Correlation Analysis of NAMPT rs61330082 Polymorphism in Type 2 Diabetes Mellitus Combined with Hypertension.

Introduction: This study aimed to investigate the association of Nicotinamide phosphoribosyl transferase (NAMPT) rs61330082 polymorphism with co-morbid hypertension (HTN) and the progression of hypertension in Chinese patients with type 2 diabetes mellitus (T2DM). Methods: A total of 453 T2DM patients were genotyped for the polymorphism of rs61330082 using SNP-scan high-throughput technology. These patients were divided into T2DM group (261 patients) and T2DM combined with hypertension group (T2MH, 192 patients). The T2MH group was further categorized into Grade I, Grade II, and Grade III based on the results of the Hypertension Grade Score. Peripheral blood plasma urea, plasma creatinine, renin-angiotensin system (RAS) indexes, and lipid biochemistry indexes were measured in patients and analyzed in relation to NAMTP polymorphisms. Results: We found that the presence of the NAMPT rs61330082-AA genotype was associated with a significantly increased risk of developing higher-grade hypertension in patients with T2MH. In addition, the A allele of the NAMPT rs61330082 gene displayed more associated in developing a higher grade of hypertension compared to the G allele. Also, the level of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) increased with hypertension grade in the NAMPT rs61330082-GG genotype. Conclusion: NAMPT rs61330082 polymorphism was significantly associated with the progression of hypertension grade in T2MH patients and also affected plasma creatinine and LDL-c levels.

College students' knowledge, attitudes, and practices of garbage sorting and their associations: a cross-sectional study of several universities in Beijing, China.

Background: In recent years, the Chinese government has placed growing emphasis on environmental development. The implementation of effective waste separation practices in schools is crucial for establishing an ecological civilization in China. Objective: The present study aimed to assess the knowledge, attitude, and practice (KAP) of waste separation among Chinese university students and to understand the demographic factors influencing the KAP of the interviewed students. These sociodemographic factors include gender, age, education, and family environment. Methods: Based on the KAP theoretical model and the Lewin behavioral model (LBM), this study developed its questionnaire on college students' KAP of rubbish sorting. A survey was conducted on 1,282 college students from five colleges and universities in Beijing. A one-way ANOVA, Pearson's correlation analysis, and multiple linear stepwise regression analyzes were employed to explore the factors influencing college students' KAP scores on waste sorting. The questionnaire's reliability and validity were effectively verified through two rounds of Delphi expert consultation. Results: The scores for KAP dimensions were 55.64, 69.18, and 54.8%, respectively. The overall KAP score of university students in waste classification was 46.93 ± 9.93, with a percentage score of 62.57%. More than half of the college students lack a clear understanding of waste classification. Grade, gender, major, highest family education, and family economic status all influence college students' KAP scores on waste classification. There is a notable deficiency in school education regarding waste classification, with only 30.7% reporting having received such education. Conclusion: This study unveils the overall KAP score of waste separation among Chinese college students, which is marginally acceptable. The interviewed students exhibit a positive attitude and a willingness to participate in waste separation. However, there is room for improvement in both knowledge and practices. A lack of knowledge about waste sorting emerges as the primary influence on individual-level practices. Consideration should be given to enhancing education and management of waste separation among college students, emphasizing the cultivation of an eco-conscious culture, and guiding students to establish correct ecological values.

Chemical characteristics of dissolved organic matter in effluent from sludge alkaline fermentation liquid-fed sequencing batch reactors.

Sludge alkaline fermentation liquid (SAFL) is a promising alternative to acetate for improving biological nitrogen removal (BNR) from wastewater. SAFL inevitably contains some refractory compounds, while the characteristics of dissolved organic matter (DOM) in effluent from SAFL-fed BNR process remain unclear. In this study, the molecular weight distribution, fluorescent composition and molecular profiles of DOM in effluent from SAFL and acetate-fed sequencing batch reactors (S-SBRs and A-SBRs, respectively) at different hydraulic retention time (12 h and 24 h) was comparatively investigated. Two carbon sources resulted in similar effluent TN, but a larger amount of DOM, which was bio-refractory or microorganisms-derived, was found in effluent of S-SBRs. Compared to acetate, SAFL increased the proportion of large molecular weight organics and humic-like substances in effluent DOM by 74.87%-101.3% and 37.52%-48.35%, respectively, suggesting their bio-refractory nature. Molecular profiles analysis revealed that effluent DOM of S-SBRs exhibited a more diverse composition and a higher proportion of lignin-like molecules. Microorganisms-derived molecules were found to be the dominant fraction (71.51%-72.70%) in effluent DOM (<800 Da) of S-SBRs. Additionally, a prolonged hydraulic retention time enriched Bacteroidota, Haliangium and unclassified_f_Comamonadaceae, which benefited the degradation of DOM in S-SBRs. The results help to develop strategies on reducing effluent DOM in SAFL-fed BNR process.

