ABL1 kinase plays an important role in spontaneous and chemotherapy-induced genomic instability in multiple myeloma.

ABSTRACT: Genomic instability contributes to cancer progression and is at least partly due to dysregulated homologous recombination (HR). Here, we show that an elevated level of ABL1 kinase overactivates the HR pathway and causes genomic instability in multiple myeloma (MM) cells. Inhibiting ABL1 with either short hairpin RNA or a pharmacological inhibitor (nilotinib) inhibits HR activity, reduces genomic instability, and slows MM cell growth. Moreover, inhibiting ABL1 reduces the HR activity and genomic instability caused by melphalan, a chemotherapeutic agent used in MM treatment, and increases melphalan's efficacy and cytotoxicity in vivo in a subcutaneous tumor model. In these tumors, nilotinib inhibits endogenous as well as melphalan-induced HR activity. These data demonstrate that inhibiting ABL1 using the clinically approved drug nilotinib reduces MM cell growth, reduces genomic instability in live cell fraction, increases the cytotoxicity of melphalan (and similar chemotherapeutic agents), and can potentially prevent or delay progression in patients with MM.

Elevated APE1 Dysregulates Homologous Recombination and Cell Cycle Driving Genomic Evolution, Tumorigenesis, and Chemoresistance in Esophageal Adenocarcinoma.

BACKGROUND & AIMS: The purpose of this study was to identify drivers of genomic evolution in esophageal adenocarcinoma (EAC) and other solid tumors. METHODS: An integrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in 6 cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as the top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells and the impact on genome stability and growth was monitored in vitro and in vivo. The impact on DNA and chromosomal instability was monitored using multiple approaches, including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing, and/or multicolor fluorescence in situ hybridization. RESULTS: Expression of 4 deoxyribonucleases correlated with genomic instability in 6 human cancers. Functional screens of these genes identified APE1 as the top candidate for further evaluation. APE1 suppression in EAC, breast, lung, and prostate cancer cell lines caused cell cycle arrest; impaired growth and increased cytotoxicity of cisplatin in all cell lines and types and in a mouse model of EAC; and inhibition of homologous recombination and spontaneous and chemotherapy-induced genomic instability. APE1 overexpression in normal cells caused a massive chromosomal instability, leading to their oncogenic transformation. Evaluation of these cells by means of whole genome sequencing demonstrated the acquisition of changes throughout the genome and identified homologous recombination as the top mutational process. CONCLUSIONS: Elevated APE1 dysregulates homologous recombination and cell cycle, contributing to genomic instability, tumorigenesis, and chemoresistance, and its inhibitors have the potential to target these processes in EAC and possibly other cancers.

Consideration of hormonal changes for orthodontic treatment during pregnancy and lactation - a review.

Hormonal changes in pregnant and lactating women significantly affect bone metabolism and overall stress levels, positioning them as a unique group within the orthodontic population. Fluctuations in estrogen, progesterone, prolactin, and other hormones are closely linked to bone remodeling and the periodontal tissue's response to inflammation caused by dental plaque. Hormones such as thyrotropin, leptin, and melatonin also play crucial roles in pregnancy and bone remodeling, with potential implications for orthodontic tooth movement. Additionally, adverse personal behaviors and changes in dietary habits worsen periodontal conditions and complicate periodontal maintenance during orthodontic treatment. Notably, applying orthodontic force during pregnancy and lactation may trigger stress responses in the endocrine system, altering hormone levels. However, these changes do not appear to adversely affect the mother or fetus. This review comprehensively examines the interaction between hormone levels and orthodontic tooth movement in pregnant and lactating women, offering insights to guide clinical practice.

The role of corticotropin-releasing hormone (CRH) family in tumors.

The corticotropin-releasing hormone (CRH) family is widely distributed among the central nervous system and peripheral tissues, such as the digestive, cardiovascular, immune, reproductive, endocrine systems. The CRH family members are widely involved in the regulation of human cell biological processes, immune response, and regulation of inflammatory processes that can affect the occurrence and development of tumors. At present, CRH family members and their receptors can be detected in many tumor tissues, and some people think that members of the CRH family may be potential tumor treatment targets as they can affect cellular processes, such as proliferation, migration, invasion, and apoptosis. However currently, there is no systematic introduction to the relationship between the CRH family and various tumors. This review introduces the molecular regulation of the CRH family in tumor formation and seeks further targeted therapy.

