PREX2 contributes to radiation resistance by inhibiting radiotherapy-induced tumor immunogenicity via cGAS/STING/IFNs pathway in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) lacks established biomarkers or molecular targets for predicting or enhancing radiation response. Phosphatidylinositol-3,4,5-triphosphate-dependent Rac exchange factor 2 (PREX2) exhibits intricate implications in tumorigenesis and progression. Nevertheless, the precise role and underlying mechanisms of PREX2 in CRC radioresistance remain unclear. METHODS: RNA-seq was employed to identify differentially expressed genes between radioresistant CRC cell lines and their parental counterparts. PREX2 expression was scrutinized using Western blotting, real-time PCR, and immunohistochemistry. The radioresistant role of PREX2 was assessed through in vitro colony formation assay, apoptosis assay, comet assay, and in vivo xenograft tumor models. The mechanism of PREX2 was elucidated using RNA-seq and Western blotting. Finally, a PREX2 small-molecule inhibitor, designated PREX-in1, was utilized to enhance the efficacy of ionizing radiation (IR) therapy in CRC mouse models. RESULTS: PREX2 emerged as the most significantly upregulated gene in radioresistant CRC cells. It augmented the radioresistant capacity of CRC cells and demonstrated potential as a marker for predicting radioresistance efficacy. Mechanistically, PREX2 facilitated DNA repair by upregulating DNA-PKcs, suppressing radiation-induced immunogenic cell death, and impeding CD8+ T cell infiltration through the cGAS/STING/IFNs pathway. In vivo, the blockade of PREX2 heightened the efficacy of IR therapy. CONCLUSIONS: PREX2 assumes a pivotal role in CRC radiation resistance by inhibiting the cGAS/STING/IFNs pathway, presenting itself as a potential radioresistant biomarker and therapeutic target for effectively overcoming radioresistance in CRC.

Multi-band reprogrammable phase-change metasurface spectral filters for on-chip spectrometers.

Active optical metasurfaces provide a platform for dynamic and real-time manipulation of light at subwavelength scales. However, most active metasurfaces are unable to simultaneously possess a wide wavelength tuning range and narrow resonance peaks, thereby limiting further advancements in the field of high-precision sensing or detection. In the paper, we proposed a reprogrammable active metasurface that employs the non-volatile phase change material Ge2Sb2Te5 and demonstrated its excellent performance in on-chip spectrometer. The active metasurfaces support magnetic modes and feature Friedrich-Wintgen quasi bound states in the continuum, capable of achieving multi-resonant near-perfect absorption, a multilevel tuning range, and narrowband performance in the infrared band. Meanwhile, we numerically investigated the coupling phenomenon and the intrinsic relationship between different resonance modes under various structural parameters. Furthermore, using the active metasurfaces as tunable filters and combined with compressive sensing algorithms, we successfully reconstructed various types of spectral signals with an average fidelity rate exceeding 0.99, utilizing only 51 measurements with a single nanostructure. A spectral resolution of 0.5 nm at a center wavelength 2.538 µm is predicted when the crystallization fractions of GST change from 0 to 20%. This work has promising potential in on-site matter inspection and point-of-care (POC) testing.

Long-acting growth hormone in the treatment of growth hormone deficiency in children: a systematic literature review and network meta-analysis.

The purpose of this study is to compare the relative efficacy and safety of long-acting growth hormone (LAGH) as a growth hormone replacement therapy in prepubertal children with growth hormone deficiency (GHD). We searched the PubMed, Embase, CNKI, and Wanfang databases from inception to July 2023 and identified eleven relevant studies. PEG-LAGH showed better effect on height velocity (mean difference [MD]: - 0.031, 95% credibility interval [CrI]: - 0.278, 0.215) than somatrogon (MD: 0.105, 95% CrI: - 0.419, 0.636), somapacitan (MD: 0.802, 95% CrI: - 0.451, 2.068) and lonapegsomatropin (MD: 1.335, 95% CrI: - 0.3, 2.989) when compared with daily growth hormone (DGH). Furthermore, in terms of height standard deviation score, PEG-LAGH demonstrated better improvement (MD: - 0.15, 95% CrI: - 1.1, 0.66) than somatrogon (MD: - 0.055, 95% CrI: - 1.3, 0.51) and somapacitan (MD: 0.22, 95% CrI: - 0.91, 1.3). PEG-LAGH (risk ratio [RR]: 1.00, 95% CrI: 0.82, 1.2) reduced the risk of adverse events compared with other LAGH (somatrogon, RR: 1.1, 95% CrI: 0.98, 1.2; somapacitan, RR: 1.1, 95% CrI: 0.96, 1.4; lonapegsomatropin, RR, 1.1, 95% CrI: 0.91, 1.3) and was comparable with DGH. This is the first study to indirectly compare the LAGH thorough a network meta-analysis and provide evidence of the optimal efficacy of various LAGH specifically PEG-LAGH and acceptable safety profile in prepubertal children with GHD.