The impact of environmental education at Chinese Universities on college students' environmental attitudes.

The purpose of this study is to examine the effects of environmental education on students' attitudes about the environment in Chinese higher education. The findings showed that students' environmental attitudes can be greatly enhanced by college-level ecology and environmental education. One of the most major factors influencing students' environmental attitudes in the context of college environmental education is subjective norms, and curriculum education also has a big impact on this. It is possible that Chinese college students today lack the self-efficacy necessary to safeguard the environment since perceived behavioral control has less of an impact on college students' environmental attitudes than subjective norms and curricular education. This highlights the need of promoting environmental practices and improving college students' self-perceive and capacity for environmental protection. The study also showed that factors including gender, location, educational level, and economic status of the family had no impact on college students' environmental attitudes. The results of this study can be used to examine the factors influencing the environmental views of Chinese college students and to teach educators how to raise college students' awareness of the environment through curricular modifications, classroom instruction, and perceived behavioral control.

EGFL6 promotes endometrial cancer cell migration and proliferation.

OBJECTIVE: EGFL6, a growth factor produced by adipocytes, is upregulated in and implicated in the tumorigenesis of multiple tumor types. Given the strong link between obesity and endometrial cancer, we sought to determine the impact of EGFL6 on endometrial cancer. METHODS: EGFL6 expression in endometrial cancer and correlation with patient outcomes was evaluated in the human protein atlas and TCGA. EGFL6 treatment, expression upregulation, and shRNA knockdown were used to evaluate the impact of EGFL6 on the proliferation and migration of 3 endometrial cancer cell lines in vitro. Similarly, the impact of EGFL6 expression and knockdown on tumor growth was evaluated. Western blotting was used to evaluate the impact of EGFL6 on MAPK phosphorylation. RESULTS: EGFL6 is upregulated in endometrial cancer, primarily in cony-number high tumors. High tumor endometrial cancer expression of EGFL6 predicts poor patient prognosis. We find that EGFL6 acts to activate the MAPK pathway increasing cellular proliferation and migration. In xenograft models, EGFL6 overexpression increases endometrial cancer tumor growth while EGFL6 knockdown decreases endometrial cancer tumor growth. CONCLUSIONS: EGFL6 is a marker of poor prognosis endometrial cancers, driving cancer cell proliferation and growth. As such EGFL6 represents a potential therapeutic target in endometrial cancer.

Cardiovascular aging: spotlight on mitochondria.

Mitochondria are cellular organelles critical for ATP production and are particularly relevant to cardiovascular diseases including heart failure, atherosclerosis, ischemia-reperfusion injury, and cardiomyopathies. With advancing age, even in the absence of clinical disease, mitochondrial homeostasis becomes disrupted (e.g., redox balance, mitochondrial DNA damage, oxidative metabolism, and mitochondrial quality control). Mitochondrial dysregulation leads to the accumulation of damaged and dysfunctional mitochondria, producing excessive reactive oxygen species and perpetuating mitochondrial dysfunction. In addition, mitochondrial DNA, cardiolipin, and N-formyl peptides are potent activators of cell-intrinsic and -extrinsic inflammatory pathways. These age-related mitochondrial changes contribute to the development of cardiovascular diseases. This review covers the impact of aging on mitochondria and links these mechanisms to therapeutic implications for age-associated cardiovascular diseases.

Optimizing waste molasses utilization to enhance electron transfer via micromagnetic carriers: Mechanisms and high-nitrate wastewater denitrification performance.

