Fibroblasts facilitate lymphatic vessel formation in transplanted heart.

Rationale: Lymphangiogenesis plays a critical role in the transplanted heart. The remodeling of lymphatics in the transplanted heart and the source of newly formed lymphatic vessels are still controversial, especially the mechanism of lymphangiogenesis remains limited. Methods: Heart transplantation was performed among BALB/c, C57BL/6J, Cag-Cre, Lyve1-CreERT2;Rosa26-tdTomato and Postn(2A-CreERT2-wpre-pA)1;Rosa26-DTA mice. scRNA-seq, Elisa assay, Western blotting, Q-PCR and immunohistochemical staining were used to identify the cells and cell-cell communications of allograft heart. Cell depletion was applied to in vivo and in vitro experiments. Whole-mount staining and three-dimensional reconstruction depicted the cell distribution within transparent transplanted heart. Results: Genetic lineage tracing mice and scRNA-seq analysis have revealed that these newly formed lymphatic vessels mainly originate from recipient LYVE1+ cells. It was found that LECs primarily interact with activated fibroblasts. Inhibition of lymphatic vessel formation using a VEGFR3 inhibitor resulted in a decreased survival time of transplanted hearts. Furthermore, when activated fibroblasts were ablated in transplanted hearts, there was a significant suppression of lymphatic vessel generation, leading to earlier graft failure. Additional investigations have shown that activated fibroblasts promote tube formation of LECs primarily through the activation of various signaling pathways, including VEGFD/VEGFR3, MDK/NCL, and SEMA3C/NRP2. Interestingly, knockdown of VEGFD and MDK in activated fibroblasts impaired cardiac lymphangiogenesis after heart transplantation. Conclusions: Our study indicates that cardiac lymphangiogenesis primarily originates from recipient cells, and activated fibroblasts play a crucial role in facilitating the generation of lymphatic vessels after heart transplantation. These findings provide valuable insights into potential therapeutic targets for enhancing graft survival.

Remote Ischemic Conditioning Mediates Cardio-protection After Myocardial Ischemia/Reperfusion Injury by Reducing 4-HNE Levels and Regulating Autophagy via the ALDH2/SIRT3/HIF1α Signaling Pathway.

Remote ischemic conditioning (RIC) can be effectively applied for cardio-protection. Here, to clarify whether RIC exerts myocardial protection via aldehyde dehydrogenase 2 (ALDH2), we established a myocardial ischemia/reperfusion (I/R) model in C57BL/6 and ALDH2 knockout (ALDH2-KO) mice and treated them with RIC. Echocardiography and single-cell contraction experiments showed that RIC significantly improved myocardial function and alleviated I/R injury in C57BL/6 mice but did not exhibit its cardioprotective effects in ALDH2-KO mice. TUNEL, Evan's blue/triphenyl tetrazolium chloride, and reactive oxygen species (ROS) assays showed that RIC's effect on reducing myocardial cell apoptosis, myocardial infarction area, and ROS levels was insignificant in ALDH2-KO mice. Our results showed that RIC could increase ALDH2 protein levels, activate sirtuin 3 (SIRT3)/hypoxia-inducible factor 1-alpha (HIF1α), inhibit autophagy, and exert myocardial protection. This study revealed that RIC could exert myocardial protection via the ALDH2/SIRT3/HIF1α signaling pathway by reducing 4-HNE secretion.

Compositional and functional changes in the salivary microbiota related to oral leukoplakia and oral squamous cell carcinoma: a case control study.

