PPARγ Antagonists Exhibit Antitumor Effects by Regulating Ferroptosis and Disulfidptosis.

Oral squamous cell carcinoma (OSCC) stands as a prevalent subtype of head and neck squamous cell carcinoma, leading to disease recurrence and low survival rates. PPARγ, a ligand-dependent nuclear transcription factor, holds significance in tumor development. However, the role of PPARγ in the development of OSCC has not been fully elucidated. Through transcriptome sequencing analysis, we discovered a notable enrichment of ferroptosis-related molecules upon treatment with PPARγ antagonist. We subsequently confirmed the occurrence of ferroptosis through transmission electron microscopy, iron detection, etc. Notably, ferroptosis inhibitors could not completely rescue the cell death caused by PPARγ inhibitors, and the rescue effect was the greatest when disulfidptosis and ferroptosis inhibitors coexisted. We confirmed that the disulfidptosis phenotype indeed existed. Mechanistically, through qPCR and Western blotting, we observed that the inhibition of PPARγ resulted in the upregulation of heme oxygenase 1 (HMOX1), thereby promoting ferroptosis, while solute carrier family 7 member 11 (SLC7A11) was also upregulated to promote disulfidptosis in OSCC. Finally, a flow cytometry analysis of flight and multiplex immunohistochemical staining was used to characterize the immune status of PPARγ antagonist-treated OSCC tissues in a mouse tongue orthotopic transplantation tumor model, and the results showed that the inhibition of PPARγ led to ferroptosis and disulfidptosis, promoted the aggregation of cDCs and CD8+ T cells, and inhibited the progression of OSCC. Overall, our findings reveal that PPARγ plays a key role in regulating cell death in OSCC and that targeting PPARγ may be a potential therapeutic approach for OSCC.

PA28γ coordinates the cross-talk between cancer-associated fibroblasts and tumor cells to promote OSCC progression via HDAC1/E2F3/IGF2 signaling.

PA28γ overexpression is aberrant and accompanied by poor patient prognosis in various cancers, the precise regulatory mechanism of this crucial gene in the tumor microenvironment remains incompletely understood. In this study, using oral squamous cell carcinoma as a model, we demonstrated that PA28γ exhibits high expression in cancer-associated fibroblasts (CAFs), and its expression significantly correlates with the severity of clinical indicators of malignancy. Remarkably, we found that elevated levels of secreted IGF2 from PA28γ+ CAFs can enhance stemness maintenance and promote tumor cell aggressiveness through the activation of the MAPK/AKT pathway in a paracrine manner. Mechanistically, PA28γ upregulates IGF2 expression by stabilizing the E2F3 protein, a transcription factor of IGF2. Further mechanistic insights reveal that HDAC1 predominantly mediates the deacetylation and subsequent ubiquitination and degradation of E2F3. Notably, PA28γ interacts with HDAC1 and accelerates its degradation via a 20S proteasome-dependent pathway. Additionally, PA28γ+ CAFs exert an impact on the tumor immune microenvironment by secreting IGF2. Excitingly, our study suggests that targeting PA28γ+ CAFs or secreted IGF2 could increase the efficacy of PD-L1 therapy. Thus, our findings reveal the pivotal role of PA28γ in cell interactions in the tumor microenvironment and propose novel strategies for augmenting the effectiveness of immune checkpoint blockade in oral squamous cell carcinoma.

The relationship between health literacy and health-related quality of life in Chinese older adults: a cross-sectional study.

Background: This study aimed to examine the relationship between health literacy and health-related quality of life in older adults. Methods: A cross-sectional survey design was used. We used a self-administered questionnaire to assess sociodemographic factors of older adults, the Chinese Citizen Health Literacy Questionnaire (HLQC) and the 36-item Chinese version of the Short Form 36 (SF-36) to measure health literacy and quality of life, respectively, among older adults. Between September 2011 and June 2012, information was collected from 1,396 older adults in 44 nursing homes in four cities through face-to-face interviews. Results: The mean health literacy level of older adults in nursing homes was relatively low (71.74 ± 28.35). Health-related quality of life scores were moderate (104.77 ± 16.92). There were statistically significant differences in the effects of health literacy, education level, former occupation (professional), marital status (widowed) and race on health-related quality of life. Conclusion: Improving health literacy is considered an important intervention to promote health-related quality of life in older adults in nursing homes.

