Glutamine promotes the proliferation of epithelial cells via mTOR/S6 pathway in oral lichen planus.

BACKGROUND: Although abnormal cell proliferation and apoptosis are associated with the pathogenesis of oral lichen planus (OLP), the exactly mechanism of which is not yet known. It has been reported that glutamine (Gln) can promote cell proliferation and inhibit apoptosis of various tumor cells. This study aims to evaluate the effect of Gln metabolism on the balance of proliferation and apoptosis in epithelial cells of OLP. METHODS: Thirty human OLP specimens and 11 normal controls were stained by immunohistochemistry to detect the levels of proliferation and Gln metabolism related proteins. Then, the critical role of Gln in cell proliferation and apoptosis was determined by Gln deprivation or treatment with glutaminase inhibitor (CB-839) to intervene Gln metabolism in human gingival epithelial cells. Cell proliferation was detected using CCK8, p-mTOR and p-S6 proteins were detected using Western Blot, cell apoptosis and cell cycle were detected using flow cytometry, and cell stress was detected using immunofluorescence. RESULTS: Compared with normal controls, OLP specimens showed higher levels of Ki-67 and Gln metabolism-related proteins, including Gln transporter (ASCT2), glutaminase (GLS), and pathway proteins (p-mTOR and p-S6). In vitro, Gln promoted cell proliferation and simultaneously upregulated the activity of mTOR/S6 pathway. Moreover, rapamycin, an mTOR pathway inhibitor, could effectively block the Gln-induced cell proliferation. MHY1485, an mTOR pathway agonist, could effectively reverse the decline of cell proliferation under Gln deprivation. In addition, inhibiting Gln metabolism caused the accumulation of intracellular radical oxygen species (ROS) and induced cell apoptosis. However, N-acetylcysteine reversed this state and then decreased cell apoptosis by eliminating intracellular ROS. CONCLUSION: Gln metabolism is essential to maintain the balance of proliferation and apoptosis in oral epithelial cells, and inhibition of Gln metabolism may have a beneficial effect on OLP treatment.

Efficacy and safety of topical administration of tacrolimus in oral lichen planus: An updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Symptomatic oral lichen planus is a common chronic T-cell-mediated disorder characterized by pain and inflammation. The meta-analysis aimed to compare and evaluate the effects and safety of tacrolimus for treating patients with symptomatic oral lichen planus. METHODS: A comprehensive literature review was performed, including PubMed, the Cochrane Library, Embase, and Web of Science published up to and including December 2020. ClinicalTrials.gov was searched for ongoing trials. There were no restrictions on language or date of publication. Using the Cochrane Collaboration tool, we assessed the risk of bias for randomized controlled trials and estimated the proportion of between-trial heterogeneity. RESULTS: A total of 9 RCTs evaluating the effects of tacrolimus were included in this study. The results revealed no significant difference in clinical resolution and relapse between tacrolimus and corticosteroids. However, tacrolimus may be more likely to cause mild adverse effects. In particular, clinical resolution was not significantly different between tacrolimus and clobetasol propionate, and between tacrolimus and triamcinolone acetonide, while tacrolimus was more likely to cause adverse effects than triamcinolone acetonide and clobetasol propionate. Moreover, there was no significant difference in pain resolution between tacrolimus and clobetasol. Furthermore, adverse effects were not significantly different between tacrolimus and pimecrolimus. CONCLUSIONS: This systematic review and meta-analysis of 9 clinical trials supported the short-term application of tacrolimus as an effective regimen in OLP patients resistant to other topical and systemic therapies. Furthermore, the adverse effects of tacrolimus were minor and transient and did not affect tacrolimus' continued application.

Epithelial-to-mesenchymal transition in oral squamous cell carcinoma: Challenges and opportunities.