BACKGROUND: Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumours with increasing incidence, and oral leukoplakia (OLK) has a strong tendency to undergo malignant transformation. The oral microbiota may influence oral cancer progression, but the salivary bacterial composition and functional changes in OSCC and OLK have not been comprehensively elucidated. Therefore, we compared salivary bacteria in OLK and OSCC patients with healthy controls (HC). METHODS: Metagenomic sequencing was used to compare the bacterial composition and functional changes of 18 OSCC patients, 21 OLK patients and 21 HC. Spearman correlation was used to identify possible associations between functions and bacteria. RESULTS: Gemella was the most differentially enriched genus in OSCC. At the species level, Streptococcus sp. NPS 308, Streptococcus agalactiae, Gemella haemolysans and Gemella morbillorum were slightly increased in OLK and OSCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) results showed that OSCC was mainly associated with metabolism functions, including lipid metabolism, carbohydrate metabolism and glycan biosynthesis and metabolism. The synthesis and degradation of ketone bodies, cysteine and methionine metabolism and glycerolipid metabolism differed significantly among the three groups, and were highest in OSCC and lowest in HC. And G. haemolysans was significantly associated with these selected metabolic pathways. CONCLUSIONS: Metagenomic analysis revealed significant differences in the salivary microbiota among OSCC, OLK and HC. Thus, salivary microbiota composition and functional changes may be associated with OSCC progression. Metabolism of nonessential amino acids such as cysteine and methionine in bacteria may play an important role in oral oncogenesis, and more studies of the mechanism between metabolisms of bacteria and oral oncogenesis are needed in the future.

The global prevalence of oral leukoplakia: a systematic review and meta-analysis from 1996 to 2022.

BACKGROUND: Oral leukoplakia(OLK) is a common oral potentially malignant disorder. The global prevalence of solely OLK was published in 2003, while the prevalence varied among different studies. In recent years, large-scale summary and definition-related analyses obtain insufficient attention. This study aimed to perform a systematic review of prevalence studies of oral leukoplakia and assess predisposing factors of its occurrence. METHODS: The search terms ("Oral leukoplakia" OR OLK OR leukoplakia) AND (prevalence OR incidence OR epidemiology) were searched in databases (Pubmed, Embase, Scopus, and Web of Science) for OLK studies published from January 1996 until December 2022. The estimated prevalence calculation and risk of bias analysis used STATA 16.0. RESULTS: We obtained 69 studies, including 1,263,028 participants, from 28 countries, and 6 continents. The prevalence was 1.39%, varying from 0.12 to 33.33%. The overall pooled estimated prevalence of OLK was 2.23% for population-based studies, 1.36% for clinic-based population studies, and 9.10% for specific populations. The pooled prevalence in different continents ranged from 0.33 to 11.74% with a statistical difference in the population-based calculation. The estimated prevalence of OLK was higher in males than in females. Those who smoked and consumed alcohol had a higher prevalence than those who did not. CONCLUSION: Combining data from 69 published studies, the prevalence of OLK was determined as 1.39% and the pooling estimated global prevalence was 3.41%. The prevalence was relatively consistent and stable across different continents and different definitions. A higher pooled estimated prevalence was found among males, those aged over 60 years old, smokers, and alcohol consumers. The results from the included studies in this systematic review revealed that the prevalence was relatively consistent and stable across various definitions and continents, which may help in developing global treatment and prevention strategies for oral leukoplakia.

Gut microbiome profile of Chinese hypertension patients with and without type 2 diabetes mellitus.

BACKGROUND: The coexistence of hypertension and type 2 diabetes mellitus (T2DM) may largely increase the risk for cardiovascular disease. However, there is no clear consensus on the association between hypertension and the risk of diabetes. Gut microbiota plays important roles in the development of hypertension and T2DM, but whether there is difference between hypertension patients with or without T2DM has not been explored yet. METHODS: We recruited 101 hypertension patients in this study (72 patients without T2DM named HT group and 29 patients with T2DM named HT-T2DM group). Their blood samples were collected for testing clinical characteristics and fecal samples were tested for bacterial DNA using 16 S ribosomal RNA gene sequencing targeting the V3 and V4 region. The data of 40 samples were downloaded from project PRJNA815750 as health control (HC group) in this study. The community composition and structure of the microbiome, taxonomic difference, co-occurrence network and functional enrichment were analyzed by alpha/beta diversity, LEfSe, Fruchterman Reingold's algorithm and PICRUSt2 functional analysis, respectively. RESULTS: Alpha and beta diversity analysis showed significant differences in microbial community richness and composition among the three groups. The HC group had a significantly higher Simpson index and a distinct microbiota community compared to the HT and HT-T2DM groups, as demonstrated by significant differences in unweighted and weighted UniFrac distances. The LEfSe analysis identified specific taxa that had significantly different abundance among the groups, such as Bacteroides uniformis, Blautia wexlerae, Alistipes putredinis, and Prevotella stercorea in the HC group, Prevotella copri and Phascolarctobacterium faecium in the HT group, and Klebsiella pneumoniae in the HT-T2DM group. Co-occurrence network analysis indicates that Prevotella copri, Mediterraneibacter gnavus, Alistipes onderdonkii and some unidentified species act as key nodes in the network. Differentially functional pathway identified by PICRUSt2 were concentrated in nutrition and energy metabolism, as well as the biosynthesis of other secondary metabolites. CONCLUSIONS: Our study found significant differences in microbial community richness, composition, and function among the healthy controls, hypertension patients with and without T2DM. Some specific taxa may explain this difference and serve as potential therapeutic targets for hypertension, T2DM, and their coexistence.

