HDAC Inhibition Increases CXCL12 Secretion to Recruit Natural Killer Cells in Peripheral T Cell Lymphoma.

Peripheral T cell lymphoma (PTCL) is a heterogeneous and aggressive disease with a poor prognosis. Histone deacetylase (HDAC) inhibitors have shown inhibitory effects on PTCL. A better understanding of the therapeutic mechanism underlying the effects of HDAC inhibitors could help improve treatment strategies. Here, we found that high expression of HDAC3 is associated with poor prognosis in PTCL. HDAC3 inhibition suppressed lymphoma growth in immunocompetent mice but not in immunodeficient mice. HDAC3 deletion delayed the progression of lymphoma, reduced the lymphoma burden in the thymus, spleen, and lymph nodes, and prolonged the survival of mice bearing MNU-induced lymphoma. Furthermore, inhibiting HDAC3 promoted the infiltration and enhanced the function of natural killer (NK) cells. Mechanistically, HDAC3 mediated ATF3 deacetylation, enhancing its transcriptional inhibitory activity. Targeting HDAC3 enhanced CXCL12 secretion through an ATF3-dependent pathway to stimulate NK cell recruitment and activation. Finally, HDAC3 suppression improved the response of PTCL to conventional chemotherapy. Collectively, this study provides insights into the mechanism by which HDAC3 regulates ATF3 activity and CXCL12 secretion, leading to immune infiltration and lymphoma suppression. Combining HDAC3 inhibitors with chemotherapy may be a promising strategy for treating PTCL. Key words: Histone deacetylases (HDACs), Natural killer (NK) cells, Peripheral T cell lymphoma (PTCL).

A chalcone-based ESIPT and AIE fluorophore for ß-gal imaging in living cells.

ß-Galactosidase (ß-gal), which is responsible for the hydrolysis of the glycosidic bond of lactose to galactose, has been recognized as an important biomarker of cell or organism status, especially cell senescence and primary ovarian cancer. Extensive efforts have been devoted to develop probes for detecting and visualizing ß-gal in cells. Herein, a fluorescent probe gal-HCA which possesses both excited-state intramolecular proton transfer (ESIPT) and aggregation-induced emission (AIE) properties was prepared to monitor ß-gal in living cells. The probe consists of 2-hydroxy-4'-dimethylamino-chalcone (HCA) capped with a D-galactose group. The cleavage of the glycosidic bond in gal-HCA triggered by ß-gal releases HCA, which results in a significant bathochromic shift in fluorescence from 532 to 615 nm. The probe exhibited high selectivity and sensitivity toward ß-gal with a detection limit as low as 0.0122 U mL-1. The confocal imaging investigation demonstrated the potential of gal-HCA in monitoring the endocellular overexpressed ß-gal in senescent cells and ovarian cancer cells. This study provides a straightforward approach for the development of fluorescent probes to monitor ß-gal and detection of ß-gal-associated diseases.

Advances in injectable hydrogels for radiation-induced heart disease.

Radiological heart damage (RIHD) is damage caused by unavoidable irradiation of the heart during chest radiotherapy, with a long latency period and a progressively increasing proportion of delayed cardiac damage due to conventional doses of chest radiotherapy. There is a risk of inducing diseases such as acute/chronic pericarditis, myocarditis, delayed myocardial fibrosis and damage to the cardiac conduction system in humans, which can lead to myocardial infarction or even death in severe cases. This paper details the pathogenesis of RIHD and gives potential targets for treatment at the molecular and cellular level, avoiding the drawbacks of high invasiveness and immune rejection due to drug therapy, medical device implantation and heart transplantation. Injectable hydrogel therapy has emerged as a minimally invasive tissue engineering therapy to provide necessary mechanical support to the infarcted myocardium and to act as a carrier for various bioactive factors and cells to improve the cellular microenvironment in the infarcted area and induce myocardial tissue regeneration. Therefore, this paper combines bioactive factors and cellular therapeutic mechanisms with injectable hydrogels, presents recent advances in the treatment of cardiac injury after RIHD with different injectable gels, and summarizes the therapeutic potential of various types of injectable hydrogels as a potential solution.

Targeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia.

Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph+ B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph+ B-ALL patients. IL-17A promotes the progression of Ph+ B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph+ B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph+ B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph+ B-ALL progression and suggest potential therapeutic options for Ph+ B-ALL with Th17-enriched niches.

SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity.

CSCs (Cancer stem cells) with distinct metabolic features are considered to cause HCC (hepatocellular carcinoma) initiation, metastasis and therapeutic resistance. Here, we perform a metabolic gene CRISPR/Cas9 knockout library screen in tumorspheres derived from HCC cells and find that deletion of SCARB2 suppresses the cancer stem cell-like properties of HCC cells. Knockout of Scarb2 in hepatocytes attenuates HCC initiation and progression in both MYC-driven and DEN (diethylnitrosamine)-induced HCC mouse models. Mechanistically, binding of SCARB2 with MYC promotes MYC acetylation by interfering with HDCA3-mediated MYC deacetylation on lysine 148 and subsequently enhances MYC transcriptional activity. Screening of a database of FDA (Food and Drug Administration)-approved drugs shows Polymyxin B displays high binding affinity for SCARB2 protein, disrupts the SCARB2-MYC interaction, decreases MYC activity, and reduces the tumor burden. Our study identifies SCARB2 as a functional driver of HCC and suggests Polymyxin B-based treatment as a targeted therapeutic option for HCC.