Oral squamous cell carcinoma (OSCC) is the most common malignancy representing 90% of all forms of oral cancer worldwide. Although great efforts have been made in the past decades, the 5-year survival rate of OSCC patients is no more than 60% due to tumor metastasis and subsequent recurrence. The metastasis from the primary site is due to a complex process known as epithelial-to-mesenchymal transition (EMT). During the EMT, epithelial cells gradually acquire the structural and functional characteristics of mesenchymal cells, leading to the upregulation of cell migration and the promotion of tumor cell dissemination. Therefore, EMT attracted broad attention due to its close relationship with cancer invasion and metastasis. Therefore, in the present review, an extensive description of the current research on OSCC and the role of EMT in this cancer type is provided, including diverse EMT markers, regulatory networks and crucial EMT-inducing transcription factors in OSCC. Moreover, a brief summary was made regarding the current application of EMT-correlated indexes in the prognostic analysis of OSCC patients, and the potential therapeutic approaches against OSCC and difficulties in the development of an effective anti-EMT treatment are discussed. Our aim is to provide novel insights to develop new strategies to combat OSCC by targeting EMT.

TLR-4 targeting contributes to the recovery of osteoimmunology in periodontitis.

OBJECTIVE: The aim of this study was to determine the potential role of TLR-4 in the osteoimmunological imbalance of periodontitis. BACKGROUND: Although current evidence supports that TLR-4 plays an important role in the inflammatory response of periodontal tissues triggered by microorganisms, little information is available regarding the function of TLR-4 in the osteoimmune regulation of homeostasis in periodontitis. METHODS: Human gingival epithelial cells (HGEC) were isolated from the gingival tissues of 3 healthy volunteers and the expression of osteoclastogenic cytokines was evaluated by ELISA and real time RT-PCR. In addition, 30 C57BL/6 mice were used and randomly divided into three groups: control group, periodontitis group (CP) and periodontitis+TAK-242 (a specific inhibitor of TLR-4) group (TAK-242) and the expression of osteoclastogenic cytokines and the osteoclast density in the periodontal tissue were evaluated by immunohistochemical staining and tartrate resistant acid phosphatase staining. Moreover, micro-computed tomography (Micro-CT) was used to assess bone resorption. RESULTS: The in vitro results showed that TAK-242 blocked the overproduction of IL-1, IL-6, TNF-α and RANKL in HGEC treated with LPS. The in vivo results revealed that TAK-242 also effectively decreased these osteoclastogenic cytokines in periodontal tissue of mice with periodontitis. More importantly, Micro-CT analysis showed a significant reduction of the alveolar bone loss in the TAK-242 group compared with the CP group. Furthermore, the TRAP staining showed a significant lower density of osteoclasts in the alveolar bone area of the TAK-242 group. CONCLUSION: TLR-4 inhibition decreased the differentiation of osteoclast through the inhibition of the overproduction of osteoclastogenic cytokines and the prevention of the alveolar bone absorption in mouse periodontitis models. Therefore, the use of TAK-242 might contribute to the recovery of the osteoimmunological homeostasis and might provide a potential strategy to treat periodontal diseases.

CCL2 promotes cell migration by inducing epithelial-mesenchymal transition in oral squamous cell carcinoma.

BACKGROUND: Although a few studies suggested that the chemokine CCL2 might be involved in the development of oral squamous cell carcinoma (OSCC), the exact mechanism remains unclear. In this study, we aimed to determine the resource of CCL2 in lesions and explored a potential mechanism that CCL2 promotes tumor progression. The study was an effort to provide new insights into the pathological role of CCL2 in OSCC. METHODS: Specimens of OSCC and normal oral mucosa were stained using immunohistochemistry (IHC) to assess the CCL2 expression. Enzyme-linked immunosorbent assay (ELISA) was used to detect the difference of CCL2 between OSCC and normal oral mucosa cell lines. In addition, we treated OSCC cells with exogenous rCCL2 combined with or without CCL2 neutralizing antibody and then determined the changes of in epithelial-mesenchymal transition (EMT) markers and cell migration capacity using immunofluorescence, Western blotting, transwell migration, and wound healing assays. RESULTS: We have found that CCL2 expression was upregulated significantly in both lesions and cell culture supernatant of OSCC compared with controls. IHC staining demonstrated that CCL2 expression was primarily located in the cytoplasm and cell membrane of cells. We have also found that rCCL2 could effectively induce EMT through upregulating Snail in OSCC cells, which was demonstrated by the decrease of E-cadherin and the increase of vimentin. In addition, we have found that CCL2 neutralizing antibody could block EMT induced by CCL2 in OSCC. CONCLUSIONS: CCL2 secreted by cancer cells can promote cell migration by inducing EMT via paracrine or autocrine in OSCC.