Rh proteins and H+ transporters involved in ammonia excretion in Amur Ide (Leuciscus waleckii) under high alkali exposure.

High alkaline environment can lead to respiratory alkalosis and ammonia toxification to freshwater fish. However, the Amur ide (Leuciscus waleckii), which inhabits an extremely alkaline lake in China with titratable alkalinity up to 53.57 mM (pH 9.6) has developed special physiological and molecular mechanisms to adapt to such an environment. Nevertheless, how the Amur ide can maintain acid-base balance and perform ammonia detoxification effectively remains unclear. Therefore, this study was designed to study the ammonia excretion rate (Tamm), total nitrogen accumulation in blood and tissues, including identification, expression, and localization of ammonia-related transporters in gills of both the alkali and freshwater forms of the Amur ide. The results showed that the freshwater form Amur ide does not have a perfect ammonia excretion mechanism exposed to high-alkaline condition. Nevertheless, the alkali form of Amur ide was able to excrete ammonia better than freshwater from Amur ide, which was facilitated by the ionocytes transporters (Rhbg, Rhcg1, Na+/H+ exchanger 2 (NHE2), and V-type H+ ATPase (VHA)) in the gills. Converting ammonia into urea served as an ammonia detoxication strategy to reduced endogenous ammonia accumulation under high-alkaline environment.

Combined Use of Helicobacter pylori Genotyping and CDX2 Expression as a Predictor of Malignant Potential in Gastric Intestinal Metaplasia.

OBJECTIVE: Gastrointestinal metaplasia (GIM) has a close relationship with gastric cancer (GC), but it is unclear how to judge which GIM could develop into GC. This study aimed to assess the role of CDX2 and its association with Helicobacter pylori (H.pylori) genotypes in GIM. METHODS: CagA and vacA genes were identified via PCR in 466 H. pylori-positive gastric tissues, including gastritis (n=104), GIM diagnosed endoscopically (GIM-1; n=82), gastric cancer (GC; n=173), and paired adjacent GIM tumors resected surgically (GIM-2; n=107). GIM was subclassified per the HID- AB pH2.5-PAS as follows: type I (n=23), type II (n=43), and type III (n=16) in GIM-1; type I (n=8), type II (n=40), and type III (n=59) in GIM-2. CDX2 expression was evaluated immunohistochemically. RESULTS: In GIM-1, the infection rate of vacAm2 (55.8%) and vacAs1m2 (53.5%) was higher in subtype II than in others (P<0.05), while that of vacAm1 (49.2%) and vacAs1m1 (33.9%) was higher in subtype III than in others. The cagA+ rate was higher in subtypes I (75.0%) and III (64.4%) than in subtype II (40.0%; P<0.05) respectively. CDX2 was upregulated in subtype I than in subtypes II and III in GIM-1 and GIM-2. In GIM-2 and GC, CDX2 was downregulated in vacAm1, vacAs1m1, and cagA+ (P<0.05). The predominant genotype was vacAs1m2 in subtype II of GIM-1, CDX2 expression remaining unaltered; however, the predominant genotype was cagA+ vacAs1m1 in subtypes II and III of GIM-2, negatively correlated with CDX2 expression. CONCLUSION: These GIM subtypes (cagA+ vacAs1m1 H. pylori-positive GIM with negative CDX2 expression) resemble GC and should be evaluated similar to cancerous GIM.

Nomogram-based risk assessment model for left ventricular hypertrophy in patients with essential hypertension: Incorporating clinical characteristics and biomarkers.

