Nutrient vitamins enabled metabolic regulation of ferroptosis via reactive oxygen species biology.

Vitamins are dietary components necessary for cellular metabolic balance, especially redox homeostasis; deficient or excessive supply may give rise to symptoms of psychiatric disorders. Exploring the nutritional and metabolic pathways of vitamins could contribute to uncovering the underlying pathogenesis of ferroptosis-associated diseases. This mini-review aims to provide insights into vitamins closely linked to the regulation of ferroptosis from the perspective of cellular reactive oxygen species biology. The mainstream reprogramming mechanisms of ferroptosis are overviewed, focusing on unique biological processes of iron metabolism, lipid metabolism, and amino acid metabolism. Moreover, recent breakthroughs in therapeutic interventions targeting ferroptosis via fully utilizing vitamin-based pharmacological tools were overviewed, covering vitamins (B, C, E, and K). Finally, mechanism insight related to vitamin-associated nutrient signaling was provided, highlighting the pharmacological benefits of metabolically reprogramming ferroptosis-associated diseases.

DTDHM: detection of tandem duplications based on hybrid methods using next-generation sequencing data.

Background: Tandem duplication (TD) is a common and important type of structural variation in the human genome. TDs have been shown to play an essential role in many diseases, including cancer. However, it is difficult to accurately detect TDs due to the uneven distribution of reads and the inherent complexity of next-generation sequencing (NGS) data. Methods: This article proposes a method called DTDHM (detection of tandem duplications based on hybrid methods), which utilizes NGS data to detect TDs in a single sample. DTDHM builds a pipeline that integrates read depth (RD), split read (SR), and paired-end mapping (PEM) signals. To solve the problem of uneven distribution of normal and abnormal samples, DTDHM uses the K-nearest neighbor (KNN) algorithm for multi-feature classification prediction. Then, the qualified split reads and discordant reads are extracted and analyzed to achieve accurate localization of variation sites. This article compares DTDHM with three other methods on 450 simulated datasets and five real datasets. Results: In 450 simulated data samples, DTDHM consistently maintained the highest F1-score. The average F1-score of DTDHM, SVIM, TARDIS, and TIDDIT were 80.0%, 56.2%, 43.4%, and 67.1%, respectively. The F1-score of DTDHM had a small variation range and its detection effect was the most stable and 1.2 times that of the suboptimal method. Most of the boundary biases of DTDHM fluctuated around 20 bp, and its boundary deviation detection ability was better than TARDIS and TIDDIT. In real data experiments, five real sequencing samples (NA19238, NA19239, NA19240, HG00266, and NA12891) were used to test DTDHM. The results showed that DTDHM had the highest overlap density score (ODS) and F1-score of the four methods. Conclusions: Compared with the other three methods, DTDHM achieved excellent results in terms of sensitivity, precision, F1-score, and boundary bias. These results indicate that DTDHM can be used as a reliable tool for detecting TDs from NGS data, especially in the case of low coverage depth and tumor purity samples.

Therapeutic Prospects of Mesenchymal Stem Cell and Their Derived Exosomes in the Regulation of the Gut Microbiota in Inflammatory Bowel Disease.

Mesenchymal stem cells (MSCs) have shown great potential in the treatment of several inflammatory diseases due to their immunomodulatory ability, which is mediated by exosomes secreted by MSCs (MSC-Exs). The incidence of inflammatory bowel disease (IBD) is increasing globally, but there is currently no long-term effective treatment. As an emerging therapy, MSC-Exs have proven to be effective in alleviating IBD experimentally, and the specific mechanism continues to be explored. The gut microbiota plays an important role in the occurrence and development of IBD, and MSCs and MSC-Exs can effectively regulate gut microbiota in animal models of IBD, but the mechanism involved and whether the outcome can relieve the characteristic dysbiosis necessary to alleviate IBD still needs to be studied. This review provides current evidence on the effective modulation of the gut microbiota by MSC-Exs, offering a basis for further research on the pathogenic mechanism of IBD and MSC-Ex treatments through the improvement of gut microbiota.