Porphyromonas gingivalis lipopolysaccharide induces over production of CC chemokine ligand 2 via toll-like receptor-4 in oral lichen planus.

BACKGROUND: We recently reported that the CC chemokine ligand 2 (CCL2)-CC receptor 2 (CCR2) axis was involved in the pathogenesis of oral lichen planus (OLP). However, the exact mechanism for the high expression of CCL2 in OLP specimens is not clear. Therefore, this study was designed to investigate the potential role of the toll-like receptor 4 (TLR-4) pathway in overproduction of CCL2 in OLP lesions. METHODS: Immunohistochemical staining and real-time RT-PCR were used to detect TLR-4, CCL2, and CCR2 expression in OLP lesions. Then, gingival epithelial cells from OLP lesions were established and treated with Porphyromonas gingivalis (P. gingivalis) lipopolysaccharide (LPS). CCL2 expression in epithelial cells was determined by Western blotting and real-time RT-PCR. In some experiments, TAK-242, a specific inhibitor of TLR-4, was used to block the TLR-4 pathway before cells were stimulated with LPS. RESULTS: We found that TLR-4 was significantly increased in the epithelium of OLP specimens, compared with controls. Moreover, LPS can induce the over production of CCL2 in epithelial cells of OLP, in vitro. TAK-242 effectively eliminated the increase in CCL2 expression induced by LPS by blocking the TLR-4/NF-κB pathway. In addition, we again confirmed that expression of CCL2 and CCR2 was increased in OLP specimens. CONCLUSION: Increased TLR-4 expression contributes to the upregulated expression of CCL2 in the epithelium of OLP lesions, which suggests that oral bacteria participate in the pathogenesis of OLP via the TLR-4 pathway.

Chemokine (CC motif) ligand 18 upregulates Slug expression to promote stem-cell like features by activating the mammalian target of rapamycin pathway in oral squamous cell carcinoma.

Chemokine (CC motif) ligand 18 (CCL18) is involved in remodeling of the tumor microenvironment and plays critical roles in oncogenesis, invasiveness, and metastasis. We previously investigated the overexpression of CCL18 in primary oral squamous cell carcinoma (OSCC) tissues and its association with advanced clinical stage in OSCC patients. However, the underlying mechanisms of this CCL18-derived activity remains unidentified. This study showed exogenous CCL18 increased cell migration and invasion and induced cell epithelial-mesenchymal transition (EMT), and that E-cadherin, an epithelial marker, decreased and N-cadherin, a mesenchymal marker, increased, compared to negative control in OSCC cells. Furthermore, we detected that CCL18 induced the acquisition of cancer stem(-like) cell characteristics in oral cancer cells, but also found a significantly positive correlation between the expression of CCL18 and Bmi-1 (P < 0.001) in OSCC surgical specimens by immunohistochemistry analysis. The expression of octamer-binding transcription factor 4 and Bmi-1 were significantly upregulated, and proportions of aldehyde dehydrogenasehigh+ cells and CD133+ cells were markedly increased in CCL18-treated cells compared to untreated cells. Sphere formation ability was observably enhanced when cells were continually exposed to high levels of CCL18. Moreover, CCL18 upregulated Slug expression by stimulating the mammalian target of rapamycin (mTOR) signaling pathway in OSCC cell lines. Inhibition of the mTOR pathway by INK128, or Slug knockdown by RNA interference, reversed CCL18-induced EMT and the stemness response at both molecular and functional levels. In conclusion, our data suggested that CCL18 upregulated Slug expression to promote EMT and stem cell-like features by activating the mTOR pathway in oral cancer. These findings provide new potential targets for the early diagnosis and treatment of OSCC.

