HOXA1 silencing inhibits cisplatin resistance of oral squamous cell carcinoma cells via IκB/NF-κB signaling pathway.

The resistance of oral squamous cell carcinoma (OSCC) cells to cisplatin remains a tough nut to crack in OSCC therapy. Homeobox A1 (HOXA1) overexpression has been detected in head and neck squamous carcinoma (HNSC). Accordingly, this study aims to explore the potential role and mechanism of HOXA1 on cisplatin resistance in OSCC. The expression of HOXA1 in HNSC and its role in overall survival (OS) rate of OSCC patients were analyzed by bioinformatic analysis. Following transfection as needed, OSCC cells were induced by different concentrations of cisplatin, and the cell viability and apoptosis were evaluated by cell counting kit-8 and flow cytometry assays. The mRNA and protein expression levels of HOXA1 and the phosphorylation of IκBα and p65 were determined by real-time quantitative PCR and western blot. HOXA1 expression level was upregulated in HNSC tissues and OSCC cells. Overexpressed HOXA1 was correlated with a low OS rate of OSCC patients. Cisplatin exerted an anti-cancer effect on OSCC cells. HOXA1 silencing or cisplatin suppressed OSCC cell viability, boosted the apoptosis, and repressed the phosphorylation of IκBα and p65. Intriguingly, the combination of HOXA1 silencing and cisplatin generated a stronger anti-cancer effect on OSCC cells than their single use. HOXA1 silencing attenuates cisplatin resistance of OSCC cells via IκB/NF-κB signaling pathway, hinting that HOXA1 is a biomarker associated with OSCC and HOXA1 silencing can enhance the sensitivity of OSCC cells to cisplatin.

SENP1 inhibits ferroptosis and promotes head and neck squamous cell carcinoma by regulating ACSL4 protein stability via SUMO1.

Head and neck squamous cell carcinoma (HNSCC) is currently one of the most common malignancies with a poor prognosis worldwide. Meanwhile, small ubiquitin­like modifier (SUMO) specific peptidase 1 (SENP1) was associated with ferroptosis. However, the specific functions and underlying mechanisms of action of SENP1 in ferroptosis and tumor progression of HNSCC remain to be established. The findings of the present study implicated a novel ferroptosis pathway in the initiation and progression of HNSCC, providing new functional targets to guide future therapy. In the present study, The Cancer Genome Atlas database was employed to establish a gene model related to ferroptosis and verified SENP1 as a key gene via transcriptome sequencing. Expression of SENP1 in HNSCC tissue and CAL­27 cells was detected based on reverse transcription­quantitative PCR and western blot analysis. Proliferation and migration abilities of cells were determined using Cell Counting Kit­8, wound healing and Transwell experiments. Expression levels of iron, glutathione (GSH) and lipid peroxidation end­product malondialdehyde (MDA) under conditions of silencing of SENP1 with shRNA lentivirus were assayed. Additionally, the relationship between SENP1 and long­chain acyl­coenzyme A synthase 4 (ACSL4) was validated with the aid of immunoblotting and co­immunoprecipitation (co­IP). Finally, the influence of shSENP1 on the expression of key ferroptosis proteins, glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11, was evaluated via western blotting. It was revealed that SENP1 was significantly overexpressed in HNSCC and associated with low patient survival. Silencing of SENP1 led to significant suppression of cell proliferation, migration and invasion, increase in the contents of iron ions and MDA and decline in GSH levels in HNSCC cells, thereby enhancing ferroptosis and inhibiting disease progression. Conversely, overexpression of SENP1 suppressed ferroptosis and promoted progression of HNSCC. Co­IP and western blot analyses revealed a SUMOylation link between SENP1 and ACSL4. SENP1 reduced the stability of ACSL4 protein through deSUMOylation, leading to inhibition of ferroptosis. SENP1 silencing further inhibited the expression of the key iron death protein, GPX4, to regulate ferroptosis. Taken together, SENP1 deficiency promoted ferroptosis and inhibited tumor progression through reduction of SUMOylation of ACSL4 in HNSCC. The collective results of the present study supported the utility of SENP1 as an effective predictive biomarker for targeted treatment of HNSCC.

Development and validation of a nomogram to predict the five-year risk of revascularization for non-culprit lesion progression in STEMI patients after primary PCI.