Comparative study of topical 5-aminolevulinic acid photodynamic therapy and surgery for recurrent cervical high-grade squamous intraepithelial lesions following surgery.

OBJECTIVE: The study aimed to compare the clinical efficacy and safety of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and surgery in treating recurrent cervical high-grade squamous intraepithelial lesions (HSIL) after surgery due to precancerous lesions. METHODS: A total of 41 patients with recurrent cervical HSIL after surgery for precancerous lesions were studied retrospectively. Patients underwent ALA-PDT or surgery and were followed up at 3, 6, 9 and 12 months and then every six months after that. Clinical data were collected and the efficacy and safety of the two treatment methods were compared. RESULTS: Of the 41 patients with recurrent cervical HSIL after conization, 15 cases received ALA-PDT and 26 received surgery. At the six-month follow-up, the lesions' complete remission (CR) rate was 93.33 % in ALA-PDT group and 88.46 % in the surgery group. The human papillomavirus (HPV) clearance rates were 66.67 % and 73.08 %, respectively. No significant differences concerning the lesions' CR rate and the HPV clearance rate were observed between the two groups (P>0.05). At the twelve-month follow-up, the HPV clearance rates were 80.00 % and 91.67 %. No significant differences concerning the HPV clearance rate were observed between the two groups (P>0.05). In the surgery group, the HPV clearance rate and the lesions' CR rate were lower in patients over 45 years of age (25.00% vs. 81.82 %, P = 0.031; 50.00% vs. 95.45 %, P = 0.052). During the follow-up, there was no significant difference in the recurrence rate between the two groups (P>0.05). In addition, none of the patients progressed. In women treated with ALA-PDT, there was no vaginal bleeding, and no harmful effects on the cervical organizational structure or functions compared to the surgery group, and two women delivered successfully after ALA-PDT treatment. CONCLUSIONS: The efficacy of ALA-PDT was similar to that of surgery in treating recurrent cervical HSIL following surgery, with fewer side effects.

Surgery combined with photodynamic therapy for early-stage endometrial carcinoma, a report of two cases.

BACKGROUND: Endometrial carcinoma (EC) is one of the most prevalent gynecological malignancies and the onset age of EC tends to be younger. This case report explored the feasibility of surgery combined with photodynamic therapy (PDT) in two young patients with early-stage EC. METHODS: A 31 years old patient and a 24 years old patient were treated with surgery and PDT, respectively. The intraoperative PDT was performed 3 h after oral administration of 5-aminolevulinic acid (ALA) with intrauterine light irradiation of 630 nm laser light. RESULTS: The patients were followed up for 3 years and 4 months, respectively. There were no signs of recurrence. CONCLUSION: Intraoperative and intrauterine PDT was feasible and might be used for EC patients who attempt to preserve fertility.

Temporal and spatial effects on C-reactive protein's regulation of inducible nitric oxide synthase production in periodontal disease.

BACKGROUND: Inducible nitric oxide synthase (iNOS) is associated with inflammation and osteoclastic differentiation in periodontal disease. This study was conducted to compare the time-dependent variation in iNOS production between the gingiva and other periodontal tissues and to explore the potential association with C-reactive protein (CRP) in early periodontal disease. METHODS: Ligature-induced periodontal disease models (0-14 days) were established in wild-type and CRP knockout rats. Changes in CRP, iNOS, and autophagy levels were examined in the gingiva and other periodontal tissues. Macrophages were treated with lipopolysaccharide and chloroquine to explore the role of autophagy in iNOS production. iNOS, CRP, and autophagy-related proteins were analyzed using Western blotting, immunostaining, and enzyme-linked immunosorbent assays. mRNA expression was detected by quantitative real-time polymerase chain reaction. Hematoxylin and eosin staining was used for histological analysis. Cathepsin K immunostaining and microcomputed tomography of the maxillae were performed to compare alveolar bone resorption. RESULTS: iNOS and CRP levels increased rapidly in periodontal tissues, as observed on Day 2 of ligature, then decreased more rapidly in the gingiva than in other periodontal tissues. CRP deficiency did not prevent iNOS generation, but effectively accelerated iNOS reduction and delayed alveolar bone loss. The CRP effect on iNOS was accompanied by a change in autophagy, which was reduced by CRP knockout. CONCLUSIONS: The regulation of iNOS by CRP shows temporospatial variation in early periodontal disease and is potentially associated with autophagy. These findings may contribute to the early detection and targeted treatment of periodontal disease.