Left ventricular hypertrophy (LVH) is a hypertensive heart disease that significantly escalates the risk of clinical cardiovascular events. Its etiology potentially incorporates various clinical attributes such as gender, age, and renal function. From mechanistic perspective, the remodeling process of LVH can trigger increment in certain biomarkers, notably sST2 and NT-proBNP. This multicenter, retrospective study aimed to construct an LVH risk assessment model and identify the risk factors. A total of 417 patients with essential hypertension (EH), including 214 males and 203 females aged 31-80 years, were enrolled in this study; of these, 161 (38.6%) were diagnosed with LVH. Based on variables demonstrating significant disparities between the LVH and Non-LVH groups, three multivariate stepwise logistic regression models were constructed for risk assessment: the "Clinical characteristics" model, the "Biomarkers" model (each based on their respective variables), and the "Clinical characteristics + Biomarkers" model, which amalgamated both sets of variables. The results revealed that the "Clinical characteristics + Biomarkers" model surpassed the baseline models in performance (AUC values of the "Clinical characteristics + Biomarkers" model, the "Biomarkers" model, and the "Clinical characteristics" model were .83, .75, and .74, respectively; P < .0001 for both comparisons). The optimized model suggested that being female (OR: 4.26, P <.001), being overweight (OR: 1.88, p = .02) or obese (OR: 2.36, p = .02), duration of hypertension (OR: 1.04, P = .04), grade III hypertension (OR: 2.12, P < .001), and sST2 (log-transformed, OR: 1.14, P < .001) were risk factors, while eGFR acted as a protective factor (OR: .98, P = .01). These findings suggest that the integration of clinical characteristics and biomarkers can enhance the performance of LVH risk assessment.

High quality holographic 3D display with enhanced focus cues based on multiple directional light reconstruction.

Holographic display faces the trade-off between image quality and focus cues, resulting from the specific choice of phase distribution. In this Letter, we propose a speckle-free holographic display with enhanced focus cues by multiple directional light reconstruction. The uniform phase hologram is first generated by the gradient descent optimization algorithm. The blazed grating phase is used to steer the object light to a specific direction. Multiple sub-holograms with different blazed gratings are refreshed fast to reconstruct the images from different directions. Thus, the defocus blur is improved due to the separation of multiple spots on the defocus plane. The multi-plane reconstruction is also realized by pre-processing the depth images to eliminate image separation. The proposed method provides apparent focus cues while maintaining high image qualities, which is expected to realize comfortable holographic near-eye display in the near future.

Label-free single-cell analysis in microdroplets using a light-scattering-based optofluidic chip.

Droplet-based single-cell analysis is a very powerful tool for studying phenotypic and genomic heterogeneity at single-cell resolution for a variety of biological problems. In conventional two-phase droplet microfluidics, due to the mismatch in optical properties between oil and aqueous phases, light scattering mainly happens at the oil/water interface that disables light-scattering-based cell analysis confined in microdroplets. Detection and analysis of cells in microdroplets thus mostly rely on the fluorescence labeling of cell samples, which may suffer from complex operation, cytotoxicity, and low fluorescence stability. In this work, we propose a novel light-scattering-based droplet screening (LSDS) that can effectively detect and characterize single cells confined in droplets by adjusting the optical properties of droplets in a multiangle optofluidic chip. Theoretical and simulated calculations suggest that refractive index (RI) matching in droplet two-phase materials can reduce or eliminate droplets' scattered signals (background signal), enabling the differentiation of scattered signals from single cells and particles within droplets. Furthermore, by using a set of multiangle (from -145° to 140°) optical fibers integrated into the optofluidic chip, the scattered light properties of droplets with the RI ranging from 1.334 to 1.429 are measured. We find that the smaller the RI and size of microparticles inside droplets are, the smaller the RI difference between two-phase materials Δn is required. Especially, when Δn is smaller than 0.02, single cells in droplets can be detected and analyzed solely based on light scattering. This capability allows to accurately detect droplets containing one single cell and one single gel bead, a typical droplet encapsulation for single-cell sequencing. Altogether, this work provides a powerful platform for high-throughput label-free single-cell analysis in microdroplets for diverse single-cell related biological assays.