Background: Acute ST-segment elevation myocardial infarction (STEMI) patients after primary PCI were readmitted for revascularization due to non-culprit lesion (NCL) progression. Objective: To develop and validate a nomogram that can accurately predict the likelihood of NCL progression revascularization in STEMI patients following primary PCI. Methods: The study enrolled 1,612 STEMI patients after primary PCI in our hospital from June 2009 to June 2018. Patients were randomly divided into training and validation sets in a 7:3 ratio. The independent risk factors were determined by LASSO regression and multivariable logistic regression analysis. Multivariate logistic regression analysis was utilized to develop a nomogram, which was then evaluated for its performance using the concordance statistics, calibration plots, and decision curve analysis (DCA). Results: The nomogram was composed of five predictors, including age (OR: 1.007 95% CI: 1.005-1.009, P < 0.001), body mass index (OR: 1.476, 95% CI: 1.363-1.600, P < 0.001), triglyceride and glucose index (OR: 1.050, 95% CI: 1.022-1.079, P < 0.001), Killip classification (OR: 1.594, 95% CI: 1.140-2.229, P = 0.006), and serum creatinine (OR: 1.007, 95% CI: 1.005-1.009, P < 0.001). Both the training and validation groups accurately predicted the occurrence of NCL progression revascularization (The area under the receiver operating characteristic curve values, 0.901 and 0.857). The calibration plots indicated an excellent agreement between prediction and observation in both sets. Furthermore, the DCA demonstrated that the model exhibited clinical efficacy. Conclusion: A convenient and accurate nomogram was developed and validated for predicting the occurrence of NCL progression revascularization in STEMI patients after primary PCI.

Association between triglyceride glucose-body mass index and heart failure in subjects with diabetes mellitus or prediabetes mellitus: a cross-sectional study.

Background: The triglyceride glucose-body mass index (TyG-BMI) is a surrogate indicator of insulin resistance. However, the association of TyG-BMI with heart failure (HF) in individuals with diabetes mellitus or prediabetes mellitus is unknown. Methods: This study included 7,472 participants aged 20-80 years old with prediabetes or diabetes from the National Health and Nutrition Examination Survey (2007-2018). The TyG-BMI was calculated as Ln [triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI, and individuals were categorized into tertiles based on TyG-BMI levels. The relationship of TyG-BMI with HF was analyzed using multiple logistic regression models. Subgroup analyses were stratified by gender, age, hypertension, and diabetes mellitus status. Results: This cross-sectional study had 7,472 participants (weighted n = 111,808,357), including 329 HF participants. Participants with a high TyG-BMI were prone to HF. The highest tertile group with a fully adjusted model was more likely to have HF compared to the lowest tertile group (odds ratio [OR], 2.645; 95% CI, 1.529-4.576). Restricted cubic spline analysis showed a significant dose-response relationship between TyG-BMI and HF (P < 0.001). In subgroup analyses, similar results were seen in terms of age (≥50 years old), gender, hypertension, and diabetes mellitus status. Conclusion: A high TyG-BMI is significantly associated with HF risk in participants with diabetes mellitus or prediabetes mellitus.

Association between sun-protective behaviors and hypertension: a cross-sectional study from National Health and Nutrition Examination Survey 2009 to 2014.

BACKGROUND: In previous studies, sun-protective behaviors increased cardiovascular incidence. Our present article is to further analyze the potential relationship between sun-protective behaviors (staying in the shade, wearing long-sleeved clothing, and applying sunscreen) and hypertension. METHOD: The present cross-sectional study evaluated 8,613 participants (aged 20-60 years) from the National Health and Nutrition Examination Survey (NHANES) obtained between 2009 and 2014. We performed multiple logistic regression analysis to examine the relationship between sun-protective behaviors and hypertension. Subgroup analysis was then performed. Multiple linear regression analysis was utilized to examine the relationship of sun-protective behaviors and each sun-protective behavior with systolic and diastolic blood pressure, stratified by sex and race. RESULTS: A total of 8,613 participants (weighted n = 127,909,475) were applied in our study, including 1,694 hypertensive subjects. Our study demonstrated that sun-protective behaviors of the 2-3 category were associated with increased risk of hypertension, but not with higher systolic and diastolic blood pressure. In subgroup analysis, men, Mexican American, and 25 < BMI ≤ 30 who reported sun-protective behaviors (2-3) were prone to hypertension. Multiple linear regression models showed that non-Hispanic white men with sun-protective behaviors (2-3) were positively associated with systolic and diastolic blood pressure. The association between other-Hispanic men with frequent wearing long-sleeved clothing and diastolic blood pressure was positively correlated. CONCLUSION: Sun-protective behaviors of the 2-3 category could increase the incidence of hypertension, but not increase systolic and diastolic blood pressure. We only found that non-Hispanic white men who reported sun-protective behaviors (2-3) were positively associated with systolic and diastolic blood pressure. These findings suggested that excessive sun-protective behaviors should be avoided.