Comparative study of topical 5-aminolevulinic acid photodynamic therapy and surgery in treating vaginal high-grade squamous intraepithelial lesions following hysterectomy.

OBJECTIVE: To compare the clinical efficacy and safety of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and surgery in treating vaginal high-grade squamous intraepithelial lesions (HSIL) after hysterectomy due to cervical cancer (CC) or precancerous lesions. METHODS: A retrospective study was performed comprising 41 women with histologically confirmed vaginal HSIL after hysterectomy for CC or cervical HSIL. Patients were treated with surgery or ALA-PDT and were followed up at 3, 6 and 12 months and then every six months afterwards. Clinical data were collected and the efficacy and safety of the two groups were analyzed. RESULTS: Of the 41 patients with vaginal HSIL after hysterectomy, 18 were treated with ALA-PDT and 23 underwent surgery. There was no significant difference in the lesions' complete remission (CR) rate or the human papillomavirus (HPV) clearance rate between the ALA-PDT group and the surgery group (P > 0.05). In the surgery group, the clearance rate of HPV16/18 was higher than that of other high-risk HPV (HR-HPV) and HPV16/18 combined with other HR-HPV (87.50 % vs. 45.45 % vs. 0.00 %, P = 0.014). No significant difference in the recurrence rate between the two groups was noted (P > 0.05). And none of the patients progressed. In the surgery group, one patient developed significant thickening of the vaginal stump, and one patient had increased vaginal discharge. In women treated with ALA-PDT, there was no vaginal bleeding or harmful effects on the organizational structure or functions compared to the surgery group. CONCLUSIONS: The efficacy of ALA-PDT was comparable to that of surgery in treating vaginal HSIL following hysterectomy due to CC or cervical HSIL, with fewer side effects.

Advanced glycation end products impair bone marrow mesenchymal stem cells osteogenesis in periodontitis with diabetes via FTO-mediated N6-methyladenosine modification of sclerostin.

BACKGROUND: Diabetes mellitus (DM) and periodontitis are two prevalent diseases with mutual influence. Accumulation of advanced glycation end products (AGEs) in hyperglycemia may impair cell function and worsen periodontal conditions. N6-methyladenosine (m6A) is an important post-transcriptional modification in RNAs that regulates cell fate determinant and progression of diseases. However, whether m6A methylation participates in the process of periodontitis with diabetes is unclear. Thus, we aimed to investigate the effects of AGEs on bone marrow mesenchymal stem cells (BMSCs), elucidate the m6A modification mechanism in diabetes-associated periodontitis. METHODS: Periodontitis with diabetes were established by high-fat diet/streptozotocin injection and silk ligation. M6A modifications in alveolar bone were demonstrated by RNA immunoprecipitation sequence. BMSCs treated with AGEs, fat mass and obesity associated (FTO) protein knockdown and sclerostin (SOST) interference were evaluated by quantitative polymerase chain reaction, western blot, immunofluorescence, alkaline phosphatase and Alizarin red S staining. RESULTS: Diabetes damaged alveolar bone regeneration was validated in vivo. In vitro experiments showed AGEs inhibited BMSCs osteogenesis and influenced the FTO expression and m6A level in total RNA. FTO knockdown increased the m6A levels and reversed the AGE-induced inhibition of BMSCs differentiation. Mechanically, FTO regulated m6A modification on SOST transcripts, and AGEs affected the binding of FTO to SOST transcripts. FTO knockdown accelerated the degradation of SOST mRNA in presence of AGEs. Interference with SOST expression in AGE-treated BMSCs partially rescued the osteogenesis by activating Wnt Signaling. CONCLUSIONS: AGEs impaired BMSCs osteogenesis by regulating SOST in an m6A-dependent manner, presenting a promising method for bone regeneration treatment of periodontitis with diabetes.