An indispensable role of CPT-1a to survive cancer cells during energy stress through rewiring cancer metabolism.

Unlike normal cells, cancer cells are recently identified to rely on aerobic glycolysis for energy production called the Warburg effect. Several attempts are being made to target this metabolic reprogramming pathway in treating cancers; however, the successful rate is very limited. In this study, we investigated the functional roles of fatty acid oxidation key enzyme carnitine palmitoyl transferase 1a (CPT-1a), during the metabolic programming of pancreatic ductal adenocarcinoma (PDAC) cells induced by glucose deprivation. Knockdown of CPT-1a decreased the intracellular nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) generation, increased reactive oxygen species (ROS) production, and induced sensitivity to glucose deprivation, whereas upregulation of CPT-1a increased the intracellular ATP required for cell survival. Further investigation showed that CPT-1a inhibitor etomoxir (ETO) can restore the sensitivity of PDAC cells to gemcitabine and regress xenograft tumors in vivo. Finally, overexpression of CPT-1a expression is associated with chemoresistance in tumor specimens. Our data suggest that CPT-1a plays a key role in reprogramming cancer metabolism to escape from energy stress.

The positive correlation of the CCL2-CCR2 axis with the disease activity may indicate the fundamental role in the pathogenesis of oral lichen planus.

BACKGROUND: The important roles of CCL2 and its receptor CCR2 had been reported in a series of inflammatory disorders. However, few studies investigated the potential role of CCL2/CCR2 axis in oral lichen planus (OLP). Therefore, this study aimed to detect the expression of CCL2 and CCR2 in OLP lesions and compare their changes before and after treatment. METHODS: CCL2 and CCR2 expression was investigated using immunohistochemical staining and real-time RT-PCR in 32 patients with OLP and eight controls. Moreover, changes in their expression after treatment with triamcinolone acetonide were assessed in lesions from three patients. RESULTS: CCL2+ and CCR2+ cells were few in the controls and remarkably increased in the epithelial and subepithelial layers of lesions (n = 32, all P < 0.001). However, the densities of CCL2+ and CCR2+ cells were not significantly different between reticular (n = 12) and erythematous/erosive lesions (n = 20), although they significantly decreased after treatment (627.7 ± 108.2 vs. 258.3 ± 148.3, P = 0.017; 1034.7 ± 74.6 vs. 648 ± 77.6, P = 0.003, respectively). CCL2+/CCR2+ cell numbers were positively correlated with disease activity (correlation coefficient, 0.588; P < 0.001; correlation coefficient, 0.409; P = 0.02, respectively). CONCLUSIONS: The results of this study indicated that the CCL2-CCR2 axis was involved in the pathogenesis of OLP and was positively correlated with disease activity.

Splice site m6A methylation prevents binding of DGCR8 to suppress KRT4 pre-mRNA splicing in oral squamous cell carcinoma.