An Apparent Diffusion Coefficient Histogram Method Versus a Traditional 2-Dimensional Measurement Method for Identifying Non-Puerperal Mastitis From Breast Cancer at 3.0 T.

PURPOSE: This study aimed to investigate the utility of a volumetric apparent diffusion coefficient (ADC) histogram method for distinguishing non-puerperal mastitis (NPM) from breast cancer (BC) and to compare this method with a traditional 2-dimensional measurement method. MATERIALS AND METHODS: Pretreatment diffusion-weighted imaging data at 3.0 T were obtained for 80 patients (NPM, n = 27; BC, n = 53) and were retrospectively assessed. Two readers measured ADC values according to 2 distinct region-of-interest (ROI) protocols. The first protocol included the generation of ADC histograms for each lesion, and various parameters were examined. In the second protocol, 3 freehand (TF) ROIs for local lesions were generated to obtain a mean ADC value (defined as ADC-ROITF). All of the ADC values were compared by an independent-samples t test or the Mann-Whitney U test. Receiver operating characteristic curves and a leave-one-out cross-validation method were also used to determine diagnostic deficiencies of the significant parameters. RESULTS: The ADC values for NPM were characterized by significantly higher mean, 5th to 95th percentiles, and maximum and mode ADCs compared with the corresponding ADCs for BC (all P < 0.05). However, the minimum, skewness, and kurtosis ADC values, as well as ADC-ROITF, did not significantly differ between the NPM and BC cases. CONCLUSIONS: Thus, the generation of volumetric ADC histograms seems to be a superior method to the traditional 2-dimensional method that was examined, and it also seems to represent a promising image analysis method for distinguishing NPM from BC.

Applicability of internet search index for asthma admission forecast using machine learning.

OBJECTIVE: This study aimed to determine whether a search index could provide insight into trends in asthma admission in China. An Internet search index is a powerful tool to monitor and predict epidemic outbreaks. However, whether using an internet search index can significantly improve asthma admissions forecasts remains unknown. The long-term goal is to develop a surveillance system to help early detection and interventions for asthma and to avoid asthma health care resource shortages in advance. METHODS: In this study, we used a search index combined with air pollution data, weather data, and historical admissions data to forecast asthma admissions using machine learning. RESULTS: Results demonstrated that the best area under the curve in the test set that can be achieved is 0.832, using all predictors mentioned earlier. CONCLUSION: A search index is a powerful predictor in asthma admissions forecast, and a recent search index can reflect current asthma admissions with a lag-effect to a certain extent. The addition of a real-time, easily accessible search index improves forecasting capabilities and demonstrates the predictive potential of search index.

[Role of cortistain alternation in rats with chronic obstructive pulmonary disease].

OBJECTIVE: To explore the role of cortistatin (CST) in rats with chronic obstructive pulmonary disease (COPD). METHODS: A total of 16 healthy male Sprague-Dawley rats were randomly divided into control and COPD model groups (n=8 each). The COPD model group received an inhalation of passive smoking while the control group was treated normally. After 4 months, pulmonary function was measured. The differential cell counts of bronchoalveolar lavage fluid (BALF) were detected. Morphology and pathology of lungs were studied via hematoxylin and eosin staining. The levels of CST in lung tissue, serum and BALF were detected by radioimmunoassay. RESULTS: Compared with the control group, the COPD group had obviously higher airway resistance and neutrophil ratio in BALF [(0.584 ± 0.021) vs (0.653 ± 0.062) mmHg·ml⁻¹·s⁻¹, 1.49% vs 0.41%, both P<0.05]. And there were significantly serious inflammation and emphysema in lung tissues. Moreover, the levels of CST increased in serum, BALF and lung tissues [(526 ± 76) vs (453 ± 41)pg/ml, (819 ± 100) vs (619 ± 101)pg/ml, (41 ± 10) vs (20 ± 7)pg/mg, all P<0.05] respectively as compared with the controls. CONCLUSION: An elevated level of CST may compensate to exert anti-inflammation effects in COPD rats.

[Hydrogen sulfide attenuates bronchial epithelial cell apoptosis by inhibiting endoplasmic reticulum stress].