Comparative study of topical 5-aminolevulinic acid photodynamic therapy and surgery for the treatment of vulvar squamous intraepithelial lesion.

BACKGROUND: Vulvar squamous intraepithelial lesion (SIL) is a precursor lesion of vulvar squamous cell carcinoma. The current clinical treatments for vulvar SIL cause damage to the vulvar structure, chronic pain and psychological distress. Topical 5-aminolevulinic acid photodynamic therapy (ALA-PDT) is a novel, non-invasive therapy for intraepithelial lesions. The objective of this study was to compare the clinical efficacy and safety of ALA-PDT with local surgical resection for vulvar SIL. METHODS: A total of 56 patients with vulvar SIL were enrolled in this retrospective study. Among them, 16 patients received local resection and 40 patients received ALA-PDT. HPV genotyping and ThinPrep cytologic test (TCT) were used to evaluate treatment efficacy. In addition, colposcopy-directed biopsy was performed in all patients at 3-month follow-up and in patients with positive high-risk human papillomavirus (HR-HPV) and/or abnormal TCT results during the follow-up. RESULTS: At 3-month follow-up and in HSIL group the complete remission (CR) rate of the ALA-PDT group and surgery group was 90.6% (29/32) and 87.5% (14/16) (P = 1.000), respectively. The HPV clearance rate of the ALA-PDT group and surgery group was 45.2% (14/31) and 43.8% (7/16) (P = 0.927), respectively. The average numbers of ALA-PDT treatments were 5.34 for HSIL patients and 4.88 for LSIL patients, respectively. The CR rate of HSIL patients and LSIL patients was 90.6% (29/32) and 75.0% (6/8) (P = 0.550), respectively. The HPV clearance rate of HSIL patients and LSIL patients was 45.2% (14/31) and 37.5% (3/8) (P = 1.000), respectively. The ALA-PDT group showed similar clinical efficacy and milder adverse effects compared with the surgical group. CONCLUSION: ALA-PDT showed similar clinical efficacy as surgery in the treatment of vulvar SIL, but with milder adverse effects and maintaining the integrity of the vulvar structure.

Genetic alterations in juvenile cervical clear cell adenocarcinoma unrelated to human papillomavirus.

Clear cell adenocarcinoma of the cervix (CCAC) is a special type of HPV-independent cervical cancer. It has a low incidence rate, can be difficult to diagnose early, has a poor prognosis. Its peak incidence is in adolescence, which poses a great threat to women's health. Therefore, it is very important to explore the pathogenesis of cervical clear cell adenocarcinoma to guide subsequent treatment and prevention. This study analyzed 3 juvenile patients with CCAC diagnosed at the First Affiliated Hospital of Zhengzhou University. Using next-generation sequencing methods, we analyzed the pathogenesis of the patients and their close relatives by analyzing the genetic alterations of patients. CMTM5 was identified as the only shared mutated gene. Using published literature and comparative analyses of related disease-causing genes, 6 of the 19 genes (ALKBH7, MYCBP, MZF1, RNF207, RRS1, and TUSC2) were screened as genes with mutations in patients and had higher mutation rates in reproductive cancers. Pathway analysis showed that downregulated genes in non-HPV cervical cancer were mainly related to the immune system response, suggesting that non-HPV cervical cancer differs from HPV-infected cervical cancer in that the immune response is weaker, which is consistent with the weak correlation with viral infection.

Clostridium butyricum MIYAIRI 588 alleviates periodontal bone loss in mice with diabetes mellitus.