The Effect of Lymphangiogenesis in Transplant Arteriosclerosis.

BACKGROUND: Transplant arteriosclerosis is a major complication in long-term survivors of heart transplantation. Increased lymph flow from donor heart to host lymph nodes has been reported to play a role in transplant arteriosclerosis, but how lymphangiogenesis affects this process is unknown. METHODS: Vascular allografts were transplanted among various combinations of mice, including wild-type, Lyve1-CreERT2;R26-tdTomato, CAG-Cre-tdTomato, severe combined immune deficiency, Ccr2KO, Foxn1KO, and lghm/lghdKO mice. Whole-mount staining and 3-dimensional reconstruction identified lymphatic vessels within the grafted arteries. Lineage tracing strategies delineated the cellular origin of lymphatic endothelial cells. Adeno-associated viral vectors and a selective inhibitor were used to regulate lymphangiogenesis. RESULTS: Lymphangiogenesis within allograft vessels began at the anastomotic sites and extended from preexisting lymphatic vessels in the host. Tertiary lymphatic organs were identified in transplanted arteries at the anastomotic site and lymphatic vessels expressing CCL21 (chemokine [C-C motif] ligand 21) were associated with these immune structures. Fibroblasts in the vascular allografts released VEGF-C (vascular endothelial growth factor C), which stimulated lymphangiogenesis into the grafts. Inhibition of VEGF-C signaling inhibited lymphangiogenesis, neointima formation, and adventitial fibrosis of vascular allografts. These studies identified VEGF-C released from fibroblasts as a signal stimulating lymphangiogenesis extending from the host into the vascular allografts. CONCLUSIONS: Formation of lymphatic vessels plays a key role in the immune response to vascular transplantation. The inhibition of lymphangiogenesis may be a novel approach to prevent transplant arteriosclerosis.

Identification of Six microRNAs as Potential Biomarkers for Pemphigus Vulgaris: From Diagnosis to Pathogenesis.

BACKGROUND: Pemphigus vulgaris (PV) is a potentially fatal autoimmune bullous disease. The role of microRNA (miRNA, miR) in the diagnosis and pathogenesis of PV remains unknown. This study aims to provide potential miRNA biomarkers for PV diagnosis and therapy options. METHODS: Serum samples were obtained from 22 PV patients, 15 mucous membrane pemphigoid (MMP) patients, and 10 normal controls (NC). Total RNA was extracted from the serum samples, and 12 selected miRNAs were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatic analyses including target gene prediction and enrichment analysis were performed. RESULTS: Twelve miRNAs were increased in the serum of the PV group compared with the NC group, in which six miRNAs had good efficacy to diagnose PV from MMP with the area under the receiver operator characteristic curves of 0.970 to 0.988. A series test for the combination of miR-584-5p and miR-155-5p reached the sensitivity and specificity of 95.5% and 100%. Bioinformatic analysis revealed target gene enrichment in the cell adhesion pathways, immune-relating pathways, and P38 mitogen-activated protein kinases signaling pathway. CONCLUSION: The study provides new insights and targets of miRNAs for the precise diagnosis and the exploration of pathogenesis for PV, which may serve as a reference for further research into autoimmune bullous diseases.

Rare mucocutaneous manifestations of ulcerative colitis: A case report of pyostomatitis vegetans and Sweet syndrome.

Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the digestive tract, and they involve systemic inflammatory diseases known as extra-intestinal manifestations (EIMs). Timely and correct diagnosis of mucocutaneous EIMs could assist with detecting and monitoring IBD. We present a case of 52-year-old male patient of ulcerative colitis with 2 rare EMIs together at the same time: pyostomatitis vegetans in the oral cavity and Sweet syndrome on the skin. They presented as multiple small white or yellow pustules on the surface of the hyperemic fragile oral mucosa and abrupt appearance of painful, swollen, and erythematous papules on the skin, respectively. The final diagnosis was made based on clinical manifestations, skin and oral tissue biopsies, and the ulcerative colitis history. This rare case report may remind dentists of rare mucocutaneous EIMs of IBD that might be overlooked. Dentists and dermatologists could contribute to the early diagnosis and management of systematic diseases.

Allergic contact stomatitis due to desensitizing toothpastes.

Toothpastes are one of the most common personal care products among people of all ages. The various toothpaste types and their complex ingredients could cause irritation or allergic reactions. Allergic contact stomatitis has been often seen in clinical practice; however, desensitizing toothpastes as a trigger are often unrecognized. Here, we report three cases of allergic contact stomatitis due to stannous chloride-containing desensitizing toothpastes. General dentists and other professionals should pay more attention to the safety and adverse effects of toothpastes.

Successful treatment of chronic hyperplastic candidiasis with 5-aminolevulinic acid photodynamic therapy: A case report.

Chronic hyperplastic candidiasis (CHC) is a chronic oral mucosal infection caused by Candida. Refractory hyperplastic lesions may lead to epithelial dysplasia and carcinogenesis. Traditional surgical resection may cause irreversible damage and effect the patient's quality of life. This paper reports the case of a 63-year-old man with CHC. After routine treatment, local hyperplastic lesions remained. Photodynamic therapy with ALA was applied to the hyperplastic lesions and yielded satisfactory results, with no recurrence at 1 year. This case report describes a promising, effective method for the treatment of CHC.

Nonbone Marrow CD34+ Cells Are Crucial for Endothelial Repair of Injured Artery.

[Figure: see text].

Direct immunofluorescence analysis of oral Tzanck smears for pemphigus vulgaris: A diagnostic test.

BACKGROUND: Pemphigus vulgaris (PV) is a rare and potentially fatal autoimmune blistering disease. Direct immunofluorescence (DIF) and histopathological analysis are crucial methods for PV diagnosis, but oral tissue biopsy is difficult to perform because of the fragile characteristics of the oral mucosa. However, no well-designed diagnostic studies addressing the validity of DIF analysis of oral Tzanck smears for the diagnosis of PV exist. We aimed to design a diagnostic test based on DIF analysis combined with oral Tzanck smears and evaluate its diagnostic accuracy for PV. METHODS: We enrolled 81 patients with oral erosive lesions, of whom 41 patients had PV and 40 were non-PV controls. Oral Tzanck smears were obtained from oral mucosal lesions and observed under a fluorescence microscope after fixing and fluorescence staining. The diagnostic efficacy indexes including sensitivity, specificity, predictive value, Youden index, diagnostic odds ratio, and likelihood ratio were calculated. RESULTS: Of the 41 PV patients, 36 showed DIF-positive findings for oral Tzanck smears, and all 36 DIF-positive PV patients showed IgG and/or C3 deposition, with seven also showing IgA and/or IgM positivity. None of the non-PV controls showed DIF positivity. The sensitivity and specificity of DIF analysis with oral Tzanck smears were 87.80% and 100%, respectively. The area under the receiver operator characteristic curve (ROC) was 0.939, with the test demonstrating significantly high diagnostic efficacy. CONCLUSION: DIF analysis of oral Tzanck smears is a minimally invasive and easy-to-operate technique that can assist the rapid and accurate diagnosis of PV in dental clinic.

Association between cheilitis granulomatosa and odontogenic infections: A case-control study.

