODS: We utilized genetic correlation and two-sample Mendelian randomization analyses based on summary statistics from genome-wide association studies of sleep duration (N = 460,099), insomnia (N = 462,341), mouth ulcer (N = 385,026), oral cavity cancer (N = 4,151), and periodontal disease (N = 527,652). RESULTS: Our results revealed a negative genetic correlation between sleep duration and mouth ulcer (genetic correlation: -0.09, P = 0.007), while a positive genetic correlation between insomnia and mouth ulcer was observed (genetic correlation: 0.18, P = 2.51E-06). Furthermore, we demonstrated that longer sleep duration is significantly associated with a reduced risk of mouth ulcers (OR: 0.67, 95% CI: 0.54-0.83, P = 2.84E-04), whereas insomnia is nominally associated with an increased risk of mouth ulcers (OR: 1.40, 95% CI: 1.01-1.95, P = 0.044). In contrast, no significant association was detected between sleep quality and periodontal disease or oral cavity cancer. CONCLUSIONS: This work provides robust evidence to support the notion that enhanced sleep quality may confer a decreased risk of oral ulcers, thereby bearing considerable clinical relevance.

Large-Scale Synthesis of High-Purity Isoguanosine and Resolution of its Crystal Structure by Microcrystal Electron Diffraction.

Isoguanosine (isoG) is a natural structural isomer of guanosine (G) with significant potential for applications in ionophores, genetics, gel formation, and cancer therapy. However, the cost of commercially available isoG on a gram scale is relatively high. To date, a detailed method for the large-scale preparation of high-purity isoG has not been reported. This study presented a simple and convenient approach for the large-scale synthesis of isoG through the diazotization of 2,6-diaminopurine riboside with sodium nitrite and acetic acid at room temperature. Further, this method could synthesize isoG derivatives (2'-fluoro-isoguanosine (1) and 2'-deoxy-isoguanosine (2)) from 2,6-diaminopurine nucleoside derivatives using diazotization. The structural information of natural and modified nucleosides is crucial for the modification and substitution of DNA/RNA. This study obtained the single-crystal structure of isoG for the first time and analyzed it in detail using microcrystal electron diffraction. The three-dimensional supramolecular structure of isoG adopted similarly base-pair motifs from π-π stacking interaction of diverse layers, intramolecular hydrogen bonding, and distinct hydrogen bonding interactions from sugar residues. This study has contributed to further isoG modification and its applications in medicinal chemistry and materials.

A double-layer thin oral film for wet oral mucosa adhesion and efficient treatment of oral ulcers.

Oral ulceration (OU), a prevalent oral mucosal condition causing significant pain and hindering eating and speaking, adversely impacts the patient's quality of life. Topical medications are preferred for their minimal side effects and convenient administration. However, existing formulations generally present discomfort and insufficient drug retention due to the thick formulations and poor adhesion, which considerably restrict their therapeutic effectiveness. In this study, a thin and lightweight double-layer oral film based on FDA approved excipients with excellent adhesion under wet oral conditions and outstanding biocompatibility is successfully developed by a simple method. It consists of an adhesive layer for anchoring in situ to delivery drugs and a hydrophobic layer to isolate the saliva for unidirectional drug delivery. The double-layer oral film with extremely thin appearance (only 0.11 mm thick) offers excellent adhesion (up to 150 min on an SD rat oral ulceration), which was also matched with its drug release time (87.47% release in 2 h). Animal experiments confirmed that the double-layer oral film carrying dexamethasone sodium phosphate achieved satisfactory efficacy in the SD rat oral ulcer model. Hence, this biologically friendly double-layer thin oral film holds great promise for clinical application in topical drug therapy for oral mucosal conditions.

Targeting cAMP signaling compartments in iPSC-derived models of cardiovascular disease.

Adenosine 3',5'-cyclic monophosphate (cAMP) acts as a second messenger that is involved in the regulation of a plethora of processes. The activation of cAMP signaling in defined compartments is critical for cells to respond to an extracellular stimulus in a specific manner. Rapid advances in the field of human induced pluripotent stem cells (iPSCs) reflect their great potential for cardiovascular disease modeling, drug screening, regenerative and precision medicine. This review discusses cAMP signaling in iPSC-derived cardiovascular disease models, and the prospects of using such systems to elucidate disease mechanisms, drug actions and to identify novel drug targets for the treatment of cardiovascular diseases with unmet medical need, such as hypertension and heart failure.

Protocatechuic Acid-Based Supramolecular Hydrogel Targets SerpinB9 to Achieve Local Chemotherapy for OSCC.

Protocatechuic acid (PCA) is a natural phenolic acid present in daily vegetables and fruits. Notably, PCA was demonstrated to inhibit the biological function of SerpinB9 (Sb9) and exhibit an excellent antitumor effect, showing great potential in cancer treatment. However, the short half-life time limits PCA's wide application against cancers. To overcome this shortage of PCA, we integrated PCA and another natural product with strong self-assembling properties, isoguanosine (isoG), to develop a novel multifunctional supramolecular hydrogel with good biocompatibility and injectability, which remarkably lengthens the releasing time of PCA and exerts considerable anticancer effects in vitro and in vivo. Besides, we surprisingly found that PCA could not only target Sb9 but also restrain cancer development through activating the JNK/P38 pathway, decreasing the ROS level, and repairing cancer stemness. In all, our results demonstrate that this PCA-based hydrogel could act as a multifunctional hydrogel system equipped with considerable anticancer effects, providing potential local administration integrating with targeted therapy and chemotherapy in one simple modality.