Metallodrugs in the battle against non-small cell lung cancer: unlocking the potential for improved therapeutic outcomes.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality worldwide. Platinum-based chemotherapy is standard-of-care but has limitations including toxicity and resistance. Metal complexes of gold, ruthenium, and other metals have emerged as promising alternatives. This review provides a comprehensive analysis of metallodrugs for NSCLC. Bibliometric analysis reveals growing interest in elucidating mechanisms, developing targeted therapies, and synergistic combinations. Classification of metallodrugs highlights platinum, gold, and ruthenium compounds, as well as emerging metals. Diverse mechanisms include DNA damage, redox modulation, and immunomodulation. Preclinical studies demonstrate cytotoxicity and antitumor effects in vitro and in vivo, providing proof-of-concept. Clinical trials indicate platinums have utility but resistance remains problematic. Non-platinum metallodrugs exhibit favorable safety but modest single agent efficacy to date. Drug delivery approaches like nanoparticles show potential to enhance therapeutic index. Future directions include optimization of metal-based complexes, elucidation of resistance mechanisms, biomarker development, and combination therapies to fully realize the promise of metallodrugs for NSCLC.

Triglyceride Glucose Index Increases Significantly Risk of Hypertension Development in Chinese Individuals Aged ≥45 Years Old: Analysis from the China Health and Retirement Longitudinal Study.

Objective: Our purpose was to explore the relationship between triglyceride glucose (TyG) index and the risk of new-onset hypertension in Chinese individuals aged ≥45 years. Methods: From 2011 to 2018, data from the China Health and Retirement Longitudinal Survey (CHARLS) were analyzed. The relationship between TyG index and hypertension was assessed utilizing Cox regression and restricted cubic spline (RCS) plot, and the importance of the TyG index in hypertension development was demonstrated by a random forest machine learning model. Finally, subgroup analysis was conducted to test for potential interactions on hypertension development between the TyG index and subgroups. Results: 19.7% of the 4755 individuals who were involved in this survey developed hypertension over an average follow-up period of 5.22 years. Compared with the first quartile of albumin, the multivariate HR (95% CI) for the risk of new-onset hypertension across the TyG index quartiles was 1.09 (0.89, 1.33), 1.09 (0.89, 1.33), and 1.29 (1.06, 1.58), respectively (P for trend <0.001). The RCS plot revealed a linear relationship (P for nonlinear = 0.322), and the random forest machine learning model illustrated that the TyG index was a significant hazard factor on hypertension development. There was no interaction between subgroups and the relationships of the TyG index with the prevalence of hypertension (all P-value >0.05). Conclusion: TyG index was an independent hazard indicator for new-onset hypertension, and routine measurement and control of TyG index level might be great for preventing hypertension development.

A Selective Fluorescent l-Lactate Biosensor Based on an l-Lactate-Specific Transcription Regulator and Förster Resonance Energy Transfer.

Selective detection of l-lactate levels in foods, clinical, and bacterial fermentation samples has drawn intensive attention. Many fluorescent biosensors based on non-stereoselective recognition elements have been developed for lactate detection. Herein, the allosteric transcription factor STLldR from Salmonella enterica serovar Typhimurium LT2 was identified to be stereo-selectively respond to l-lactate. Then, STLldR was combined with Förster resonance energy transfer (FRET) to construct a fluorescent l-lactate biosensor FILLac. FILLac was further optimized by truncating the N- and C-terminal amino acids of STLldR between cyan and yellow fluorescent proteins. The optimized biosensor FILLac10N0C exhibited a maximum emission ratio change (ΔRmax) of 33.47 ± 1.91%, an apparent dissociation constant (Kd) of 6.33 ± 0.79 µM, and a limit of detection of 0.68 µM. FILLac10N0C was applied in 96-well microplates to detect l-lactate in bacterial fermentation samples and commercial foods such as Jiaosu and yogurt. The quantitation results of FILLac10N0C exhibited good agreement with that of a commercial l-lactate biosensor SBA-40D bioanalyzer. Thus, the biosensor FILLac10N0C compatible with high-throughput detection may be a potential choice for quantitation of l-lactate in different biological samples.