Analysis of the predictive value of the Geriatric Nutritional Risk Index for osteoporosis in elderly patients with T2DM: a single-center retrospective study.

BACKGROUND: Malnutrition is recognized as a risk factor for osteoporosis and T2DM. Previous studies have demonstrated the relationship between nutritional assessment tools and BMD. However, few studies have compared the effects of three nutritional risk assessment tools (GNRI, CONUT, and PNI). This study aimed to investigate the correlation between three nutritional assessment tools and BMD and to compare their validity in predicting osteoporosis in type 2 diabetes mellitus in the elderly. METHODS: This retrospective study collected clinical data from 525 elderly patients with type 2 diabetes mellitus and categorized the patients into osteoporotic and non-osteoporotic groups. The correlation between the three nutritional assessment tools and BMD was analyzed using Spearman partial correlation. Binary logistics regression was used to analyze the relationship between GNRI and osteoporosis. ROC curves were used to compare the validity of GNRI, PNI, and CONUT in predicting osteoporosis. RESULTS: Spearman's partial correlation showed a positive correlation between femoral neck BMD and lumbar spine BMD, but no correlation was observed between total hip BMD and GNRI. Logistic regression analyses showed no association between PNI, CONUT scores, and the development of osteoporosis. After adjusting for age, sex, smoking, alcohol consumption, BMI, ALB, Cr, UA, FBG, TG, and HDL, the correlation between GNRI and osteoporosis remained. ROC curve analysis showed that GNRI in combination with age and albumin had better predictive ability for osteoporosis than PNI and CONUT. CONCLUSION: GNRI was an independent protective factor against osteoporosis in elderly patients with T2DM, and the predictive ability of GNRI for osteoporosis in elderly patients with T2DM was better than that of PNI and CONUT scores.

Hypoxia-inducible factor 1α activates the NLRP3 inflammasome to regulate epithelial differentiation in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is an upper airway inflammation disease associated with hypoxia-mediated inflammation. The effect of hypoxia-inducible factor 1α (HIF-1α) on NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation in the pathogenesis of sinonasal mucosa is unclear. OBJECTIVE: We investigated the effect and mechanism of HIF-1α on NLRP3 inflammasome activation in the primary human nasal epithelial cells (hNECs). METHODS: We measured the expression levels of HIF-1α and the NLRP3 inflammasome in nasal biopsy samples and hNECs derived from negative controls (healthy) and patients with CRS with and without nasal polyps, then further analyzed the specific mechanism of HIF-1α regulation of the NLRP3 inflammasome and its effect on hNEC differentiation. RESULTS: Increased mRNA and protein expression levels of HIF-1α and the NLRP3 inflammasome were found in all CRS biopsy samples. HIF-1α enhanced expression of phosphorylated NLRP3 (S295) in both HEK293T cells and hNECs; it also promoted recruitment of caspase-1 and apoptotic speck-like protein containing caspase recruitment domain (aka ASC) by NLRP3. HIF-1α also improved NLRP3's stability by preventing NLRP3 degradation caused by hypoxia-mediated inflammation. In addition, HIF-1α could also increase expression of Mucin5AC and decrease expression of α-tubulin by promoting activation of the NLRP3 inflammasome in hNECs. In addition, HIF-1α could also directly promote P63 expression in hNECs. CONCLUSION: HIF-1α could potentially induce cilia loss and enhance the proliferation of goblet cells, possibly mediated by the regulation of NLRP3 phosphorylation in CRS inflammation.

Transcription factor E4F1 as a regulator of cell life and disease progression.