OBJECTIVE: To explore the effects of hydrogen sulfide on nicotine-induced bronchial epithelial cell endoplasmic reticulum (ER) stress and apoptosis. METHODS: Nicotine was used to establish the apoptotic model in human bronchial epithelial cell line (16HBE) for mimicing the effect of cigarette smoke on apoptosis. The 16HBE cells were grouped by the concentration gradients of 0 (control), 5, 10, 20, 40, 80 µmol/L nicotine dosing. All groups were treated for 72 h. And 16HBE cells were grouped by the time gradients of 0 (control), 24, 48, 72 h of nicotine dosing. For control group, the nicotine concentration was 40 µmol/L. Then the protein expression level of CCAAT/enhancer binding protein homologous protein (CHOP) was measured by Western blot to define the effect of various concentrations of nicotine and different dosing periods of nicotine on the protein expression level of CHOP. For observing the role of hydrogen sulfide in ER stress-mediated apoptosis, 16HBE cells were divided into 6 groups of control, 40 µmol/L nicotine, 100 µmol/L sodium hydrosulfide (NaHS) + 40 µmol/L nicotine, 200 µmol/L NaHS + 40 µmol/L nicotine, 400 µmol/L NaHS + 40 µmol/L nicotine and 10 mmol/L taurine + 40 µmol/L nicotine. NaHS or taurine was pretreated for 30 min and then nicotine dosed for 72 h. The protein expression levels of GRP78 and ER stress-mediated apoptosis markers, such as cleaved caspase-12 and CHOP, were measured by Western blot. And chromatin dye Hoechst 33258 was used to detect the morphological changes of apoptotic 16HBE cells and apoptotic index calculated. RESULTS: Nicotine could concentration and time-dependently improve the expression of CHOP in 16HBE cells. The ratio of CHOP to average absorbance of glyceraldehyde phosphate dehydrogenase (GAPDH) was significantly higher in 40 µmol/L nicotine group than that in control group (1.04 ± 0.32 vs 0.30 ± 0.17, P < 0.05). The ratio of GRP78 to average absorbance of ß-actin (0.59 ± 0.19 vs 1.00 ± 0.08), cleaved caspase-12 to average absorbance of procaspase-12 (0.06 (0.01, 6.06) vs 20.30(12.79, 23.78)) and CHOP to average absorbance of ß-actin (0.18 ± 0.10 vs 0.53 ± 0.09) in 200 µmol/L NaHS + 40 µmol/L nicotine group were all significantly lower than those in 40 µmol/L nicotine group (all P < 0.05). The apoptotic index in 200 µmol/L NaHS + 40 µmol/L nicotine group (3.04 ± 1.83 vs 16.60 ± 3.32) and apoptotic index in 10 mmol/L taurine + 40 µmol/L nicotine group (4.08 ± 2.04 vs 16.60 ± 3.32) were significantly lower than those in 40 µmol/L nicotine group (all P < 0.01). CONCLUSIONS: NaHS exerts its protection against nicotine-induced bronchial epithelial cell apoptosis through suppressing ER stress. And the underlying mechanism may be through a down-regulation of ER stress-mediated apoptosis markers of cleaved caspase-12 and CHOP.

Metformin enhances the therapeutic effects of extracellular vesicles derived from human periodontal ligament stem cells on periodontitis.

Metformin has shown outstanding anti-inflammatory and osteogenic abilities. Mesenchymal stem cell-derived extracellular vesicles (EVs) reveal promising therapeutic potency by carrying various biomolecules. This study explored the effects of metformin on the therapeutic potential of EVs derived from human periodontal ligament stem cells (PDLSCs) for periodontitis. PDLSCs were cultured in osteogenic medium with or without metformin, and the supernatant was then collected separately to extract EVs and metformin-treated EVs (M-EVs). After identifying the characteristics, we evaluated the anti-inflammatory and osteogenic effects of EVs and M-EVs in vivo and in vitro. Osteogenic differentiation of PDLSCs was markedly enhanced after metformin treatment, and the effect was dramatically inhibited by GW4896, an inhibitor of EVs' secretion. Metformin significantly increased EVs' yields and improved their effects on cell proliferation, migration, and osteogenic differentiation. Moreover, metformin significantly enhanced the osteogenic ability of EVs on inflammatory PDLSCs. Animal experiments revealed that alveolar bone resorption was dramatically reduced in the EVs and M-EVs groups when compared to the periodontitis group, while the M-EVs group showed the lowest levels of alveolar bone loss. Metformin promoted the osteogenic differentiation of PDLSCs partly through EVs pathway and significantly enhanced the secretion of PDLSCs-EVs with superior pro-osteogenic and anti-inflammatory potential, thus improving EVs' therapeutic potential on periodontitis.