Oral squamous cell carcinoma (OSCC) is the 11th most prevalent tumor worldwide. Despite advantages of therapeutic approaches, the 5-year survival rate of patients with OSCC is less than 50%. It is urgent to elucidate mechanisms underlying OSCC progression for developing novel treatment strategies. Our recent study has revealed that Keratin 4 (KRT4) suppresses OSCC development, which is downregulated in OSCC. Nevertheless, the mechanism downregulating KRT4 in OSCC remains unknown. In this study, touchdown PCR was utilized to detect KRT4 pre-mRNA splicing, while m6A RNA methylation was identified by methylated RNA immunoprecipitation (MeRIP). Besides, RNA immunoprecipitation (RIP) was used to determine RNA-protein interaction. Herein, this study indicated that intron splicing of KRT4 pre-mRNA was suppressed in OSCC. Mechanistically, m6A methylation of exon-intron boundaries prevented intron splicing of KRT4 pre-mRNA in OSCC. Besides, m6A methylation suppressed the binding of splice factor DGCR8 microprocessor complex subunit (DGCR8) to exon-intron boundaries in KRT4 pre-mRNA to prohibit intron splicing of KRT4 pre-mRNA in OSCC. These findings revealed the mechanism downregulating KRT4 in OSCC and provided potential therapeutic targets for OSCC.

ASCT2-mediated glutamine uptake promotes Th1 differentiation via ROS-EGR1-PAC1 pathway in oral lichen planus.

Oral lichen planus (OLP) is a T cell-mediated autoimmune disease of oral mucosa concerning with the redox imbalance. Although glutamine uptake mediated by alanine-serine-cysteine transporter 2 (ASCT2) is critical to T cell differentiation, the exact mechanism remains ambiguous. Here, we elucidate a novel regulatory mechanism of ASCT2-mediated uptake in the differentiation and proliferation of T cells through maintaining redox balance in OLP. The results of immunohistochemistry (IHC) showed that both ASCT2 and glutaminase (GLS) were obviously upregulated compared to controls in OLP. Moreover, correlation analyses indicated that ASCT2 expression was significantly related to GLS level. Interestingly, the upregulation of glutamine metabolism in epithelial layer was consistent with that in lamina propria. Functional assays in vitro revealed the positive association between glutamine metabolism and lymphocytes infiltration. Additionally, multiplex immunohistochemistry (mIHC) uncovered a stronger colocalization among ASCT2 and CD4 and IFN-γ, which was further demonstrated by human Th1 differentiation assay in vitro. Mechanistically, targeting glutamine uptake through interference with ASCT2 using L-γ-Glutamyl-p-nitroanilide (GPNA) decreased the glutamine uptake of T cells and leaded to the accumulation of intracellular reactive oxygen species (ROS), which promoted dual specificity phosphatase 2 (DUSP2/PAC1) expression through activation of early growth response 1 (EGR1) to induce dephosphorylation of signal transducer and activator of transcription 3 (STAT3) and inhibit Th1 differentiation in turn. These results demonstrated that glutamine uptake mediated by ASCT2 induced Th1 differentiation by ROS-EGR1-PAC1 pathway, and restoring the redox dynamic balance through targeting ASCT2 may be a potential treatment for T cell-mediated autoimmune diseases.

Upregulation of IL-37 in epithelial cells: A potential new mechanism of T cell inhibition induced by tacrolimus.

Oral lichen planus (OLP) is a chronic T cell-mediated mucocutaneous disease characterized by T cell infiltration at the connective tissue-epithelium interface. Traditionally, topical corticosteroids are used as the first-line drugs to treat OLP. However, long-term use of corticosteroids may lead to drug tolerance, secondary candidiasis, and autoimmune adrenal insufficiency. Although topical tacrolimus has often been recommended for short-term use in corticosteroid-refractory OLP, the precise role of tacrolimus in epithelial cells remains elusive. This study showed that tacrolimus could directly upregulate the expression of IL-37 in human gingival epithelial cells by promoting the TGF-ßRI/Smad3 pathway independently of calcineurin inhibition and MAPKs. In contrast, dexamethasone, one of the corticosteroids, did not have the same effect. Moreover, IL-37 could inhibit the proliferation of activated T cells and the secretion of effector cytokines and alleviate epithelial cell apoptosis and death caused by activated T cells ina co-culturesystem. Furthermore, compared with healthy controls, IL-37 and p-Smad3 levels significantly increased in the oral mucosa affected by OLP, especially in the epithelium. IL-37 might have mediated a negative feedback mechanism to curb excessive inflammation in OLP. However, the expression of IL-37 was not associated with the infiltration of CD8+ T cells and Tregs in OLP, implying that IL-37 might mostly affect T cell activation rather than T cell differentiation and migration. Overall, this study discovered a potential novel mechanism by which tacrolimus might indirectly inhibit T cell-mediated immune damage by upregulating IL-37 in human gingival epithelial cells.