E4F transcription factor 1 (E4F1), a member of the GLI-Kruppel family of zinc finger proteins, is now widely recognized as a transcription factor. It plays a critical role in regulating various cell processes, including cell growth, proliferation, differentiation, apoptosis and necrosis, DNA damage response, and cell metabolism. These processes involve intricate molecular regulatory networks, making E4F1 an important mediator in cell biology. Moreover, E4F1 has also been implicated in the pathogenesis of a range of human diseases. In this review, we provide an overview of the major advances in E4F1 research, from its first report to the present, including studies on its protein domains, molecular mechanisms of transcriptional regulation and biological functions, and implications for human diseases. We also address unresolved questions and potential research directions in this field. This review provides insights into the essential roles of E4F1 in human health and disease and may pave the way for facilitating E4F1 from basic research to clinical applications.

ICI-based therapies: A new strategy for oral potentially malignant disorders.

Oral potentially malignant disorders (OPMDs) are linked with an escalated risk of developing cancers, particularly oral squamous cell carcinoma (OSCC). Since prevailing therapies cannot effectively forestall the exacerbation and recurrence of OPMDs, halting their malignant progression is paramount. The immune checkpoint serves as a cardinal regulator of the immune response and the primary cause of adaptive immunological resistance. Although the exact mechanism remains elusive, elevated expression of multiple immune checkpoints in OPMDs and OSCC relative to healthy oral mucosa has been ascertained. This review delves into the immunosuppressive microenvironment of OPMDs, the expression of diverse immune checkpoints such as programmed death receptor-1 (PD-1) and programmed death receptor-1 ligand (PD-L1) in OPMDs, and the potential application of corresponding inhibitors. In addition, synergistic strategies incorporating combined immune checkpoint inhibitors, such as cGAS-STING, costimulatory molecules, cancer vaccines, and hydrogels, are discussed to gain a more comprehensive understanding of the role and application of immune checkpoint inhibitors (ICIs) in oral carcinogenesis.

Current status and influencing factors of health literacy among older adults in combined medical and nursing care institutions: a cross-sectional study.

Introduction: Health literacy is linked to the health status of older adults and is a critical component in achieving active aging. This study to characterize the current health literacy status among older adults in combined medical and nursing care institutions, as well as the factors that influenced this status. Methods: This cross-sectional study used a convenience sampling method to select 740 older adults who were in 16 combined medical and nursing care institutions in Chengdu, China, from July 2022 to June 2023, using the Health Literacy Management Scale, the Social Support Rating Scale, and the Short Form-36 Health Survey. Results: The results showed a health literacy score of 75.25 ± 12.33, the percentage of older adults with basic health literacy was 6.33%, a social support score of 37.37 ± 6.10, and a health-related quality of life score of 55.34 ± 15.48. Factors influencing health literacy included age, educational level, previous occupation, family size, monthly per capita household income, and health-related quality of life. Discussion: Health literacy is an essential factor in improving the health status of older adults. Relevant departments should therefore improve health education and health promotion interventions for older adults in combined medical and nursing care institutions to improve health literacy.

Efficacy and safety of PD-1/PD-L1 inhibitors plus chemotherapy for triple-negative breast cancer: a systematic review and meta-analysis.

OBJECTIVE: The results of PD-1/PD-L1 inhibitor combined with chemotherapy for TNBC are controversial. Therefore, a meta-analysis was conducted to evaluate the efficacy and safety after PD-1/PD-L1 inhibitors plus chemotherapy in TNBC patients. METHODS: We systematically searched seven databases and several mainly oncology conferences for prospective clinical trials of chemotherapy combined with immunotherapy to treat TNBC, and we included pathologic complete response (PCR), progression-free survival (PFS), overall survival (OS) and adverse effects as outcome indicators of the study. RESULTS: We analyzed data from six studies involving 4,187 patients. The efficacy analysis indicated that PD1/PD-L1 inhibitor combined with chemotherapy significantly increased PCR rates in neoadjuvant patients (OR: 1.60; 95% CI: 1.18-2.17; p=0.003). There was no correlation between increases in PCR rates and the expression of PD-L1, but the PCR rate was higher in PD-L1+ patients. Subgroup analysis suggested that the lymph node-positive (OR: 2.52; 95% CI: 1.69-3.77; p<0.001) and ECOG PS 0 (OR: 1.9; 95% CI: 1.42-2.53; p<0.001) subgroups benefited from the combination of PD-1/PD-L1 inhibitor plus chemotherapy. In TNBC receiving advanced rescue treatment, PFS was higher in the group receiving PD-1/PD-L1 inhibitor plus chemotherapy than in the group receiving chemotherapy alone (HR: 0.78; 95% CI: 0.70-0.86; p<0.001). Compared with chemotherapy alone, PD-1/PD-L1 inhibitors combined with chemotherapy did not increase the OS of patients (HR=0.88, 95% CI: 0.76~1.03, p=0.12). In addition, the toxicity analysis showed that more grade 3-4 adverse effects and severe adverse effects occurred in the PD-1/PD-L1 inhibitor combined with chemotherapy group. CONCLUSIONS: PD-1/PD-L1 inhibitors combined with chemotherapy can improve the PCR and PFS rate of TNBC patients, but did not improve the OS, and had a higher risk of AEs.