Development and validation of a predictive model for adverse left ventricular remodeling in NSTEMI patients after primary percutaneous coronary intervention.

INTRODUCTION: To develop and validate clinical evaluators that predict adverse left ventricular remodeling (ALVR) in non-ST-elevation myocardial infarction (NSTEMI) patients after primary percutaneous coronary intervention (PCI). METHODS: The retrospective study analyzed the clinical data of 507 NSTEMI patients who were treated with primary PCI from the Affiliated Hospital of Xuzhou Medical University and the Second Affiliated Hospital of Xuzhou Medical University, between January 1, 2019 and September 31, 2021. The training cohort consisted of patients admitted before June 2020 (n = 287), and the remaining patients (n = 220) were assigned to an external validation cohort. The endpoint event was the occurrence of ALVR, which was described as an increase ≥ 20% in left ventricular end-diastolic volume (LVEDV) at 3-4 months follow-up CMR compared with baseline measurements. The occurrence probability of ALVR stemmed from the final model, which embodied independent predictors recommended by logistic regression analysis. The area under the receiver operating characteristic curve (AUC), Calibration plot, Hosmer-Lemeshow method, and decision curve analysis (DCA) were applied to quantify the performance. RESULTS: Independent predictors for ALVR included age (odds ratio (OR): 1.040; 95% confidence interval (CI): 1.009-1.073), the level of neutrophil to lymphocyte ratio (OR: 4.492; 95% CI: 1.906-10.582), the cardiac microvascular obstruction (OR: 3.416; 95% CI: 1.170-9.970), peak global longitudinal strain (OR: 1.131; 95% CI: 1.026-1.246), infarct size (OR: 1.082; 95% CI: 1.042-1.125) and left ventricular ejection fraction (OR: 0.925; 95% CI: 0.872-0.980), which were screened by regression analysis then merged into the nomogram model. Both internal validation (AUC: 0.805) and external validation (AUC: 0.867) revealed that the prediction model was capable of good discrimination. Calibration plot and Hosmer-Lemeshow method showed high consistency between the probabilities predicted by the nomogram (P = 0.514) and the validation set (P = 0.762) and the probabilities of actual occurrence. DCA corroborated the clinical utility of the nomogram. CONCLUSIONS: In this study, the proposed nomogram model enabled individualized prediction of ALVR in NSTEMI patients after reperfusion and conduced to guide clinical therapeutic schedules.

A d,l-lactate biosensor based on allosteric transcription factor LldR and amplified luminescent proximity homogeneous assay.

Lactate, a hydroxycarboxylic acid commercially produced by microbial fermentation, is widely applied in diverse industrial fields. Lactate exists in two stereoisomeric forms (d-lactate and l-lactate). d-Lactate and l-lactate are often simultaneously present in many biological samples. Therefore, a biosensor able to detect both d- and l-lactate is required but previously unavailable. Herein, an allosteric transcription factor LldR from Pseudomonas aeruginosa PAO1, which responds to both d-lactate and l-lactate, was combined with amplified luminescent proximity homogeneous assay technology to develop a d,l-lactate biosensor. The proposed biosensor was optimized by mutation of DNA sequence in binding site of LldR. The optimized biosensor BLac-6 can accurately detect the concentration of lactate independent on ratio of the two isomers in pending test samples. The biosensor was also tentatively used in quantitative analysis of d-lactate, l-lactate, or d,l-lactate in fermentation samples produced by three recombinant strains of Klebsiella oxytoca. With its desirable properties, the biosensor BLac-6 may be a potential choice for monitoring the concentration of lactate during industrial fermentation.

A D-2-hydroxyglutarate biosensor based on specific transcriptional regulator DhdR.