The gut microbiota is a bridge linking periodontitis and systemic diseases, such as diabetes mellitus (DM). The probiotic Clostridium butyricum MIYAIRI 588 (CBM588) is reportedly an effective therapeutic approach for gut dysbiosis. Here, in a mouse model, we explored the therapeutic effect of CBM588 on periodontal bone destruction in DM and DM-associated periodontitis (DMP), as well as the underlying mechanism. Micro-computed tomography revealed that DM and DMP both aggravated periodontal bone destruction, which was alleviated by intragastric supplementation with CBM588. Moreover, 16S rRNA sequencing and untargeted metabolite analysis indicated that CBM588 ameliorated DMP-triggered dysbiosis and led to reduced oxidative stress associated with elevated 4-hydroxybenzenemethanol (4-HBA) in serum. Furthermore, in vitro and in vivo experiments found that the metabolite 4-HBA promoted nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and modulated the polarization of macrophages, thus ameliorating inflammatory bone destruction in DMP. Our study demonstrates the protective effects of CBM588 in DM-induced mice, with and without ligature-induced periodontitis. The mechanism involves regulation of the gut microbiota and restoration of the integrity of the gut barrier to alleviate oxidative damage by elevating serum 4-HBA. This study suggests the possibility of CBM588 as a therapeutic adjuvant for periodontal treatment in diabetes patients.

Increased serum α-tocopherol acetate mediated by gut microbiota ameliorates alveolar bone loss through the STAT3 signalling pathway in diabetic periodontitis.

AIM: To evaluate whether and how gut microbiota-meditated metabolites regulate alveolar bone homeostasis in diabetic periodontitis (DP). MATERIALS AND METHODS: Lactobacillus casei (L. casei) was employed as a positive modulator of gut microbiota in DP mice. The destruction of alveolar bone was evaluated. Untargeted metabolomics was conducted to screen out the pivotal metabolites. A co-housing experiment was conducted to determine the connection between the gut microbiota and alpha-tocopherol acetate (α-TA). α-TA was applied to DP mice to investigate its effect against alveolar bone loss. Human periodontal ligament cells (hPDLCs) and human gingival fibroblasts (HGFs) were extracted for the in vitro experiment. Transcriptomic analysis and immunohistochemistry were performed to detect the major affected signalling pathways. RESULTS: Positive regulation of the gut microbiota significantly attenuated alveolar bone loss and increased the serum α-TA level. The alteration in gut microbiota composition could affect the serum α-T (the hydrolysates of α-TA) level. α-TA could alleviate alveolar bone destruction in DP mice and α-T exert beneficial effects on hPDLCs and HGFs. Mechanistically, the STAT3 signalling pathway was the pivotal pathway involved in the protective role of α-TA. CONCLUSIONS: The gut microbiota-α-TA-STAT3 axis plays an important role in the regulation of diabetic alveolar bone homeostasis.

Low-intensity pulsed ultrasound regulates osteoblast-osteoclast crosstalk via EphrinB2/EphB4 signaling for orthodontic alveolar bone remodeling.