Extracellular vesicles from apoptotic BMSCs ameliorate osteoporosis via transporting regenerative signals.

Rationale: Mesenchymal stromal cells (MSCs) are considered a promising resource for cell therapy, exhibiting efficacy in ameliorating diverse bone diseases. However, most MSCs undergo apoptosis shortly after transplantation and produce apoptotic extracellular vesicles (ApoEVs). This study aims to clarify the potential role of ApoEVs from apoptotic MSCs in ameliorating osteoporosis and molecular mechanism. Methods: In this study, Dio-labeled bone marrow mesenchymal stem cells (BMSCs) were injected into mice to track BMSCs apoptosis and ApoEVs production. ApoEVs were isolated from BMSCs after inducing apoptosis, the morphology, size distribution, marker proteins expression of ApoEVs were characterized. Protein mass spectrometry analysis revealed functional differences in proteins between ApoEVs and BMSCs. BMSCs were adopted to test the cellular response to ApoEVs. Ovariectomy mice were used to further compare the ability of ApoEVs in promoting bone formation. SiRNA and lentivirus were used for gain and loss-of-function assay. Results: The results showed that BMSCs underwent apoptosis within 2 days after being injected into mice and produce a substantial quantity of ApoEVs. Proteomic analysis revealed that ApoEVs carried a diverse functional array of proteins, and easily traversed the circulation to reach the bone. After being phagocytized by endogenous BMSCs, ApoEVs efficiently promoted the proliferation, migration, and osteogenic differentiation of BMSCs. In an osteoporosis mouse model, treatment of ApoEVs alleviated bone loss and promoted bone formation. Mechanistically, ApoEVs carried Ras protein and activated the Ras/Raf1/Mek/Erk pathway to promote osteogenesis and bone formation in vitro and in vivo. Conclusion: Given that BMSC-derived ApoEVs are high-yield and easily obtained, our data underscore the substantive role of ApoEVs from dying BMSCs to treat bone loss, presenting broad implications for cell-free therapeutic modalities.

Nanotube topography rejuvenates the senescence of mesenchymal stem cells by activating YAP signalling.

Improving the regenerative ability of senescent stem cells is a critical issue in combating aging. The destiny and function of senescent stem cells are controlled by the niche, including the physical architecture of the surface of the extracellular matrix (ECM). In this study, we explored the functions of TiO2 nanotube topography on mesenchymal stem cells (MSCs) under senescence, as well as its mechanical effects on senescence. First, we created different nanotube topographies on the titanium samples. Next, we cultured senescent mesenchymal stem cells (S-MSCs) on samples with various nanotube topographies to determine suitable parameters. We found nanotube with a diameter of 10 nm significantly alleviated the cellular senescence of S-MSCs and improved the osteogenic differentiation of S-MSCs in vitro. Using an ectopic periodontium regeneration model, we confirmed that specific nanotube topography could promote tissue regeneration of S-MSCs in vivo. Moreover, we demonstrated that nanotube topography activated YAP in S-MSCs and reformed nuclear-cytoskeletal morphology to inhibit senescence. Taken together, our study establishes a bridge linking between nano-topography, mechanics, and senescence, suggesting a potential strategy to improve tissue regeneration in aged individuals by providing optimized surface topography on biomaterials.

Spatial and temporal gene expression patterns during early human odontogenesis process.