The biological denitrification of high-nitrate wastewater (HNW) is primarily hindered by insufficient carbon sources and excessive nitrite accumulation. In this study, micromagnetic carriers with varying micromagnetic field (MMF) strengths (0.0, 0.3, 0.6, 0.9 mT) were employed to enhance the denitrification of HNW using waste molasses (WMs) as a carbon source. The results revealed that 0.6 mT MMF significantly improved the total nitrogen removal (TN) efficiency at 96.3%. A high nitrate (NO3--N) removal efficiency at 99.3% with a low nitrite (NO2--N) accumulation at 25.5 mg/L was achieved at 0.6 mT MMF. The application of MMF facilitated the synthesis of adenosine triphosphate (ATP) and stimulated denitrifying enzymes (e.g., nitrate reductase (NAR), nitrite reductase (NIR), and nitric oxide reductase (NOR)), which thereby promoting denitrification. Moreover, the effluent chemical oxygen demand (COD), tryptophan and fulvic-like substances exhibited their lowest levels at 0.6 mT MMF. Analysis through 16S ribosomal ribonucleic acid gene sequencing indicated a significant enrichment of denitrifying bacteria including Castellaniella Klebsiella under the influence of MMF. Besides, the proliferation of Acholeplasma, Klebsiella and Proteiniphilum at 0.6 mT MMF promoted the hydrolysis and acidification of WMs. This study offers new insights into the enhanced utilization of WMs and the denitrification of HNW through the application of MMF.

A Novel Humanized Immune Stroma PDX Cancer Model for Therapeutic Studies.

Standard preclinical human tumor models lack a human tumor stroma. However, as stroma contributes to therapeutic resistance, the lack of human stroma may make current models less stringent for testing new therapies. To address this, using patient-derived tumor cells, patient derived cancer-associated mesenchymal stem/progenitor cells, and human endothelial cells, we created a Human Stroma-Patient Derived Xenograft (HS-PDX) tumor model. HS-PDX, compared to the standard PDX model, demonstrate greater resistance to targeted therapy and chemotherapy, and better reflect patient response to therapy. Furthermore, HS-PDX can be grown in mice with humanized bone marrow to create humanized immune stroma patient-derived xenograft (HIS-PDX) models. The HIS-PDX model contains human connective tissues, vascular and immune cell infiltrates. RNA sequencing analysis demonstrated a 94-96% correlation with primary human tumor. Using this model, we demonstrate the impact of human tumor stroma on response to CAR-T cell therapy and immune checkpoint inhibitor therapy. We show an immunosuppressive role for human tumor stroma and that this model can be used to identify immunotherapeutic combinations to overcome stromally mediated immunosuppression. Combined, our data confirm a critical role for human stoma in therapeutic response and indicate that HIS-PDX can be an important tool for preclinical drug testing. Statement of Significance: We developed a tumor model with human stromal, vascular, and immune cells. This model mirrors patient response to chemotherapy, targeted therapy, and immunotherapy, and can be used to study therapy resistance.

Generation and characterization of humanized affinity-matured EGFL6 antibodies for ovarian cancer therapy.

OBJECTIVES: Epidermal growth factor EGF-like domain multiple-6 (EGFL6) is highly expressed in high grade serous ovarian cancer and promotes both endothelial cell proliferation/angiogenesis and cancer cell proliferation/metastasis. As such it has been implicated as a therapeutic target. As a secreted factor, EGFL6 is a candidate for antibody therapy. The objectives of this study were to create and validate humanized affinity-matured EGFL6 neutralizing antibodies for clinical development. METHODS: A selected murine EGFL6 antibody was humanized using CDR grafting to create 26 variant humanized antibodies. These were screened and the lead candidate was affinity matured. Seven humanized affinity-matured EGFL6 antibodies were screened for their ability to block EGFL6 activity on cancer cells in vitro, two of which were selected and tested their therapeutic activity in vivo. RESULTS: Humanized affinity matured antibodies demonstrated high affinity for EGFL6 (150 pM to 2.67 nM). We found that several humanized affinity-matured EGFL6 antibodies specifically bound to recombinant, and native human EGFL6. Two lead antibodies were able to inhibit EGFL6-mediated (i) cancer cell migration, (ii) proliferation, and (iii) increase in ERK phosphorylation in cancer cells in vitro. Both lead antibodies restricted growth of an EGFL6 expressing ovarian cancer patient derived xenograft. Analysis of treated human tumor xenografts indicated that anti-EGFL6 therapy suppressed angiogenesis, inhibited tumor cell proliferation, and promoted tumor cell apoptosis. CONCLUSIONS: Our studies confirm the ability of these humanized affinity-matured antibodies to neutralize EGFL6 and acting as a therapeutic to restrict cancer growth. This work supports the development of these antibody for first-in-human clinical trials.