Quality of Life and Glucose Regulation in Pediatric Patients with Type 1 Diabetes: A Study in the Ningxia Hui Autonomous Region.

Objective: In this study, we aimed to evaluate the current status of the quality of life (QOL) of pediatric patients and plasma glucose concentration regulation in children with type 1 diabetes (T1DM) in the Ningxia Hui autonomous region. Methods: The study involved children with T1DM admitted to the General Hospital of Ningxia Medical University between October 2011 and October 2021. The children and their parents completed general information and quality of life (QOL) questionnaires. The regulation of plasma glucose concentration was assessed based on HbA1c levels, and plasma glucose and QOL-influencing components were investigated. Results: Among the 136 pediatric patients diagnosed with T1DM, the mean glycated hemoglobin (HbA1c) level was recorded at 8.7% (7.2%, 10.5%). A breakdown of the patient cohort revealed that 44 patients (32.4%) demonstrated good regulation of plasma glucose, 33 patients (24.3%) exhibited acceptable glycemic control, and 59 patients (43.3%) displayed poor regulation of plasma glucose. The control of plasma glucose in pediatric patients diagnosed with T1DM was affected by the duration of the disease, the patient's age, the frequency of daily plasma glucose measurements, the use of CGM, diabetic ketoacidosis (DKA), and the education level of the mother. The control of plasma glucose, dietary management, DKA, the ability to learn, and health education are interfering factors of quality of life in children diagnosed with T1DM. Effective control of plasma glucose may ensure the QOL in children with T1DM, and DKA was the risk factor for QOL. Conclusion: In Ningxia, the regulation of plasma glucose in pediatric and adolescent patients with T1DM remains suboptimal, leading to poor QOL. There is a pressing need to enhance glucose regulation and QOL through comprehensive strategies, which include reinforced dietary management, rigorous monitoring of plasma glucose levels, and heightened health education levels.

[Effect of Film Mulching Age and Organic Fertilizer Application on the Distribution Characteristics of Microplastics in the Soil of a Peanut Field].

The large input of mulch film and organic fertilizer have led to increasingly serious microplastic pollution in farmland soil of China. In this study, the microplastic pollution of peanut farmland in Dezhou City, Shandong Province was investigated. The effects of different mulching years (0, 3, 5, and 8 years) and organic fertilizer application on the abundance, particle size, color, and shape of microplastics in farmland soil were analyzed. The results showed that the average abundances of microplastics in peanut soil were 65.33, 316.00, 1 098.67, and 1 346.34 n·kg-1, respectively, after 0, 3, 5, and 8 years of film mulching. The abundance of microplastics decreased with the increase in soil depth. The abundance of microplastics in 0-10, 10-20, and 20-30 cm topsoil was 1 076.00, 603.5, and 440.25 n·kg-1, respectively, and the abundance of microplastics increased significantly with increasing years of film mulching and organic fertilizer application (P<0.05). The particle size of microplastics in the sample plot <1 mm accounted for 77.30% of the total content, and with the increase in film mulching age, the proportion of microplastics with small particle size (<1 mm) increased significantly (P < 0.05). With the increase in soil depth, the proportion of microplastics with small particle size also gradually increased, whereas the application of organic fertilizer had no significant effect on the particle size of microplastics. The color of microplastics in the plot was mainly transparent (49.77%), followed by black (16.35%) and white (16.27%). The planting age and organic fertilizer application had no significant effect on the color of microplastics in the soil (P > 0.05), but the mulching age significantly increased the proportion of transparent microplastics. The abundance proportion of the five types of microplastics were 49.77%, 25.41%, 19.15%, 3.26%, and 2.41%, respectively. These field soil microplastics were mainly composed of polyethylene (PE), polypropylene (PP), and polystyrene (PS) polymers, accounting for 21.37%, 18.57%, and 19.77% of the total, respectively. Therefore, microplastics were widely present in the soil of the peanut field cultivated layer in Dezhou, Shandong, and the applications of mulch film and organic fertilizer were the main source. This study provides an important basis for the prevention and control of soil microplastic pollution in peanut fields.

SBFI26 induces triple-negative breast cancer cells ferroptosis via lipid peroxidation.