Background: The limited regenerative potential of periodontal tissue remains a challenge in orthodontic treatment, especially with respect to alveolar bone remodeling. The dynamic balance between the bone formation of osteoblasts and the bone resorption of osteoclasts controls bone homeostasis. The osteogenic effect of low-intensity pulsed ultrasound (LIPUS) is widely accepted, so LIPUS is expected to be a promising method for alveolar bone regeneration. Osteogenesis is regulated by the acoustic mechanical effect of LIPUS, while the cellular perception, transduction mode and response regulation mechanism of LIPUS stimuli are still unclear. This study aimed to explore the effects of LIPUS on osteogenesis by osteoblast-osteoclast crosstalk and the underlying regulation mechanism. Methods: The effects of LIPUS on orthodontic tooth movement (OTM) and alveolar bone remodeling were investigated via rat model by histomorphological analysis. Mouse bone marrow mesenchymal stem cells (BMSCs) and bone marrow monocytes (BMMs) were purified and used as BMSC-derived osteoblasts and BMM-derived osteoclasts, respectively. The osteoblast-osteoclast co-culture system was used to evaluate the effect of LIPUS on cell differentiation and intercellular crosstalk by Alkaline phosphatase (ALP), Alizarin Red S (ARS), tartrate-resistant acid phosphatase (TRAP) staining, real-time quantitative PCR, western blotting and immunofluorescence. Results: LIPUS was found to improve OTM and alveolar bone remodeling in vivo, promote differentiation and EphB4 expression in BMSC-derived osteoblasts in vitro, particularly when cells were directly co-cultured with BMM-derived osteoclasts. LIPUS enhanced EphrinB2/EphB4 interaction between osteoblasts and osteoclasts in alveolar bone, activated the EphB4 receptor on osteoblasts membrane, transduced LIPUS-related mechanical signals to the intracellular cytoskeleton, and gave rise to the nuclear translocation of YAP in Hippo signaling pathway, thus regulating cell migration and osteogenic differentiation. Conclusions: This study shows that LIPUS modulates bone homeostasis by osteoblast-osteoclast crosstalk via EphrinB2/EphB4 signaling, which benefits the balance between OTM and alveolar bone remodeling.

Extracellular vesicles derived from human dental mesenchymal stem cells stimulated with low-intensity pulsed ultrasound alleviate inflammation-induced bone loss in a mouse model of periodontitis.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have emerged as a new mode of intercellular crosstalk and are responsible for many of the therapeutic effects of MSCs. To promote the application of MSC-EVs, recent studies have focused on the manipulation of MSCs to improve the production of EVs and EV-mediated activities. The current paper details an optimization method using non-invasive low-intensity pulsed ultrasound (LIPUS) as the stimulation for improving oral MSC-EV production and effectiveness. Stem cells from apical papilla (SCAP), a type of oral mesenchymal stem cell, displayed intensity-dependent pro-osteogenic and anti-inflammatory responses to LIPUS without significant cytotoxicity or apoptosis. The stimuli increased the secretion of EVs by promoting the expression of neutral sphingomyelinases in SCAP. In addition, EVs from LIPUS-induced SCAP exhibited stronger efficacy in promoting the osteogenic differentiation and anti-inflammation of periodontal ligament cells in vitro and alleviating oral inflammatory bone loss in vivo. In addition, LIPUS stimulation affected the physical characteristics and miRNA cargo of SCAP-EVs. Further investigations indicated that miR-935 is an important mediator of the pro-osteogenic and anti-inflammatory capabilities of LIPUS-induced SCAP-EVs. Taken together, these findings demonstrate that LIPUS is a simple and effective physical method to optimize SCAP-EV production and efficacy.

Incidence and risk factors of postoperative acute myocardial injury in noncardiac patients: A systematic review and meta-analysis.

INTRODUCTION: Postoperative myocardial injury after noncardiac surgery is common and is associated with short- and long-term morbidity and mortality. However, the incidence and risk factors for postoperative acute myocardial injury (POAMI) are currently unknown due to inconsistent definitions. METHODS: We systematically searched PubMed and Web of Science to identify studies that applied the change value of preoperative and postoperative cardiac troponins to define cardiac injury. We estimated the pooled incidence, risk factors, and 30-day and long-term mortality of POAMI in noncardiac patients. The study protocol was registered with PROSPERO, CRD42023401607. RESULTS: Ten cohorts containing 11,494 patients were included for analysis. The pooled incidence of POAMI was 20% (95% CI: 16% to 23%). Preoperative hypertension (OR: 1.47; 95% CI: 1.30 to 1.66), cardiac failure (OR: 2.63; 95% CI: 2.01 to 3.44), renal impairment (OR: 1.66; 95% CI: 1.48 to 1.86), diabetes (OR: 1.43; 95% CI: 1.27 to 1.61), and preoperative beta-blocker intake (OR: 1.65; 95% CI: 1.10 to 2.49) were the risk factors for POAMI. Age (mean difference: 2.08 years; 95% CI: -0.47 to 4.62), sex (male, OR: 1.16; 95% CI: 0.77 to 1.76), body mass index (mean difference: 0.35; 95% CI: -0.86 to 1.57), preoperative coronary artery disease (OR: 2.10; 95% CI: 0.85 to 5.21), stroke (OR: 0.90; 95% CI: 0.50 to 1.59) and preoperative statins intake (OR: 0.65; 95% CI: 0.21 to 2.02) were not associated with POAMI. Patients with POAMI had higher preoperative hsTnT levels (mean difference: 5.92 ng/L; 95% CI: 4.17 to 7.67) and lower preoperative hemoglobin levels (mean difference: -1.29 g/dL; 95% CI: -1.43 to -1.15) than patients without. CONCLUSION: Based on this meta-analysis, approximately 1 in 5 of noncardiac patients develop POAMI. However, the lack of a universally recognized definition for POAMI, which incorporates diverse cardiac biomarkers and patient groups, poses a challenge in accurately characterizing its incidence, risk factors, and clinical outcomes.