Synthesis of 5α,6-Dihydroveragranines A and B.

The 5α,6-dihydro congeners of veragranines A and B, two steroidal alkaloids with an unprecedented hexacyclic skeleton and potent analgesic effects, were synthesized from hecogenin acetate within six steps. This work enables quick access to the hexacyclic skeleton and is amendable to prepare other D-ring-modified congeners.

Study on the advanced nitrogen removal under low temperature by biofilm on weak magnetic carriers.

The advanced nitrogen removal under low temperature is inhibited because of reduction of the microbial activity. Packed bed reactors filled with different magnetic carriers (0, 0.3, 0.6, 0.9 mT) were constructed to enhance advanced denitrification under low temperature (5 ℃). Results showed that 0.3 and 0.9 mT carriers significantly improved denitrification, indicating the "window" effect. Total nitrogen removals were increased by 6.96% and 8.25%, and NO2- accumulation decreased by 25.70% and 13.90% in 0.3 and 0.9 mT reactors, respectively. Analysis of enzyme activity and electron transport chain showed that 0.3 mT carrier mainly increased NIR activity by improving compound III and cytC abundance while 0.9 mT carrier mainly increased NAR activity by improving compound I and NADH abundance, indicating different pathways. Similar microbial community in 0.3 and 0.9 mT reactors were revealed. Overall, weak magnetic carriers can be used to enhance advanced nitrogen removal under low temperature.

Targeting Therapeutic Resistance and Multinucleate Giant Cells in CCNE1-Amplified HR-Proficient Ovarian Cancer.

Approximately 20% of high-grade serous ovarian cancers (HGSOC) have CCNE1 amplification. CCNE1-amplified tumors are homologous recombination (HR) proficient and resistant to standard therapies. Therapy resistance is associated with increased numbers of polyploid giant cancer cells (PGCC). We sought to identify new therapeutic approaches for patients with CCNE1-amplified tumors. Using TCGA data, we find that the mTOR, HR, and DNA checkpoint pathways are enriched in CCNE1-amplified ovarian cancers. Furthermore, Interactome Mapping Analysis linked the mTOR activity with upregulation of HR and DNA checkpoint pathways. Indeed, we find that mTOR inhibitors (mTORi) downregulate HR/checkpoint genes in CCNE1-amplified tumors. As CCNE1-amplified tumors are dependent on the HR pathway for viability, mTORi proved selectively effective in CCNE1-amplified tumors. Similarly, via downregulation of HR genes, mTORi increased CCNE1-amplifed HGSOC response to PARPi. In contrast, overexpression of HR/checkpoint proteins (RAD51 or ATR), induced resistance to mTORi. In vivo, mTORi alone potently reduced CCNE1-amplified tumor growth and the combination of mTORi and PARPi increased response and tumor eradication. Tumors treated with mTORi demonstrated a significant reduction in ALDH+ PGCCs. Finally, as a proof of principle, we identified three patients with CCNE1 amplified tumors who were treated with an mTORi. All three obtained clinical benefits from the therapy. Our studies and clinical experience indicate mTORi are a potential therapeutic approach for patients with CCNE1-amplified tumors.

Shifting the Soil: Metformin Treatment Decreases the Protumorigenic Tumor Microenvironment in Epithelial Ovarian Cancer.