The association between cheilitis granulomatosa and dental infections (dental caries and apical periodontitis) is still not well understood. Herein, we aimed to investigate the association in large hospital cases with cohort controls. Cheilitis granulomatosa cases (n = 181) were retrieved from Peking University Hospital of Stomatology and age- and sex-matched to controls (n = 181). The χ2 -test, Student's t-test, and Mann-Whitney U-test were used to compare the differences between groups. The χ2 -test and odds ratio were used to verify if there was an association and risk relationship. The results showed that both dental caries and apical periodontitis were associated with cheilitis granulomatosa (p < 0.001). Individuals with cheilitis granulomatosa had approximately a twofold increased frequency of dental caries than those without cheilitis granulomatosa (104/181, 57.5% vs. 53/181, 29.3%) (p < 0.001). The odds ratio of dental caries occurring in the case group compared to the control group was 3.211. The frequency of apical periodontitis in patients with cheilitis granulomatosa was significantly greater than in those without cheilitis granulomatosa (109/181, 60.2% vs. 28/181, 15.5%) (p < 0.001). The odds ratio was 8.272. Moreover, apical periodontitis was also locationally related to cheilitis granulomatosa (p < 0.001). Collectively, our study showed that the foci of dental infections are associated with cheilitis granulomatosa, suggesting that proper treatment of focal teeth may be important in the management of cheilitis granulomatosa.

Impact of Left Atrial Sphericity Index on the Outcome of Catheter Ablation for Atrial Fibrillation.

Left atrial sphericity index (LASI) is one significant geometric remodeling parameter to evaluate the prognosis of atrial fibrillation (AF). We aimed to determine whether transthoracic echocardiography (TTE)-derived LASI may help predict the outcomes following AF radiofrequency catheter ablation (RFCA). This prospective study enrolled 190 consecutive AF patients who underwent TTE 24 h before RFCA. LASI was calculated as the ratio of left atrial maximum volume to spherical volume. After 1-year follow-up, 56 patients (29.5%) relapsed. Multivariate Cox regression showed that LASI (hazard ratio = 1.48, 95% Cl 1.15-1.92, P = 0.003) was an independent predictor of AF recurrence. Stratifying patients into four subgroups with different LAVI showed that high LASI value indicated a high risk of recurrence, especially in patients with mildly and moderately enlarged atria (the recurrence rate was 0% vs. 26.3%, P = 0.049; 9.5% vs. 40.9%, P = 0.018, respectively). In conclusion, TTE-derived LASI may be useful to predict AF recurrence after RFCA.

Circulating long noncoding RNA, GAS5, as a novel biomarker for patients with atrial fibrillation.

BACKGROUND: Circulating long noncoding RNA (lncRNA) plays a vital role in clinical disease diagnosis and prognosis. Here, we evaluate the role of a lncRNA, named growth arrest specific 5 (GAS5), in atrial fibrillation (AF). METHODS: Expression of GAS5 was measured by qRT-PCR. Diagnostic and prognostic values of GAS5 were assessed by the receiver operating characteristics curve (ROC), Kaplan-Meier (KM) and Cox regression analyses. RESULTS: A total of 173 participants were enrolled in this study. Circulating GAS5 expression was significantly down-regulated in AF patients. This change occurred prior to enlargement of the left atrial volume and was strongly associated with AF progression, which demonstrates the potential use of GAS5 as an early biomarker. The area under the ROC curve (AUC) was 0.858 (95% CI 0.789-0.926, P < .001). Seventy of the 85 AF patients received radiofrequency catheter ablation (RFCA), and 22 (31.4%) had relapsed by the 1-year follow-up. The KM analysis (log-rank test, P = .031) and multivariable Cox analysis (HR = 0.127, 95% CI 0.026-0.616; P = .01) revealed that GAS5 has a role in predicting recurrence after RFCA. CONCLUSION: Circulating lncRNA GAS5 is a potential biomarker for AF diagnosis and prognosis. Down-regulation of GAS5 occurs prior to left atrial enlargement and can be used for the prognosis of AF progression and recurrence.

Noncoding RNAs in Atrial Fibrillation: Current Status and Prospect.