Portable Handheld "SkinPen" Loaded with Biomaterial Ink for In Situ Wound Healing.

In situ bioprinting has emerged as an attractive tool for directly depositing therapy ink at the defective area to adapt to the irregular wound shape. However, traditional bioprinting exhibits an obvious limitation in terms of an unsatisfactory bioadhesive effect. Here, a portable handheld bioprinter loaded with biomaterial ink is designed and named "SkinPen". Gelatin methacrylate (GelMA) and Cu-containing bioactive glass nanoparticles (Cu-BGn) serve as the main components to form the hydrogel ink, which displays excellent biocompatibility and antibacterial and angiogenic properties. More importantly, by introducing ultrasound and ultraviolet in a sequential programmed manner, the SkinPen achieves in situ instant gelation and amplified (more than threefold) bioadhesive shear strength. It is suggested that ultrasound-induced cavitation and the resulting topological entanglement contribute to the enhanced bioadhesive performance together. Combining the ultrasound-enhanced bioadhesion with the curative role of the hydrogel, the SkinPen shows a satisfactory wound-healing effect in diabetic rats. Given the detachable property of the SkinPen, the whole device can be put in a first-aid kit. Therefore, the application scenarios can be expanded to many kinds of accidents. Overall, this work presents a portable handheld SkinPen that might provide a facile but effective approach for clinical wound management.

Co-delivery of gemcitabine and Triapine by calcium carbonate nanoparticles against chemoresistant pancreatic cancer.

Pancreatic cancer is a malignant disease with high mortality, and its systemic treatment strategy mainly focuses on chemotherapy. Yet, the overall prognosis of pancreatic cancer patients is still extremely poor with a low survival rate. Gemcitabine (GEM) is a widely used chemotherapeutic agent for the treatment of pancreatic cancer. However, GEM chemoresistance remains the major challenge. In this study, we prepared calcium carbonate nanoparticles (CaCO3 NPs) loaded with a nucleotide reductase inhibitor (Triapine) and GEM to suppress the GEM resistance of pancreatic cancer cells (PANC-1/GEM) and solve the problem of poor solubility of Triapine. CaCO3-GEM-Triapine NPs nano-formulations enhanced the therapeutic effect of GEM-based chemotherapy by inhibiting cancer cell proliferation, migration, and resistance to GEM using both 2D PANC-1/GEM cells and 3D tumor spheroids. The study indicated that CaCO3 NPs loaded with GEM and Triapine could provide an effective treatment option to overcome drug resistance in pancreatic cancer.

Knockdown of SIRT3 perturbs protective effects of irisin against bone loss in diabetes and periodontitis.