Exhaled breath analysis in disease detection.

Investigating the use of exhaled breath analysis to diagnose and monitor different diseases has attracted much interest in recent years. This review introduces conventionally used methods and some emerging technologies aimed at breath analysis and their relevance to lung disease, airway inflammation, gastrointestinal disorders, metabolic disorders and kidney diseases. One section correlates breath components and specific diseases, whereas the other discusses some unique ideas, strategies, and devices to analyze exhaled breath for the diagnosis of some common diseases. This review aims to briefly introduce the potential application of exhaled breath analysis for the diagnosis and screening of various diseases, thereby providing a new avenue for the detection of non-invasive diseases.

Photodynamic therapy combined with laser drilling successfully prevents the recurrence of refractory oral proliferative verrucous leukoplakia.

Oral proliferative verrucous leukoplakia is a potentially malignant disorder with high rates of recurrence and malignant transformation. Proliferative verrucous leukoplakia is often refractory to various treatments, including topical drugs, surgical resection, cryotherapy, and laser therapy. Topical 5-aminolevulinic acid-mediated photodynamic therapy is an innovative and effective treatment for potentially malignant oral disorders and has the potential to control the recurrence of precancerous lesions and cancer. Various pre-treatments or combined therapies have been proposed to increase the efficacy of topical 5-aminolevulinic acid-mediated photodynamic therapy, especially for large, thick, or highly keratinised lesions. We report a case of refractory proliferative verrucous leukoplakia in a 58-year-old female patient who showed rapid recurrence within 1 week of topical 5-aminolevulinic acid-mediated photodynamic therapy despite pre-treatment with microneedle puncture, combined intralesional injection of 5-aminolevulinic acid, and shortened treatment interval. We applied three sessions of topical 5-aminolevulinic acid-mediated photodynamic therapy combined with diode laser drilling pre-treatment at 1-week intervals, which successfully eradicated the lesions without any adverse effects and without any signs of recurrence at the 10-month follow-up. Topical 5-aminolevulinic acid-mediated photodynamic therapy combined with diode laser drilling pre-treatment is safe and well-tolerated and could have synergistic efficacy against refractory oral proliferative verrucous leukoplakia.

Chirality from D-guanosine to L-guanosine shapes a stable gel for three-dimensional cell culture.

It is proved that L-guanosine (L-G) as an enantiomer of D-guanosine (D-G) forms more stable gels than D-G, suggesting that alteration of chirality may be a new strategy for improving the lifetime stability of supramolecular hydrogels. Experiments for three-dimensional cell culture reveal that the L-G gel is a candidate for the extracellular matrix.

A novel therapeutic hypothesis for craniosynostosis syndromes: Clover to clever.

Cloverleaf skull is a complex skull deformity named after its cloverleaf shape. The primary pathogenic factor is craniosynostosis. Craniosynostosis could result in limited development of skull, brain, maxillofacial and nervous system, thus arising a series of complex syndromes, including Crouzon, Apert, Pfeiffer, Saethre-Chotzen and Muenke syndromes. Craniosynostosis syndromes exhibit a group of similar symptoms because of the mutual cause, craniosynostosis, with Crouzon syndrome being the most common one. At present, the surgical approach for Craniosynostosis syndromes has been established and generally accepted, including a series of surgical interventions in stages according to patients' age, severity and function of skull malformation. It's a large, complex, long time span deformity correcting procedure with formidable limitations, including high risk, expensive cost, quantity shortage of qualified surgeons and unsatisfactory successful rate for complicated cases. Hence, a new nonsurgical therapy for patients with craniosynostosis syndromes is seriously needed. A concept of Dynamic Cranial Suture Management (DCSM) was introduced. It includes objective and evaluable monitoring tools and craniosynostosis patent modifying drugs or medications tools which consist of regulatory factors for osteoclasts, osteoblasts and mesenchymal stem cells. By using these tools alternatively in different skull developing stages, DCSM is designed to prevent craniosynostosis. A Crouzon syndrome case was also presented.

Recurrent oral erythema multiforme: a case series report and review of the literature.

Recurrent oral erythema multiforme (ROEM) is now accepted as a less-recognized subtype of erythema multiforme (EM). The diagnosis is based on the exclusion of other similar diseases; typical clinical features, such as mutiple recurrent irregular painful erosions of oral mucosa without skin lesions, and, frequently, evidence of past herpes simplex virus infection. Here, we report 3 cases diagnosed as ROEM according to the 3 characteristics mentioned before. In addition, the article reviews the epidemiology, etiology, clinical manifestations, basis for diagnosis, and treatment of ROEM and highlights the need for prophylaxis.