Atrial fibrillation (AF) is an important cause of cardiovascular morbidity and mortality. Current therapies for AF are ineffective, mainly due to incomplete understanding of the pathogenesis of AF. Atrial remodeling contributes to the occurrence and progression of AF, but molecular mechanisms underlying AF remain unclear. Noncoding RNAs, including microRNAs, long noncoding RNAs and circular RNAs, are now considered to play an important role in the pathophysiology of AF. In this review, we summarize recent evidence supporting the role of noncoding RNAs in AF and highlight their diagnostic and prognostic applications as potential biomarkers and therapeutic strategies.

Characteristics of the salivary microbiota in cheilitis granulomatosa

BACKGROUND: Cheilitis granulomatosa (CG) is a disturbing and persistent idiopathic lip swelling. The cause and treatment has not been wholly elucidated. Some reports infer that CG is mainly associated with dental infection but no firm or reliable microbiological evidence has been provided for a causative organism. This study aimed to evaluate whether microorganisms contribute to the etiology of CG in order to inform appropriate treatment op-tions in clinic. MATERIAL AND METHODS: Unstimulated saliva was collected from 15 CG patients who were diagnosed clinically and pathologically and 15 healthy controls (HC). DNA was extracted from the precipitate of the centrifuged saliva for 16s rRNA high-throughput sequencing using the Miseq PE300 platform. The distribution of the microbiome between the two groups was compared. RESULTS: CG patients had a greater microbial flora that was more diverse than the HC. Prevotella, Alloprevotella, Porphyromonas, Actinomyces, Rothia, Fusobacterium, Haemophilus, and Aggregatibacter had a significantly higher abundance in CG patients. In contrast, Streptococcus and Campylobacter were the most abundant genera in HC with a mean relative abundance of 63% and 2%, respectively. The microbiological network indicated that most of the bacteria that were enriched at greater levels in CG patients were likely to be Prevotella, Actinomyces, and Rothia. These have been shown to co-exist with other bacteria. CONCLUSIONS: The composition and structure of bacterial communities in CG patients were different from HC. Most of the genera observed in CG patients were associated with periodontitis and pulp infection. These findings might be helpful in understanding the etiology of CG. Further study will be needed to confirm these findings and explore the underlying pathological mechanism

No disponible

The deficiency of miR-214-3p exacerbates cardiac fibrosis via miR-214-3p/NLRC5 axis.

Cardiac fibrosis is a common pathological feature of many cardiovascular diseases. The regulatory mechanisms of miRNAs in cardiac fibrosis are still unknown. Previous studies on miR-214-3p in cardiac fibroblasts reached contradictory conclusions. Thus the role of miR-214-3p in cardiac fibrosis deserves further exploration. Using a combination of in vitro and in vivo studies, we identified miR-214-3p as an important regulator of cardiac fibrosis, and the proliferation and activation of cardiac fibroblasts. We demonstrated that the expression of miR-214-3p is down-regulated in TGF-ß1-treated myofibroblasts and transverse aortic constriction (TAC)-induced murine model. Additionally, miR-214-3pflox/flox/FSP1-cre mice and miR-214-3pwt/wt/FSP1-cre mice were subjected to TAC operation or sham operation, and the conditional knockout of miR-214-3p in cardiac fibroblasts aggravates TAC-induced cardiac fibrosis. In vitro, our results indicate that miR-214-3p is an important repressor for fibroblasts proliferation and fibroblast-to-myofibroblast transition by functionally targeting NOD-like receptor family CARD domain containing 5 (NLRC5). In conclusion, our findings show that the deficiency of miR-214-3p exacerbates cardiac fibrosis and reveal a novel miR-214-3p/NLRC5 axis in the regulation of cardiac fibrosis.

[Research progress on miR-21 in heart diseases].

Pathological processes such as myocardial apoptosis, cardiac hypertrophy, myocardial fibrosis, and cardiac electrical remodeling are involved in the development and progression of most cardiac diseases. MicroRNA-21 (miR-21) has been found to play an important role in heart diseases as a novel type of endogenous regulators, which can inhibit cardiomyocyte apoptosis, improve hypertension and cardiac hypertrophy, promote myocardial fibrosis and atrial electrical remodeling. In this review, we summarize the research progress on the function of miR-21 in heart diseases and its mechanism, and discuss its potential application in diagnosis and treatment of heart diseases.