Studies on odontogenesis are of great importance to treat dental abnormalities and tooth loss. However, the odontogenesis process was poorly studied in humans, especially at the early developmental stages. Here, we combined RNA sequencing (RNA-seq) with Laser-capture microdissection (LCM) to establish a spatiotemporal transcriptomic investigation for human deciduous tooth germs at the crucial developmental stage to offer new perspectives to understand tooth development and instruct tooth regeneration. Several hallmark events, including angiogenesis, ossification, axonogenesis, and extracellular matrix (ECM) organization, were identified during odontogenesis in human dental epithelium and mesenchyme from the cap stage to the early bell stage. ECM played an essential role in the shift of tooth-inductive capability. Species comparisons demonstrated these hallmark events both in humans and mice. This study reveals the hallmark events during odontogenesis, enriching the transcriptomic research on human tooth development at the early stage.

Halting multiple myeloma with MALT1 inhibition: suppressing BCMA-induced NF-κB and inducing immunogenic cell death.

ABSTRACT: Because multiple myeloma (MM) poses a formidable therapeutic challenge despite recent progress, exploring novel targets is crucial. Mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) emerges as a promising paracaspase with druggable potential, especially unexplored in MM. Our study provided compelling evidence demonstrating a statistically significant elevation of MALT1 expression in human primary MM cells. Moreover, elevated MALT1 expression was associated with a poorer prognosis in MM. Genetic deletion of MALT1 reduced cell growth, colony formation, and tumor growth in vivo. Pharmacological inhibition with 1 µM of a small-molecular MALT1 inhibitor, Mi-2, effectively inhibited cell growth, inducing mitochondria-dependent apoptotic cell death. Mechanistically, MALT1 inhibition disrupted diverse signal transduction pathways, notably impeding nuclear factor κB (NF-κB). Significantly, the inhibition of MALT1 demonstrated a substantial suppression of NF-κB activation by elevating inhibitor of NF-κB, disrupting the nuclear localization of p65 and c-REL. This effect was observed in both the basal state and when stimulated by B-cell maturation antigen, highlighting the pivotal role of MALT1 inhibition in influencing MM cell survival. It was noteworthy that Mi-2 induces properties associated with immunogenic cell death (ICD), as evidenced by increased calreticulin, adenosine triphosphate release, and high-mobility group protein B1 upregulation, consequently triggering ICD-associated immune activation and enhancing CD8+ T-cell cytotoxicity in vitro. In conclusion, our research highlights MALT1 as a promising druggable target for therapeutic interventions in MM, providing insights into its molecular mechanisms in MM progression.

Comparison of the Efficacy and Safety of Axi-Cel and Tisa-Cel Based on Meta-Analysis.

This study aimed to analyze the efficacy and safety of chimeric antigen receptor T-cell (CAR-T) therapy for B-cell lymphoma using published literature data. Literature on CAR-T therapy for B-cell lymphoma was collected by searching common databases. The literature was screened, quality assessed, and data extracted according to the inclusion and exclusion criteria. We performed a quantitative meta-analysis of the efficacy and safety of combined literature data. If the data could not be combined, descriptive analysis was performed. The meta-analysis results indicated that compared with tisagenlecleucel (tisa-cel), axicabtagene ciloleucel (axi-cel) had higher objective response rate (ORR) and complete response rate, with odds ratio (OR) of 0.63 for both sides (95% confidence interval [CI], 0.50-0.79) and statistically significant differences. Partial response rate was lower with axi-cel than with tisa-cel, with an OR of 1.02 for tisa-cel versus axi-cel (95% CI, 0.75-1.40) and no statistically significant difference. Compared with tisa-cel, axi-cel had longer progression-free survival and overall survival, with risk ratios of 0.70 (95% CI, 0.62-0.80) and 0.71 (95% CI, 0.61-0.84) for axi-cel and tisa-cel, respectively. Compared with tisa-cel, axi-cel had higher incidence rates of cytokine release syndrome (CRS) and immune effector cell-related neurotoxicity syndrome (ICANS), with ORs of 3.84 (95% CI, 2.10-7.03) and 4.4 (95% CI, 2.81-6.91), respectively. CAR T-cell therapy is an effective treatment option for relapsed/refractory B-cell lymphoma. Axi-cel has better ORR and survival advantages compared with tisa-cel; however, axi-cel has higher incidence rates of CRS and ICANS compared with tisa-cel.

Effect of chewing gum on orthodontic pain in patients receiving fixed orthodontic treatment: a systematic review and meta-analysis.