SBFI26, an inhibitor of FABP5, has been shown to suppress the proliferation and metastasis of tumour cells. However, the underlying mechanism by which SBFI26 induces ferroptosis in breast cancer cells remains largely unknown. Three breast cancer cell lines were treated with SBFI26 and CCK-8 assessed cytotoxicity. Transcriptome was performed on the Illumina platform and verified by qPCR. Western blot evaluated protein levels. Malondialdehyde (MDA), total superoxide dismutase (T-SOD), Fe, glutathione (GSH) and oxidized glutathione (GSSG) were measured. SBFI26 induced cell death time- and dose-dependent, with a more significant inhibitory effect on MDA-MB-231 cells. Fer-1, GSH and Vitamin C attenuated the effects but not erastin. RNA-Seq analysis revealed that SBFI26 treatment significantly enriched differentially expressed genes related to ferroptosis. Furthermore, SBFI26 increased intracellular MDA, iron ion, and GSSG levels while decreasing T-SOD, total glutathione (T-GSH), and GSH levels.SBFI26 dose-dependently up-regulates the expression of HMOX1 and ALOX12 at both gene and protein levels, promoting ferroptosis. Similarly, it significantly increases the expression of SAT1, ALOX5, ALOX15, ALOXE3 and CHAC1 that, promoting ferroptosis while downregulating the NFE2L2 gene and protein that inhibit ferroptosis. SBFI26 leads to cellular accumulation of fatty acids, which triggers excess ferrous ions and subsequent lipid peroxidation for inducing ferroptosis.

Study on the saltiness-enhancing mechanism of chicken-derived umami peptides by sensory evaluation and molecular docking to transmembrane channel-like protein 4 (TMC4).

The previously obtained chicken-derived umami peptides in the laboratory were evaluated for their saltiness-enhancing effect by sensory evaluation and S-curve, and the results revealed that peptides TPPKID, PKESEKPN, TEDWGR, LPLQDAH, NEFGYSNR, and LPLQD had significant saltiness-enhancing effects. In the binary solution system with salt, the ratio of the experimental detection threshold (129.17 mg/L) to the theoretical detection threshold (274.43 mg/L) of NEFGYSNR was 0.47, which had a synergistic saltiness-enhancing effect with salt. The model of transmembrane channel-like protein 4 (TMC4) channel protein was constructed by homology modeling, which had a 10-fold transmembrane structure and was well evaluated. Molecular docking and frontier molecular orbitals showed that the main active sites of TMC4 were Lys 471, Met 379, Cys 475, Gln 377, and Pro 380, and the main active sites of NEFGYSNR were Tyr, Ser and Asn. This study may provide a theoretical reference for low-sodium diets.

Changes of Mycobacterium tuberculosis specific antigen-stimulated CD27-CD38+IFN-γ+CD4+ T cells before and after anti-tuberculosis treatment.

BACKGROUND: The aim of the study was to investigate whether the expression of CD27-CD38+ in interferon (IFN)-γ+CD4+ T cells stimulated by the specific antigen early secreted antigenic target-6 (ESAT-6)/culture filter protein-10 (CFP-10) could be a potential new therapeutic evaluation indicator for anti-tuberculosis (TB) treatment. METHODS: Newly diagnosed active pulmonary TB patients, latent TB infection (LTBI) and healthy controls were enrolled from January 2021 to December 2021. PTB patients were treated by standard anti-TB regimen 2HREZ/4HR (2 months of isoniazid (H), rifampin (R), ethambutol (E), and pyrazinamide (Z) followed by 4 months of isoniazid (H) and rifampin (R)). The difference of CD27-CD38+ expression in IFN-γ+CD4+ T cells before treatment, 2 months after treatment, and 6 months after treatment were compared. RESULTS: Total 45 PTB patients, 38 LTBI cases and 43 healthy controls were enrolled. The expression of CD27-CD38+ decreased significantly after anti-TB treatment and was comparable with that in LTBI and healthy controls when the 6-month anti-TB treatment course was completed. The decline rate of CD27-CD38+ between 6 months after treatment and baseline was positively correlated with erythrocyte sedimentation rate (r = 0.766, P < 0.0001), C-reactive protein (r = 0.560, P = 0.003) and chest computerized tomography severity score (r = 0.632, P = 0.0005). The area under receiver operator characteristic curve of CD27-CD38+ in distinguish pulmonary TB patients before and after treatment was 0.779. CONCLUSION: The expression of CD27-CD38+ in ESAT-6/CFP-10 stimulated IFN-γ+CD4+T cells can well reflect the changes of the disease before and after anti-TB treatment, which is expected to be a potential new therapeutic evaluation index. Clinical Registry number chiCTR1800019966.