Manganese suppresses the development of oral leukoplakia by activating the immune response.

OBJECTIVE: Manganese ion (Mn2+ ) is reported to promote the antitumor immune response by activating the cGAS-STING pathway, but it is unknown whether Mn2+ can prevent the malignant transformation of precancerous lesions. The effects of Mn2+ in treating oral leukoplakia (OLK) were explored in this work. METHODS: Peripheral blood Mn analysis of the patients was performed using inductively coupled plasma atomic emission spectroscopy (ICP-AES). A coculture model of dendritic cells (DCs)/macrophages, CD8+ T cells, and dysplastic oral keratinocytes (DOKs) was employed to analyze the role and mechanism of Mn2+ in a simulated OLK immune microenvironment. Western blot, RT-PCR, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and lactate dehydrogenase (LDH) assays were adopted to detect the mechanism of Mn2+ in this model. 4-nitroquinoline oxide (4NQO)-induced OLK mice were used to assess the role of Mn2+ in suppressing OLK progression, and a novel Mn2+ -loaded guanosine-tannic acid hydrogel (G-TA@Mn2+ hydrogel) was fabricated and evaluated for its advantages in OLK therapy. RESULTS: The content of Mn in patients' peripheral blood was negatively related to the progression of OLK. Mn2+ promoted the maturation and antigen presentation of DCs and macrophages and enhanced the activation of CD8+ T cells in the coculture model, resulting in effective killing of DOKs. Mechanistic analysis found that Mn2+ enhanced the anti-OLK immune response by activating the cGAS-STING pathway. Moreover, Mn2+ suppressed the development of 4NQO-induced carcinogenesis in the mouse model. In addition, the G-TA@Mn2+ hydrogel had better anti-OLK effects. CONCLUSIONS: Mn2+ enhanced the anti-OLK immune response by activating the cGAS-STING pathway, and the G-TA@Mn2+ hydrogel is a potential novel therapeutic approach for OLK treatment.

Identification of a BRAF/PA28γ/MEK1 signaling axis and its role in epithelial-mesenchymal transition in oral submucous fibrosis.

Oral submucous fibrosis (OSF) is a chronic and insidious oral potentially malignant disorder associated with a 4-17% risk of oral squamous cell carcinoma (OSCC). Our previous study found that proteasomal activator 28 gamma (PA28γ) is frequently overexpressed in oral squamous cell carcinoma and negatively correlated with poor patient prognosis. However, the role of PA28γ in the occurrence and development of OSF remains unclear. Here, we screened PA28γ-related genes and investigated their function in OSF. We demonstrated that the expression of PA28γ was positively associated with MEK1 and gradually elevated from normal to progressive stages of OSF tissue. Arecoline, a pathogenic component of OSF, could upregulate the protein levels of PA28γ and phosphorylated MEK1 and contribute to epithelial to mesenchymal transition (EMT) in epithelial cells. Notably, PA28γ could interact with MEK1 and upregulate its phosphorylation level. Furthermore, arecoline upregulated BRAF, which can interact with PA28γ and upregulate its protein level. Additionally, BRAF, PA28γ, and MEK1 could form protein complexes and then enhance the MEK1/ERK signaling pathways. The concrete mechanism of the protein stability of PA28γ is that BRAF mediates its degradation by inhibiting its ubiquitination. These findings underscore the instrumental role of PA28γ in the BRAF/MEK1 pathway and enhanced EMT through MEK1/ERK activation in OSF.