OBJECTIVES: The objective of this systematic review and meta-analysis was to evaluate the effect of chewing gum on orthodontic pain and to determine the rate of bracket breakage associated with fixed orthodontic appliances. METHODS: This review and its reporting were performed according to the Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA guidelines. Six electronic databases were searched up to March 16, 2023, to identify relevant studies that met the inclusion and exclusion criteria. Furthermore, grey literature resources were searched. The Cochrane Collaboration Risk of Bias tool 2 was used to assess the quality of the included studies. Meta-analysis was conducted using RevMan, and sensitivity analysis and publication bias analysis were performed using STATA software. GRADE tool was used to evaluate the certainty of evidence. RESULTS: Fifteen studies with 2116 participants were ultimately included in this review, and 14 studies were included in the meta-analysis. Compared with the blank group, chewing gum had a significant pain relieving effect at all times after fixation of the initial archwire (P ≤ 0.05). No significant difference was found between the chewing gum group and the analgesics group at any timepoints (P > 0.05). Only four studies evaluated the rate of bracket breakage and revealed that chewing gum did not increase the rate of bracket breakage. The sensitivity analysis showed that there was no significant difference in the pooled outcomes after the included studies were removed one at times, and Egger analysis revealed no significant publication bias in included studies (P > 0.05). CONCLUSIONS: Chewing gum is a non-invasive, low-cost and convenient method that has a significant effect on relieving orthodontic pain and has no effect on the rate of bracket breakage. Therefore, chewing gum can be recommended as a suitable substitute for analgesics to reduce orthodontic pain.

The Biological Significance Of AFF4: Promoting Transcription Elongation, Osteogenic Differentiation and Tumor Progression.

As a member of the AF4/FMR2 (AFF) family, AFF4 is a scaffold protein in the superelongation complex (SEC). In this mini-view, we discuss the role of AFF4 as a transcription elongation factor that mediates HIV activation and replication and stem cell osteogenic differentiation. AFF4 also promotes the progression of head and neck squamous cell carcinoma, leukemia, breast cancer, bladder cancer and other malignant tumors. The biological function of AFF4 is largely achieved through SEC assembly, regulates SRY-box transcription factor 2 (SOX2), MYC, estrogen receptor alpha (ESR1), inhibitor of differentiation 1 (ID1), c-Jun and noncanonical nuclear factor-κB (NF-κB) transcription and combines with fusion in sarcoma (FUS), unique regulatory cyclins (CycT1), or mixed lineage leukemia (MLL). We explore the prospects of using AFF4 as a therapeutic in Acquired immunodeficiency syndrome (AIDS) and malignant tumors and its potential as a stemness regulator.

Interaction between UV-B and plant anthocyanins.

UV-B is an important light condition for inducing anthocyanin synthesis in plants. Plants have corresponding photoreceptors such as UV RESISTANCE LOCUS8 (UVR8) and transduce light signals to the nucleus, which regulate the expression of structural and regulatory genes for anthocyanin synthesis through members such as ELONGATED HYPOCOTYL 5 (HY5), thereby increasing or decreasing anthocyanin accumulation. At the same time, excessive UV-B irradiation (artificial light experiments or extreme environmental conditions) is a light stress for plants, which can damage plants and cause DNA damage or even cell death and other adverse effects. In addition, the effect of UV-B on anthocyanin accumulation in plants is usually combined with other abiotic factors, including other wavelengths of light, water deficit conditions, high or low temperatures, and heavy metal ions, all of which cause plants to change their anthocyanin accumulation in time to adapt to variable survival conditions. The review aims to bring together our understanding of the interactions between UV-B and anthocyanins, which can help further the development of the anthocyanin industry.

[Experimental study of APB-DOCK8 transgenic tomato vaccine for caries prevention].