PM2.5 exposure-induced senescence-associated secretory phenotype in airway smooth muscle cells contributes to airway remodeling.

Fine particulate matter (PM2.5) has been linked to increased severity and incidence of airway diseases, especially chronic obstructive pulmonary disease (COPD) and asthma. Airway remodeling is an important event in both COPD and asthma, and airway smooth muscle cells (ASMCs) are key cells which directly involved in airway remodeling. However, it was unclear how PM2.5 affected ASMCs. This study investigates the effects of PM2.5 on airway smooth muscle and its mechanism. We first showed that inhaled particulate matter was distributed in the airway smooth muscle bundle, combined with increased airway smooth muscle bundle and collagen deposition in vivo. Then, we demonstrated that PM2.5 induced up-regulation of collagen-I and alpha-smooth muscle actin (α-SMA) expression in rat and human ASMCs in vitro. Next, we found PM2.5 led to rat and human ASMCs senescence and exhibited senescence-associated secretory phenotype (SASP) by autophagy-induced GATA4/TRAF6/NF-κB signaling, which contributed to collagen-I and α-SMA synthesis as well as airway smooth muscle remodeling. Together, our results provided evidence that SASP induced by PM2.5 in airway smooth muscle cells prompted airway remodeling.

Bacillus phage phi18-2 is a novel temperate virus with an unintegrated genome present in the cytoplasm of lysogenic cells as a linear phage-plasmid.

Bacillus subtilis is a Gram-positive bacterium that is widely used in fermentation and in the pharmaceutical industry. Phage contamination occasionally occurs in various fermentation processes and causes significant economic loss. Here, we report the isolation and characterization of a temperate B. subtilis phage, termed phi18-2, from spore powder manufactured in a fermentation plant. Transmission electron microscopy showed that phi18-2 has a symmetrical polyhedral head and a long noncontractile tail. Receptor analysis showed that phi18-2 recognizes wall teichoic acid (WTA) for infection. The phage virions have a linear double-stranded DNA genome of 64,467 bp with identical direct repeat sequences of 309 bp at each end of the genome. In lysogenic cells, the phage genome was found to be present in the cytoplasm without integration into the host cell chromosome, and possibly as a linear phage-plasmid with unmodified ends. Our data may provide some insight into the molecular basis of the unique lysogenic cycle of phage phi18-2.

A case report: Nonsecretory multiple myeloma presenting with bone pain.

RATIONALE: Nonsecretory multiple myeloma (NSMM) is a rare subtype of multiple myelom, occurring in 1% to 2% of multiple myelom and characterized by the inability of clonal plasma cells to synthesize or secrete immunoglobulins. We describe a 71-year-old male patient who began with bone pain and was referred to hospital several times, but was not properly diagnosed and effectively treated. PATIENT CONCERNS: A 71-year-old male patient visited our hematology department, complaining of lumbago for 1 year and back pain for half a year. DIAGNOSES: Low-dose whole-body bone computed tomography: multiple bone destruction of the sternum, ribs, multiple vertebrae and accessories of the spine, pelvis, bilateral humerus, and proximal femur. Monoclonal plasma cells accounted for 17.5% of nuclear cells in bone marrow puncture smear. Fluorescence in situ hybridization detected amplification of CKS1B (1q21) gene. Immunofixation electrophoresis negative. About 10.72% of monoclonal plasma cells were detected by flow cytometry. Finally, he was diagnosed with NSMM. INTERVENTIONS: The patients received VCD chemotherapy (bortezomib 1.3 mg/m2, d1, d4, d8, d11; cyclophosphamide 300 mg/m2, d1-2, d8-9; dexamethasone sodium phosphate 20 mg, d1-2, d4-5, d8-9, d11-12, once every 21 days). OUTCOMES: After 2 cycles of VCD treatment, the symptoms of bone pain were significantly relieved, and the efficacy was evaluated as partial response. Follow-up chemotherapy will continue to be completed on schedule. We will continue to follow up to further evaluate the overall survival and progression-free survival. LESSONS: This case shows that NSMM is easily missed or misdiagnosed.