A well-recognized risk factor for periodontitis, diabetes mellitus (DM) aggravates periodontal disease with increasing alveolar bone loss. As a novel myokine, irisin is closely linked with bone metabolism. Nonetheless, the effects of irisin on periodontitis under diabetic conditions and the underlying mechanisms remain poorly understood. Here, we showed that local irisin treatment ameliorates alveolar bone loss and oxidative stress, increases SIRT3 expression within periodontal tissues of our experimentally-induced diabetes and periodontitis (DP) rat models. By culturing the periodontal ligament cells (PDLCs) in vitro, we found that irisin could partially rescue inhibited cell viability, mitigate accumulated intracellular oxidative stress, ameliorate mitochondrial dysfunctions, and restore disturbed osteogenic and osteoclastogenic capacities of PDLCs when exposed to high glucose and pro-inflammatory stimulation. Furthermore, lentivirus-mediated SIRT3 knockdown was employed to unravel the underlying mechanism by which SIRT3 mediated irisin's beneficial effects on PDLCs. Meanwhile, in SIRT3-deficient mice, irisin treatment did not protect against alveolar bone destruction and oxidative stress accumulation in DP models, which underlined the crucial role of SIRT3 in mediating the positive effects of irisin on DP. Our findings, for the first time, revealed that irisin attenuates alveolar bone loss and oxidative stress via activation of the SIRT3 signaling cascade, and highlighted its therapeutic potential for the treatment of DP.

Increased retinoic acid signaling decreases lung metastasis in salivary adenoid cystic carcinoma by inhibiting the noncanonical Notch1 pathway.

MYB-NFIB fusion and NOTCH1 mutation are common hallmark genetic events in salivary gland adenoid cystic carcinoma (SACC). However, abnormal expression of MYB and NOTCH1 is also observed in patients without MYB-NFIB fusion and NOTCH1 mutation. Here, we explore in-depth the molecular mechanisms of lung metastasis through single-cell RNA sequencing (scRNA-seq) and exome target capture sequencing in two SACC patients without MYB-NFIB fusion and NOTCH1 mutation. Twenty-five types of cells in primary and metastatic tissues were identified via Seurat clustering and categorized into four main stages ranging from near-normal to cancer-based on the abundance of each cell cluster in normal tissue. In this context, we identified the Notch signaling pathway enrichment in almost all cancer cells; RNA velocity, trajectory, and sub-clustering analyses were performed to deeply investigate cancer progenitor-like cell clusters in primary tumor-associated lung metastases, and signature genes of progenitor-like cells were enriched in the "MYC_TARGETS_V2" gene set. In vitro, we detected the NICD1-MYB-MYC complex by co-immunoprecipitation (Co-IP) and incidentally identified retinoic acid (RA) as an endogenous antagonist of genes in the "MYC_TARGETS_V2" gene set. Following this, we confirmed that all-trans retinoic acid (ATRA) suppresses the lung metastasis of SACC by correcting erroneous cell differentiation mainly caused by aberrant NOTCH1 or MYB expression. Bioinformatic, RNA-seq, and immunohistochemical (IHC) analyses of primary tissues and metastatic lung tissues from patients with SACC suggested that RA system insufficiency partially promotes lung metastasis. These findings imply the value of the RA system in diagnosis and treatment.

The diagnostic and prognostic potential of gut bacteria in inflammatory bowel disease.

The gut microbiome serves as a signaling hub that integrates environmental inputs with genetic and immune signals to influence the host's metabolism and immunity. Gut bacteria are intricately connected with human health and disease state, with specific bacteria species driving the characteristic dysbiosis found in gastrointestinal conditions such as inflammatory bowel disease (IBD); thus, gut bacteria changes could be harnessed to improve IBD diagnosis, prognosis, and treatment. The advancement in next-generation sequencing techniques such as 16S rRNA and whole-genome shotgun sequencing has allowed the exploration of the complexity of the gut microbial ecosystem with high resolution. Current microbiome data is promising and appears to perform better in some studies than the currently used fecal inflammation biomarker, calprotectin, in predicting IBD from healthy controls and irritable bowel syndrome (IBS). This study reviews current data on the differential potential of gut bacteria within IBD cohorts, and between IBD and other gastrointestinal diseases.