Controversy persists regarding metformin's role in cancer therapy. Our recent work suggested metformin acts by impacting the tumor microenvironment (TME), normalizing the epigenetic profile of cancer-associated mesenchymal stem cells (CA-MSC). As CA-MSC can negatively impact tumor immune infiltrates, we evaluated metformin's impact on the human TME, focusing on the interplay of stroma and immune infiltrates. Tumor samples from (i) 38 patients treated with metformin and chemotherapy and (ii) 44 non-metformin matched controls were included in a tissue microarray (TMA). The TMA was used to compare the presence of CA-MSC, desmoplasia and immune infiltrates in the TME. In vitro and in vivo models examined metformin's role in alteration of the CA-MSC phenotype. The average percentage of CA-MSC was significantly lower in metformin-treated than in chemotherapy alone-treated tumors (p = 0.006). There were fewer regulatory T-cells in metformin-treated tumors (p = 0.043). Consistent with CA-MSC's role in excluding T-cells from tumor islets, the T-cells were primarily present within the tumor stroma. Evaluation of metformin's impact in vitro suggested that metformin cannot reverse a CA-MSC phenotype; however, the in vivo model where metformin was introduced prior to the establishment of the CA-MSC phenotype supported that metformin can partially prevent the reprogramming of normal MSC into CA-MSC. Metformin treatment led to a decrease in both the presence of protumorigenic CA-MSC and in immune exclusion of T cells, leading to a more immune-permissive environment. This suggests clinical utility in prevention and in treatment for early-stage disease and putatively in immune therapy.

Performance evaluation and mechanism of nitrogen removal in a packed bed reactor using micromagnetic carriers at different carbon to nitrogen ratios.

Advanced nitrogen removal of effluent discharged from secondary treatment systems can avoid eutrophication. However, the lack of biodegradable organics limits biodenitrification. Packed bed reactors filled with carriers with different micromagnetic field (MMF) strengths were used to perform tertiary denitrification. The results showed that MMF significantly improved the denitrification performance, especially at low C/N ratios. Total nitrogen (TN) removal was increased by 4.12% with 0.6 mT MMF when C/N = 4 and increased by 7.06% and 8.06% with 0.3 mT and 0.9 mT MMFs when C/N = 3, respectively. Zooglea, Flavobacterium, and Denitratisoma contributed to the advanced denitrification performance under MMF. In addition, 0.6 mT MMF enhanced nitrogen metabolism and ABC transporter protein and two-component system activities of microorganisms under C/N = 4; 0.3 mT and 0.9 mT MMFs increased nitrogen, carbohydrate, and amino acid metabolism and ABC transporter protein activities under C/N = 3. These findings indicate that MMF has great potential for advanced denitrification from secondary effluent.

Bacterial survival strategies in sludge alkaline fermentation for volatile fatty acids production: Study on the physiological properties, temporal evolution and spatial distribution of bacterial community.

This study investigated the dynamics of ATP synthase activity, phospholipid fatty acid (PLFA) profile, and temporal evolution and spatial distribution of bacterial community to analyze bacterial survival strategies in sludge alkaline fermentation (SAF) for volatile fatty acids (VFAs) production. The results revealed a significant increase in ATP synthase activity at pH 9 and 10 (p < 0.05), which could contribute to proton entry into cells and benefit bacterial survival. PLFA analysis indicated that the unsaturated fatty acids content increased with the increase of pH. Firmicutes were the dominant microorganisms in the running stage of the pH 10 reactor (35.81-62.34%) and might have been the key microbes that influenced VFAs production. Further analysis of the spatial distribution of microbial community suggested that Firmicutes mainly lived inside flocs during SAF. These findings provide an understanding for bacterial survival strategies in SAF, which could help to develop methods to further improve VFAs yield.

Identifying prognostic lncRNAs based on a ceRNA regulatory network in laryngeal squamous cell carcinoma.