ASCT2-mediated glutamine uptake of epithelial cells facilitates CCL5-induced T cell infiltration via ROS-STAT3 pathway in oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is a chronic inflammatory disease characterized by T cell infiltration at lesion sites. T cell migration is greatly facilitated by chemokines produced by epithelial cells. Studies have noted the potential role of glutamine uptake in OLP and other inflammatory diseases. Here, we investigated the effect of altered glutamine uptake of epithelial cells on T cell infiltration and its underlying mechanisms in OLP. METHODS: Immunohistochemistry was used to identify the expressions of glutamine transporter alanine-serine-cysteine transporter 2 (ASCT2) and C-C motif chemokine ligand 5 (CCL5) in oral tissues of OLP and healthy controls. Human gingival epithelial cells (HGECs) were treated with glutamine deprivation and ASCT2 inhibiter GPNA respectively to detect the expressions of CCL5 and its related signaling molecules. Additionally, we had determined the impact of epithelial cell-derived CCL5 on T-cell migration using a co-culture system in vitro. RESULTS: ASCT2 and CCL5 expressions in OLP were significantly higher than healthy controls and positively correlated with the density of inflammatory infiltrations. Glutamine supplement significantly increased CCL5 production in HGECs, which was effectively inhibited by GPNA. Besides, glutamine could inhibit reactive oxygen species (ROS) production to activate the signal transducer and activator of transcription 3 (STAT3) causing higher expression level of CCL5 in HGECs. Simultaneously, T cell migration could be blocked by anti-CCL5 neutralizing antibody and STAT3 inhibitor stattic in the co-culture system. CONCLUSION: The upregulated ASCT2-mediated glutamine uptake in epithelial cells promotes CCL5 production via ROS-STAT3 signaling, which boosts the T-cell infiltration in OLP lesion.

Cellular hierarchy framework based on single-cell/multi-patient sample sequencing reveals metabolic biomarker PYGL as a therapeutic target for HNSCC.

BACKGROUND: A growing body of research has revealed the connection of metabolism reprogramming and tumor progression, yet how metabolism reprogramming affects inter-patient heterogeneity and prognosis in head and neck squamous cell carcinoma (HNSCC) still requires further explorations. METHODS: A cellular hierarchy framework based on metabolic properties discrepancy, METArisk, was introduced to re-analyze the cellular composition from bulk transcriptomes of 486 patients through deconvolution utilizing single-cell reference profiles from 25 primary and 8 metastatic HNSCC sample integration of previous studies. Machine learning methods were used to identify the correlations between metabolism-related biomarkers and prognosis. The functions of the genes screened out in tumor progression, metastasis and chemotherapy resistance were validated in vitro by cellular functional experiments and in vivo by xenograft tumor mouse model. RESULTS: Incorporating the cellular hierarchy composition and clinical properties, the METArisk phenotype divided multi-patient cohort into two classes, wherein poor prognosis of METArisk-high subgroup was associated with a particular cluster of malignant cells with significant activity of metabolism reprogramming enriched in metastatic single-cell samples. Subsequent analysis targeted for phenotype differences between the METArisk subgroups identified PYGL as a key metabolism-related biomarker that enhances malignancy and chemotherapy resistance by GSH/ROS/p53 pathway, leading to poor prognosis of HNSCC. CONCLUSION: PYGL was identified as a metabolism-related oncogenic biomarker that promotes HNSCC progression, metastasis and chemotherapy resistance though GSH/ROS/p53 pathway. Our study revealed the cellular hierarchy composition of HNSCC from the cell metabolism reprogramming perspective and may provide new inspirations and therapeutic targets for HNSCC in the future.