Nitrogen Regulates the Distribution of Antibiotic Resistance Genes in the Soil-Vegetable System.

The increasing antibiotic resistance genes (ARGs) in fertilizer-amended soils can potentially enter food chains through their transfer in a soil-vegetable system, thus, posing threats to human health. As nitrogen is an essential nutrient in agricultural production, the effect of nitrogen (in the forms NH4 +-N and NO3 --N) on the distribution of ARGs (blaTEM-1, sul1, cmlA, str, and tetO) and a mobile genetic element (MGE; tnpA-4) in a soil-Chinese cabbage system was investigated. Not all the tested genes could transfer from soil to vegetable. For transferable ones (blaTEM-1, sul1, and tnpA-4), nitrogen application influenced their abundances in soil and vegetable but did not impact their distribution patterns (i.e., preference to either leaf or root tissues). For ARGs in soil, effects of nitrogen on their abundances varied over time, and the positive effect of NH4 +-N was more significant than that of NO3 --N. The ARG accumulation to vegetables was affected by nitrogen application, and the nitrogen form was no longer a key influencing factor. In most cases, ARGs were found to prefer being enriched in roots, and nitrogen application may slightly affect their migration from root to leaf. The calculated estimated human intake values indicated that both children and adults could intake 106-107 copies of ARGs per day from Chinese cabbage consumption, and nitrogen application affected ARG intake to varying degrees. These results provided a new understanding of ARG distribution in vegetables under the agronomic measures such as nitrogen application, which may offer knowledge for healthy vegetable cultivation in future.

Comparison between anterolateral thigh free flap and jejunal flap for tissue reconstruction in patients underwent resection of pharyngoesophageal squamous cell carcinoma after radiotherapy failure: a retrospective study.

BACKGROUND: Anterolateral thigh (ALT) free flap and jejunal flap (JF) were commonly used in tissue reconstruction for pharyngoesophageal squamous cell carcinoma (PESCC) with worsening tissue adhesion and necrosis after radiotherapy failure. However, the results of tissue reconstruction and postoperative complications of these two flaps are controversial. The purpose of this study was to compare outcomes between group ALT free flap and group JF in PESCC after radiotherapy failure. METHODS: Intraoperative information and postoperative outcomes of patients with PESCC after radiotherapy failure who underwent ALT and JF reconstruction from January 2005 to December 2019 were compared and analyzed. RESULTS: The defect size of ALT (Numbers, 34) and JF (Numbers, 31) was 36.19 ± 11.35 cm2 and 35.58 ± 14.32 cm2 (p = 0.884), respectively. ALT and JF showed no significant difference in operation time (p = 0.683) and blood loss (p = 0.198). For postoperative outcomes within 30 days both in recipient site and donor site including wound bleeding, wound dehiscence, wound infection, and pharyngocutaneous fistula, ALT free flap and JF showed similar results. Flap compromise (Numbers, 2 VS.3, p = 0.663), flap take backs (Numbers, 1 VS.1, p = 1.000), partial flap failures (Numbers, 4 VS.2, p = 0.674), and total flap failures (Numbers, 0 VS.0, p = 1.000) showed no difference between the two groups. In addition, no significance was found in hypoproteinemia between the two groups (Numbers, 4 VS.2, p = 0.674). ALT free flap was not statistically different from JF in the incidence of dysphagia at the postoperative 6 months (Numbers of liquid diet, 5VS.5; Numbers of partial tube feeding, 6VS.7; Numbers of total tube feeding, 3VS.1, p = 0.790) and 12 months (Numbers of liquid diet, 8VS.7; Numbers of partial tube feeding, 8VS.7; Numbers of total tube feeding, 5VS.5, p = 0.998). The cause of dysphagia not found to differ between the two groups both in postoperative 6 months (p = 0.814) and 12 months (p = 0.845). CONCLUSION: Compared with JF, ALT free flap for PESCC patients after radiotherapy failure showed similar results in postoperative outcomes. ALT free flap may serve as a safe and feasible alternative for PESCC patients after radiotherapy failure.