PURPOSE: Growing evidence demonstrates that long non-coding RNAs (lncRNAs) play a crucial role as competing endogenous RNAs (ceRNAs) in tumor occurrence. The lncRNAs' functions and clinical significance in laryngeal squamous cell carcinoma (LSCC) remain unclear. The study aims to reveal the lncRNA-associated ceRNA regulatory network of LSCC and clarify its clinical relevance. METHODS: Here, we obtained LSCC transcriptome data from The Cancer Genome Atlas (TCGA) database and identified the differential expression profile of lncRNAs, miRNAs, and mRNAs by the EdgeR R package. The function enrichment analysis of mRNAs was performed using clusterProfiler R package and GSEA3.0. Then, we constructed a ceRNA network and prognosis model based on lncRNAs through bioinformatic methods. Moreover, we explored the functions of prognosis-related lncRNA in LSCC by CCK-8 and transwell assay. RESULTS: 1961 lncRNAs, 69 miRNAs, and 2224 mRNAs were identified as differentially expressed genes in LSCC tissues. According to the transcriptome differential expression profile, a ceRNA network containing 61 lncRNAs, 21 miRNAs, and 77 mRNAs was established. Then, four lncRNAs (AC011933.2, FAM30A, LINC02086, LINC02575) were identified from the ceRNA network to build a prognosis model for LSCC patients. And we found that LINC02086 and LINC02575 promoted the proliferation, migration, and invasion of LSCC cells while AC011933.2 and FAM30A inhibited these biological functions in vitro. Furthermore, we validated that LINc02086/miR-770-5p/SLC26A2 axis promoted migration in LSCC. CONCLUSION: Four lncRNAs of the ceRNA network were abnormally expressed and related to patient prognosis in LSCC. They played a significant role in the progress of LSCC via affecting the proliferation and metastasis of tumor cells.

Aldehyde dehydrogenase inhibitors promote DNA damage in ovarian cancer and synergize with ATM/ATR inhibitors.

Rationale: Aldehyde dehydrogenase (ALDH) enzymes are often upregulated in cancer cells and associated with therapeutic resistance. ALDH enzymes protect cells by metabolizing toxic aldehydes which can induce DNA double stand breaks (DSB). We recently identified a novel ALDH1A family inhibitor (ALDHi), 673A. We hypothesized that 673A, via inhibition of ALDH1A family members, could induce intracellular accumulation of genotoxic aldehydes to cause DSB and that ALDHi could synergize with inhibitors of the ATM and ATR, proteins which direct DSB repair. Methods: We used immunofluorescence to directly assess levels of the aldehyde 4-hydroxynonenal and comet assays to evaluate DSB. Western blot was used to evaluate activation of the DNA damage response pathways. Cell counts were performed in the presence of 673A and additional aldehydes or aldehyde scavengers. ALDH inhibition results were confirmed using ALDH1A3 CRISPR knockout. Synergy between 673A and ATM or ATR inhibitors was evaluated using the Chou-Talalay method and confirmed in vivo using cell line xenograft tumor studies. Results: The ALDHi 673A cellular accumulation of toxic aldehydes which induce DNA double strand breaks. This is exacerbated by addition of exogenous aldehydes such as vitamin-A (retinaldehyde) and ameliorated by aldehyde scavengers such as metformin and hydralazine. Importantly, ALDH1A3 knockout cells demonstrated increased sensitivity to ATM/ATR inhibitors. And, ALDHi synergized with inhibitors of ATM and ATR, master regulators of the DSB DNA damage response, both in vitro and in vivo. This synergy was evident in homologous recombination (HR) proficient cell lines. Conclusions: ALDHi can be used to induce DNA DSB in cancer cells and synergize with inhibitors the ATM/ATR pathway. Our data suggest a novel therapeutic approach to target HR proficient ovarian cancer cells.

Effect of DLT-SML on Chronic Stable Angina Through Ameliorating Inflammation, Correcting Dyslipidemia, and Regulating Gut Microbiota.