PURPOSE: To observe the anti-caries effect of transgenic tomato anti-caries vaccine after immunization with SD rats by gavage and to explore its immunity mechanism initially. METHODS: SD rats were used to establish an experimental caries model. The transgenic anti-caries tomatoes expressing the target protein were cultivated and identified. The SIgA and IgG contents of specific anti-PAcA in saliva and blood samples of SD rats were detected by ELISA. Then, the SD rats were sacrificed, the maxillary and mandibular bones were taken for Keyes dental caries score, and spleens were taken for the analysis of RNA-seq. Statistical analysis was performed with SPSS 18.0 software package. RESULTS: The target protein concentration in the transgenic tomato anti-caries vaccine was 36.28 µg/mL. After vaccine immunization of SD rats, group D (8 mL/kg) produced the highest levels of specific SIgA and IgG antibodies at week 6 and was significantly different from the other groups(P＜0.05), and caries counting score was also significantly different than the other groups (P＜0.05). The spleen mRNA of SD rats in group D was extracted and sequenced by RNA-seq, and 40 genes with significant differences in mRNA expression were obtained(P-adjust＜0.05, |Fold Change|≥1.5). 26 genes were significantly upregulated, including IGFBP6 and COL15A1. The upregulated gene GO enrichment was enriched to humoral immune response, B-cell activation, and immunoglobulin receptor binding; KEGG enrichment was enriched to 56 signaling pathways, including PI3K-AKT and NF-κB, and F＜0.001. Fourteen genes were significantly downregulated, but the analysis of downregulated gene GO and KEGG enrichment was not statistically significant(F＞0.1). CONCLUSIONS: Transgenic tomato anti-caries vaccine may reduce caries occurrence by upregulating the activation of PI3K-AKT signaling pathway mediated by IGFBP6 in SD rats.

Skeletal muscle-derived extracellular vesicles transport glycolytic enzymes to mediate muscle-to-bone crosstalk.

Identification of cues originating from skeletal muscle that govern bone formation is essential for understanding the crosstalk between muscle and bone and for developing therapies for degenerative bone diseases. Here, we identified that skeletal muscle secreted multiple extracellular vesicles (Mu-EVs). These Mu-EVs traveled through the bloodstream to reach bone, where they were phagocytized by bone marrow mesenchymal stem/stromal cells (BMSCs). Mu-EVs promoted osteogenic differentiation of BMSCs and protected against disuse osteoporosis in mice. The quantity and bioactivity of Mu-EVs were tightly correlated with the function of skeletal muscle. Proteomic analysis revealed numerous proteins in Mu-EVs, some potentially regulating bone metabolism, especially glycolysis. Subsequent investigations indicated that Mu-EVs promoted the glycolysis of BMSCs by delivering lactate dehydrogenase A into these cells. In summary, these findings reveal that Mu-EVs play a vital role in BMSC metabolism regulation and bone formation stimulation, offering a promising approach for treating disuse osteoporosis.

ApoSEVs-Mediated Modulation of Versatile Target Cells Promotes Diabetic Wound Healing: Unveiling a Promising Strategy.

Background: Diabetic chronic wounds present a formidable challenge in clinical management, lacking effective treatment options. Mesenchymal stem cell (MSC) transplantation has emerged as a promising therapy for tissue repair and regeneration. However, transplanted MSCs often undergo rapid apoptosis, giving rise to heterogeneous extracellular vesicles (EVs), including apoptotic bodies (apoBDs) and apoptotic small extracellular vesicles (apoSEVs). The potential stimulatory role of these EVs in diabetic wound healing remains unknown. Methods: In this study, we investigated the effects of apoSEVs derived from adipose-derived mesenchymal/stromal cells (ADSCs) on the recovery of diabetic wounds by modulating the function of versatile target cells. First, we characterized the apoSEVs and apoBDs derived from apoptotic ADSCs. Subsequently, we evaluated the effects of apoSEVs and apoBDs on macrophages, endothelial cells, and fibroblasts, three essential cell types in wound healing, under high-glucose conditions. Furthermore, we developed a gelatin methacryloyl (GelMA) hydrogel for the sustained release of apoSEVs and investigated its therapeutic effects on wound healing in type 2 diabetic mice in vivo. Results: apoSEVs facilitated the polarization of M1 phenotype macrophages to M2 phenotype, promoted proliferation, migration, and tube formation of endothelial cells, and enhanced fibroblast proliferation and migration. However, apoBDs failed to improve the function of endothelial cells and fibroblasts. In vivo, the apoSEVs-loaded GelMA effectively promoted wound healing by facilitating collagen fiber deposition, angiogenesis, and immune regulation. Conclusion: Our study elucidates the beneficial effects of apoSEVs on wound recovery in diabetes and introduces a novel strategy for diabetic wound treatment based on apoSEVs.