D-2-Hydroxyglutarate (D-2-HG) is a metabolite involved in many physiological metabolic processes. When D-2-HG is aberrantly accumulated due to mutations in isocitrate dehydrogenase or D-2-HG dehydrogenase, it functions in a pro-oncogenic manner and is thus considered a therapeutic target and biomarker in many cancers. In this study, DhdR from Achromobacter denitrificans NBRC 15125 is identified as an allosteric transcriptional factor that negatively regulates D-2-HG dehydrogenase expression and responds to the presence of D-2-HG. Based on the allosteric effect of DhdR, a D-2-HG biosensor is developed by combining DhdR with amplified luminescent proximity homogeneous assay (AlphaScreen) technology. The biosensor is able to detect D-2-HG in serum, urine, and cell culture medium with high specificity and sensitivity. Additionally, this biosensor is used to identify the role of D-2-HG metabolism in lipopolysaccharide biosynthesis of Pseudomonas aeruginosa, demonstrating its broad usages.

Anisodamine ameliorates ischemia/reperfusion-induced renal injury in rats through activation of the extracellular signal-regulated kinase (ERK) pathway and anti-apoptotic effect.

Anisodamine exerts significant protective effect on ischemia/reperfusion (I/R) injury in various organs. However, little is known about the mechanisms of anisodamine in renal I/R injury. Activation of extracellular regulated protein kinases (ERK) pathway promotes the repair of renal epithelial cells following oxidant injury. The present study investigated whether the renoprotective role of anisodamine against renal I/R injury in rats was associated with the activation of ERK signaling pathway. Male Sprague-Dawley (SD) rats were separated into the following groups: Sham-operated group, I/R group, anisodamine-treated group, PD98059 (MEK-1/ERK inhibitor)-treated group and anisodamine plus PD98059-treated group. A rat model of renal I/R was established by excising the right kidney and then clamping the left renal pedicle for 45 min followed by reperfusion for 24 h. Serum and renal tissue samples were obtained for assays of the associated morphological, molecular and biochemical parameters. Treatment with anisodamine ameliorated renal I/R injury, as evidenced by improvements of renal histology and kidney function, a decrease in paller's score and apoptosis index. Anisodamine also upregulated the phosphorylation levels of ERK1/2 and its downstream targets, including 90 ribosomal S6 kinase (p90rsk) and Bad, as well as the expression of antiapoptotic Bcl-2 protein, downregulated the expression levels of proapoptotic proteins Bax and cleaved-caspase-3, whereas these effects were greatly abolished by administration of PD98059. In conclusion, the results suggest that anisodamine prevents renal I/R injury in rats as a result of an activation of the ERK signaling pathway and anti-apoptotic properties.

Investigation on the variation law of gas liquid solid three phase boundary in porous gas diffusion electrode.

The three-phase boundary length will change with the electrochemical reaction in the working process of the gas diffusion electrode. The process of porous media fluid interface movement is investigated by establishing the physical and mathematical model of the microporous electrode. Using a numerical simulation method, the electrode section electron micrographs are topologically gridded to investigate the micro flow phenomenon of the gas diffusion electrode in the zinc-air battery. By simulating the development process of the electrolyte interface in the porous electrode, the law for the variation of the total length of the three-phase boundary is observed. The results show that the total length of the three-phase boundary increases first and then shortens with the change of gas diffusion and electrolyte electrode movement. A similar trend is observed when the peak power is varied. A theoretical expression for that defines the changes in the length of the three-phase boundary is provided. Finally, we show that the topology and the grid method are feasible means that can be used to analyze electrochemical reactions in complex multiphase flows.

Numerical Study of Pillar Shapes in Deterministic Lateral Displacement Microfluidic Arrays for Spherical Particle Separation.

Deterministic lateral displacement (DLD) arrays containing shaped pillars have been found to be more effective in biomedical sample separation. This study aims to numerically investigate the interplay between particles and microfluidic arrays, and to find out the key factors in determining the critical size of a DLD device with shaped pillars. A new formula is thus proposed to estimate the critical size for spherical particle separation in this kind of new DLD microfluidic arrays. The simulation results show that both rectangular and I-shaped arrays have considerably smaller critical sizes. The ratio of sub-channel widths is also found to play an important role in reducing the critical sizes. This paves a valuable way toward designing high-performance DLD microfluidic arrays.