Expressions of CXCL12/CXCR4 in oral premalignant and malignant lesions.

OBJECTIVE: The chemokine receptor CXCR4 and its ligand CXCL12 have been suggested to play important roles in the initiation or progression of cancers. The goal of the present study was to investigate alterations of CXCL12/CXCR4 in oral premalignant lesions and oral squamous cell carcinoma (OSCC). METHODS: In 13 normal oral epithelia, 24 dysplastic oral leukoplakia (OLK), and 40 OSCC specimens, expressions of CXCL12 and CXCR4 were evaluated by immunohistochemistry. RESULTS: CXCR4 was expressed in 37.5% of OLK and 60% of OSCC. CXCL12 was detected in 50% of OLK and 62.5% of OSCC. In OLK, CXCR4 positive ratio showed no significant difference from normal epithelia, but the CXCL12 positive ratio was significantly higher. Significant relationship between CXCL12 and CXCR4 was found both in OLK and OSCC. CONCLUSION: Our results indicated that CXCL12/CXCR4 axis may play roles from early steps of oral malignant transformation and contribute to the progress of oral carcinogenesis.

Abnormal lipid synthesis as a therapeutic target for cancer stem cells.

Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.

Application of online learning combined with case-based discussion in oral medicine education.

BACKGROUND: During the past decades, the rapid development of modern teaching tools and methods has been observed, and the new teaching module constructed through digitization or networking has been widely used in the field of medical education. This study aimed to investigate the effectiveness and acceptability of the online learning combined with case-based discussion (CBD) approach in oral medicine education. METHODS: Sixty senior students majoring in stomatology were randomly divided into two groups. One group (new module-based teaching group [NG], n = 30) watched an online teaching video and discussed clinical cases in groups. The control group (traditional lecture-based group [TG], n = 30) was assigned to the traditional lecture-based teaching. Subsequently, a theory assessment was conducted on the topics taught, and the scores of both groups were compared. Feedback about this teaching model was obtained from the NG. RESULTS: The results showed that students in the NG had significantly better performance in terms of mastering professional knowledge than did students in the TG. Moreover, most students in the NG had a high degree of satisfaction with this new teaching method, as they agreed that it can mobilize their learning enthusiasm and promote their engagement, interaction, and cooperation in the learning of oral medicine. CONCLUSIONS: Our findings indicate the effectiveness and high satisfaction of CBD combined with online learning in the teaching of oral medicine. This study is expected to provide new ideas for improving the dental teaching quality.

Retinoids in cancer chemoprevention and therapy: Meta-analysis of randomized controlled trials.