ABSTRACT: Chronic stable angina (CSA) is caused by coronary atherosclerosis. The gut microbiota (GM) and their metabolite trimethylamine-N-oxide (TMAO) levels are associated with atherosclerosis. Danlou tablet (DLT) combined with Salvia miltiorrhiza ligustrazine (SML) injection has been used to treat CSA. This study aims to investigate how DLT combined with SML (DLT-SML) regulates serum lipids, inflammatory cytokines, GM community, and microbial metabolite in patients with CSA. In this study, 30 patients with CSA were enrolled in the DLT-SML group, and 10 healthy volunteers were included in the healthy control group. The patients in the DLT-SML group were subdivided as the normal total cholesterol (TC) group and high-TC group according to their serum TC level before treatment. Blood samples were collected to investigate the (1) lipid content, including triglyceride (TG), TC, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol, (2) fasting blood glucose (Glu), (3) inflammatory cytokines, including interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-10 (IL-10), and tumor necrosis factor-α (TNF-α), and (4) gut-derived metabolite, including lipopolysaccharides and TMAO level. GM composition was analyzed by sequencing 16S rRNA of fecal samples. Results showed that DLT-SML significantly decreased serum TG, TC, low-density lipoprotein cholesterol, IL-1ß, TNF-α, and TMAO levels of patients with CSA. DLT-SML increased the abundance of Firmicutes and decreased Proteobacteria, which were significantly lower or higher in patients with CSA, respectively, compared with the healthy control group. In particular, DLT-SML increased the microbial diversity and decreased Firmicutes/Bacteroidetes ratio of patients with high-TC. The abundance of Sarcina, Anaerostipes, Streptococcus, Weissella, and Erysipelatoclostridium was decreased, whereas Romboutsia, Faecalibacterium, and Subdoligranulum were increased by DLT-SML treatment in patients with CSA. These findings indicated that DLT-SML improved patients with CSA by ameliorating dyslipidemia profile, decreasing the circulating inflammatory cytokines, and regulating the GM composition and their metabolites.

Targeting SKA3 suppresses the proliferation and chemoresistance of laryngeal squamous cell carcinoma via impairing PLK1-AKT axis-mediated glycolysis.

Spindle and kinetochore-associated complex subunit 3 (SKA3) is a well-known regulator of chromosome separation and cell division, which plays an important role in cell proliferation. However, the mechanism of SKA3 regulating tumor proliferation via reprogramming metabolism is unknown. Here, SKA3 is identified as an oncogene in laryngeal squamous cell carcinoma (LSCC), and high levels of SKA3 are closely associated with malignant progression and poor prognosis. In vitro and in vivo experiments demonstrate that SKA3 promotes LSCC cell proliferation and chemoresistance through a novel role of reprogramming glycolytic metabolism. Further studies reveal the downstream mechanisms of SKA3, which can bind and stabilize polo-like kinase 1 (PLK1) protein via suppressing ubiquitin-mediated degradation. The accumulation of PLK1 activates AKT and thus upregulates glycolytic enzymes HK2, PFKFB3, and PDK1, resulting in enhancement of glycolysis. Furthermore, our data reveal that phosphorylation at Thr360 of SKA3 is critical for its binding to PLK1 and the increase in glycolysis. Collectively, the novel oncogenic signal axis "SKA3-PLK1-AKT" plays a critical role in the glycolysis of LSCC. SKA3 may serve as a prognostic biomarker and therapeutic target, providing a potential strategy for proliferation inhibition and chemosensitization in tumors, especially for LSCC patients with PLK1 inhibitor resistance.

Serum Exosomal miR-941 as a promising Oncogenic Biomarker for Laryngeal Squamous Cell Carcinoma.

At present, no blood-based biomarkers have been used in clinical practice for laryngeal squamous cell carcinoma (LSCC). Increasing evidence suggests that circulating exosomal microRNAs (miRNAs) may serve as potential diagnostic biomarkers for various cancers. This study aims to identify and evaluate serum exosomal miRNAs for LSCC diagnosis. The ExoQuick solution (EQ), which provides a high-yield and is a highly efficient exosome isolation method, was selected to isolate serum exosomes in the current study. In LSCC samples, exosome concentrations were higher than in healthy control (HC) samples. RNA-seq analysis identified a total of 1608 miRNAs, with 34 upregulated and 41 downregulated in LSCC samples relative to HC samples. Furthermore, qRT-PCR showed that miR-941 is significantly upregulated in LSCC serum exosomes, with this same trend seen in LSCC tissues and cells. Moreover, when examining miR-941 in cell lines, miR-941 overexpression promoted proliferation and invasion, while miR-941 knockdown inhibited cell proliferation and invasion. ROC curve analysis showed that miR-941 has an area under the curve (AUC) of 0.797 (95% CI = 0.676-0.918) for distinguishing LSCC patients from HCs. In conclusion, serum exosomal miR-941 may serve as a promising oncogenic biomarker for diagnosing LSCC, and has the potential as a therapeutic target.