CIP2A induces PKM2 tetramer formation and oxidative phosphorylation in non-small cell lung cancer.

Tumor cells are usually considered defective in mitochondrial respiration, but human non-small cell lung cancer (NSCLC) tumor tissues are shown to have enhanced glucose oxidation relative to adjacent benign lung. Here, we reported that oncoprotein cancerous inhibitor of protein phosphatase 2A (CIP2A) inhibited glycolysis and promoted oxidative metabolism in NSCLC cells. CIP2A bound to pyruvate kinase M2 (PKM2) and induced the formation of PKM2 tetramer, with serine 287 as a novel phosphorylation site essential for PKM2 dimer-tetramer switching. CIP2A redirected PKM2 to mitochondrion, leading to upregulation of Bcl2 via phosphorylating Bcl2 at threonine 69. Clinically, CIP2A level in tumor tissues was positively correlated with the level of phosphorylated PKM2 S287. CIP2A-targeting compounds synergized with glycolysis inhibitor in suppressing cell proliferation in vitro and in vivo. These results indicated that CIP2A facilitates oxidative phosphorylation by promoting tetrameric PKM2 formation, and targeting CIP2A and glycolysis exhibits therapeutic potentials in NSCLC.

Characterization and sweetness-enhancing effect of peptides from yeast extract based on sensory evaluation and molecular docking approaches.

Yeast extract (YE) is derived from the soluble component in yeast cells, which is rich in peptides and has been used as a sweet-enhancing agent. It has the potential to be utilized to produce natural sweet-flavored peptides or sweet-enhancing peptides. To study the synergistic effect and mechanism of sweetness-enhancing peptides derived from YE, ultrafiltration fraction with molecular weight less than 1 kDa was screened according to sensory analysis, which showed a synergistic sweetening effect in stevioside and mogroside solution. Twenty potential taste peptides were identified from the screened fractions, among which EV, AM, AVDNIPVGPN and VDNIPVGPN showed sweetness-enhancing effects on both stevioside and mogroside. The sweetener-receptor-peptide complex was constructed to investigate the interaction of stevioside and mogroside to taste receptor type 1 member 2 accompanied by these peptides. The results of the molecular docking indicated that new hydrophobic interactions (Leu 279, Pro 308, Val 309, etc.) and hydrogen bonds (Ser 40, Ala 43, Asp 278, etc.) were formed between sweeteners and active sites in the venus flytrap domain. In conclusion, the presence of sweetness-enhancing peptides from YE improved the binding stability of sweeteners and receptors by increasing the binding interaction, especially the hydrophobic interactions, which contribute to the synergistic effect of sweetness-enhancing peptides.

Toxicity and oxidative stress of HepG2 and HL-7702 cells induced by PAH4 using oil as a carrier.

Polycyclic aromatic hydrocarbons (PAHs), a widespread class of food pollutants, are commonly exposed to humans along with edible oil. The dietary exposure pattern of PAH4 was simulated to study the toxicity and oxidative stress of oil-based PAH4 on hepatocytes. The findings demonstrated that oil-based PAH4 induced cell viability and mitochondrial membrane potential decreased and promoted apoptosis and oxidative stress in a concentration-dependent manner. Benzo[a]pyrene had the strongest toxicity and HL-7702 cells were more sensitive to toxicity than HepG2 cells, due to differences in induced CYP1A enzyme activity. Oil-based PAH4 had greater cytotoxicity than PAH4, attributed to the synergistic effect of oil and PAH4. Furthermore, oil-based PAH4 induced oxidative stress in HepG2 and HL-7702 cells through the same AHR-Nrf2-KEAP1 pathway, which was elucidated by detecting genes and proteins expression. This study lays the foundation for elucidating the harm of dietary exposure to PAHs and reminds us that food composition may increase the harm of PAHs.