PA28γ, an Accomplice to Malignant Cancer.

PA28γ is a nuclear activator of the 20S proteasome, which is involved in the regulation of several essential cellular processes and angiogenesis. Over the past 20 years, many amino acid sites and motifs have been proven to play important roles in the characteristic functions of PA28γ. The number of binding partners and validated cellular functions of PA28γ have increased, which has facilitated the clarification of its involvement in different biological events. PA28γ is involved in the progression of various diseases, and its aberrant overexpression in cancer is remarkable. Patients with low levels of PA28γ expression have a higher survival rate than those with high levels of PA28γ expression, as has been shown for a wide variety of tumors. The functions of PA28γ in cancer can be divided into five main categories: cell proliferation, cell apoptosis, metastasis and invasion, cell nuclear dynamics that have relevance to angiogenesis, and viral infection. In this review, we focus on the role of PA28γ in cancer, summarizing its aberrant expression, prooncogenic effects and underlying mechanisms in various cancers, and we highlight the possible cancer-related applications of PA28γ, such as its potential use in the diagnosis, targeted treatment and prognostic assessment of cancer.

Management of burning mouth Syndrome: A position paper of the Chinese Society of Oral Medicine.

BACKGROUND: Burning mouth syndrome is a syndrome with tongue as the main affected site and burning pain as the main complaint. Although a variety of therapies have been reported to treat BMS, there is a lack of widely recognized therapies and it is still a dilemma for clinicians to treat BMS. OBJECTIVE: To develop the position paper and provide the references for clinical practice of BMS in China. METHODS: Under the guidance of WHO (World Health Organization) Handbook for Guideline Development, we used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach as a tool to develop this position paper in the following steps: setting up the groups, formulating the clinical questions and choosing the outcomes, retrieving and synthesizing of evidence, assessing the evidence, investigating the patients' values and preferences, developing the recommendations, reviewing the recommendations, and writing the position paper. RESULTS: The 27 recommendations were formed from the following 7 aspects: pre-treatment examination, removal of stimuli, medication, physical therapy, psychological therapy, and antipsychotics. There are 3 strong recommendations and 12 weak recommendations in pre-treatment examination and removal of stimuli, as well as 12 weak recommendations in therapies. CONCLUSION: The Chinese position paper for management of BMS has been developed, which could provide the references for clinical practice of BMS in China. Twenty-seven recommendations were formed based on consensus of experts on the balance of benefits vs side effects, evidence, cost, and patients' values and preferences, although the quality of evidence is relatively low.

Risk factors for lower respiratory tract infection in children with tracheobronchial foreign body aspiration.

The aim of this study was to determine the risk factors for lower respiratory tract infection (LRTI) in children caused by tracheobronchial foreign body aspiration (TFBA).A total of 351 patients were retrospectively reviewed; all patients were diagnosed with TFBA at West China Hospital of Sichuan University from 2015 to 2017. Univariate analyses and multivariate analysis were used.Age (<2 years) (P < .001), type of foreign body (plant) (P < .001), shape of foreign body (nonsmooth) (P < .001), and residence time of foreign body (>7 days) (P = .001) were risk factors for LRTI on univariate analysis. Multivariate analysis showed age (<2 years) (hazard ratio [HR] = 4.457; 95% confidence interval [CI] = 2.031-6.884; P < .001), type of foreign body (plant) (HR = 2.686; 95% CI = 1.577-3.452; P < .001), shape of foreign body (nonsmooth) (HR = 1.649; 95% CI = 1.437-3.663; P < .008), and residence time of foreign body (>7 days) (HR = 1.751; 95% CI = 1.329-3.554; P = .004) were independent risk factors for LRTI. Furthermore, children with LRTI also had longer lengths of hospital stays and antibiotic use than did children without LRTI.Age, plant foreign body, nonsmooth foreign body, and long-term incarceration were all independent risk factors for LRTI in children. These results can help us to select more appropriate intervention times and stratified treatment for children with TFBA.