Retinoids, natural and synthetic derivatives of vitamin A, have many regulatory functions in human body, including regulating cellular proliferation, differentiation, apoptosis. Moreover, retinoids have been used successfully for the treatment of certain malignancies, especially acute promyelocytic leukemia (APL) in adults and neuroblastoma in children. However, retinoids have not yet been translated into effective systemic treatments for most solid cancers. Some recent studies have shown that retinoids promote tumorigenesis. Therefore, we performed this meta-analysis to systematically evaluate the efficacy of retinoids in the chemoprevention and treatment of cancers. We performed literature search of several electronic databases, including PubMed, Embase and Cochrane Library from 2000 January to 2021 November. Various outcomes were applied to investigate the potential of retinoids for prevention and treatment of cancers. The primary outcomes in this study were disease recurrence and clinical response. The secondary outcomes included overall survival (OS), cancer development, disease progression and event-free survival. We identified 39 randomized controlled trials with 15,627 patients in this study. Our results showed that lower recurrence rate and better clinical response were obtained in retinoids treated patients with cancer or premalignancy as compared with control. The differences were statistically significant (RR = 0.85, 95% CI = 0.74-0.96, p = 0.01; RR = 1.24, 95% CI = 1.03-1.49, p = 0.02, respectively). Retinoids treatment was not associated with improvement in overall survival, cancer development, disease progression or event-free survival. Subgroup analysis conducted based on cancer type showed that patients benefited from retinoids treatment in APL, renal cell carcinoma, hepatocellular carcinoma, lung cancer, Kaposi sarcoma, and complete hydatidiform mole. No significant therapeutic effect was noted in head and neck cancer, acute myeloid leukemia (AML), melanoma, breast cancer, bladder cancer, cervical intraepithelial neoplasia (CIN) or cervical carcinoma. Subgroup analysis based on tumor classification demonstrated that retinoids group obtained a lower recurrence rate and better clinical response than control group in solid cancers. In conclusion, clinical application of retinoids was associated with reduction in disease recurrence and improvement in clinical response, illustrating that retinoids play a key role in cancer prevention and therapy. Further research is needed to broaden the utility of retinoids in other types of cancers. Systematic Review Registration: PROSPERO, identifier CRD42022296706.

Targeting CCL2-CCR4 axis suppress cell migration of head and neck squamous cell carcinoma.

For head and neck squamous cell carcinoma (HNSCC), the local invasion and distant metastasis represent the predominant causes of mortality. Targeted inhibition of chemokines and their receptors is an ongoing antitumor strategy established on the crucial roles of chemokines in cancer invasion and metastasis. Herein, we showed that C-C motif chemokine ligand 2 (CCL2)- C-C motif chemokine receptor 4 (CCR4) signaling, but not the CCL2- C-C motif chemokine receptor 2 (CCR2) axis, induces the formation of the vav guanine nucleotide exchange factor 2 (Vav2)- Rac family small GTPase 1 (Rac1) complex to activate the phosphorylation of myosin light chain (MLC), which is involved in the regulation of cell motility and cancer metastasis. We identified that targeting CCR4 could effectively interrupt the activation of HNSCC invasion and metastasis induced by CCL2 without the promoting cancer relapse observed during the subsequent withdrawal period. All current findings suggested that CCL2-CCR4-Vav2-Rac1-p-MLC signaling plays an essential role in cell migration and cancer metastasis of HNSCC, and CCR4 may serve as a new potential molecular target for HNSCC therapy.

Neutrophils infiltration is early event of an oral mucosal xenotransplantation model.

INTRODUCTION: As important effector cells of the innate immune system, neutrophils are involved in rejection of solid organ and/or tissue transplants. But their role in rejection of oral mucosa transplantation (OMT) remains unclear. The aim of this study is to observe the spatial-temporal change of neutrophils during acute rejection of OMT. METHODS: In a rat model of oral mucosal xenotransplantation, myeloperoxidase (MPO), an indicator of influx of neutrophils was detected by technique of ELISA on day 7 and 30 (D7, D30) of posttransplantation. RESULTS: On D7, MPO level (6.183±0.416, x102 ng/mg) in the OMT group was significantly higher than in trauma (0.681±0.073, x102 ng/mg) and normal controls (0.262±0.043, x102 ng/mg) (P<0.001, respectively), and this level was found to correlate with the index of submandibular lymph nodes (ILN), an indicator of inflammation of rejection (r=0.909, P<0.05). Moreover, this level was decreased significantly under FK506 treatment (2.103±0.146, x102 ng/mg, P=0.005). On D30, MPO in the OMT group (1.063±0.096, x102 ng/mg) was lower significantly than that on D7 (P<0.001), although this level was still higher that of normal controls on D30 (0.532±0.112, x102 ng/mg, P=0.042). CONCLUSION: Neutrophils infiltration was an early event of OMT, which may play important roles on acute rejection of OMT.