Magnetic deep eutectic solvent-based dispersive liquid-liquid microextraction for determination of strobilurin fungicides in water, juice, and vinegar by high-performance liquid chromatography.

In this study, a magnetic deep eutectic solvent coupled with dispersive liquid-liquid microextraction using high-performance liquid chromatography (MDES-DLLME-HPLC) was developed to detect strobilurin fungicides. The green hydrophobic MDES synthesized by methyltrioctylammonium chloride, ferric chloride, and heptanoic acid was used as an extraction solvent, which was dispersed by vortex and separated by an external magnetic field. The use of toxic solvents was avoided, and the separation time was reduced. The best experimental results were obtained through single factor and response surface optimization. The method had a good linear relationship with R2 > 0.996. The limit of detection (LOD) ranged from 0.001 to 0.002 mg L-1. The extraction recoveries were 81.9-108.9%. The proposed method was rapid and green, and it has been successfully applied to detection of strobilurin fungicides in water, juice, and vinegar.

Comprehensive transcriptomic analysis of three varieties with different brown planthopper-resistance identifies leaf sheath lncRNAs in rice.

BACKGROUND: Long non-coding RNAs (lncRNAs) have been brought great attention for their crucial roles in diverse biological processes. However, systematic identification of lncRNAs associated with specialized rice pest, brown planthopper (BPH), defense in rice remains unexplored. RESULTS: In this study, a genome-wide high throughput sequencing analysis was performed using leaf sheaths of susceptible rice Taichung Native 1 (TN1) and resistant rice IR36 and R476 with and without BPH feeding. A total of 2283 lncRNAs were identified, of which 649 lncRNAs were differentially expressed. During BPH infestation, 84 (120 in total), 52 (70 in total) and 63 (94 in total) of differentially expressed lncRNAs were found only in TN1, IR36 and R476, respectively. Through analyzing their cis-, trans-, and target mimic-activities, not only the lncRNAs targeting resistance genes (NBS-LRR and RLKs) and transcription factors, but also the lncRNAs acting as the targets of the well-studied stress-related miRNAs (miR2118, miR528, and miR1320) in each variety were identified. Before the BPH feeding, 238 and 312 lncRNAs were found to be differentially expressed in TN1 vs. IR36 and TN1 vs. R476, respectively. Among their putative targets, the plant-pathogen interaction pathway was significantly enriched. It is speculated that the resistant rice was in a priming state by the regulation of lncRNAs. Furthermore, the lncRNAs extensively involved in response to BPH feeding were identified by Weighted Gene Co-expression Network Analysis (WGCNA), and the possible regulation networks of the key lncRNAs were constructed. These lncRNAs regulate different pathways that contribute to the basal defense and specific resistance of rice to the BPH. CONCLUSION: In summary, we identified the specific lncRNAs targeting the well-studied stress-related miRNAs, resistance genes, and transcription factors in each variety during BPH infestation. Additionally, the possible regulating network of the lncRNAs extensively responding to BPH feeding revealed by WGCNA were constructed. These findings will provide further understanding of the regulatory roles of lncRNAs in BPH defense, and lay a foundation for functional research on the candidate lncRNAs.

Dispersive liquid‒liquid microextraction combined with enzyme-linked immunosorbent assay for the analysis of chlorpyrifos in cereal samples.

In this paper, an analysis method for chlorpyrifos (CPF) in cereal samples was proposed using dispersive liquid‒liquid microextraction combined with an enzyme-linked immunosorbent assay. In the dispersive liquid‒liquid microextraction, deep eutectic solvents and fatty acids were used as solvents to extract, purify, and concentrate CPF in cereals. In the enzyme-linked immunosorbent assay, gold nanoparticles were utilized to enrich and conjugate more antibodies and horseradish peroxidase, while magnetic beads were used as solid supports to amplify the signal and shorten the detection time of CPF. The linearity range was 0.002-1 µg kg-1, and the limit of detection was 0.0006 µg kg-1. The extraction recoveries were 86.7-99.9% with a relative standard deviation of less than 7.0%. The proposed method was successfully used to analyze CPF in cereal samples (rice, wheat, maize, and millet) and has prospects for the pretreatment and detection of CPF residues in other food samples.

Hydrophilic and hydrophobic deep eutectic solvent-based extraction to determine parathion in cereals by digital image colorimetry integrated with smartphones.

To determine parathion in cereals, hydrophilic and hydrophobic deep eutectic solvents (DESs) were used by digital image colorimetry with smartphones. In the solid-liquid extraction part, hydrophilic DESs were used as extractants to extract parathion from cereals. In the liquid-liquid microextraction part, hydrophobic DESs dissociated into terpineol and tetrabutylammonium bromide in situ. The dissociated hydrophilic tetrabutylammonium ions reacted with parathion extracted in hydrophilic DESs under alkaline conditions to produce a yellow product, which was extracted and concentrated by dispersed organic phase terpinol. Digital image colorimetry integrated with the use of a smartphone was used for quantitative analysis. The limit of detection and quantification were 0.003 mg kg-1 and 0.01 mg kg-1, respectively. The recoveries for parathion were 94.8-106.2% with a relative standard deviation less than 3.6%. The proposed method was applied to analyze parathion in cereal samples: the method has the potential to be applied to pesticide residue analysis in food products.

Key secondary metabolite markers for Wuchang Daohuaxiang rice discrimination in China.

This study aimed to comprehensively elucidate the vital secondary metabolites of Wuchang Daohuaxiang (DHX) rice through widely targeted metabolomics analysis. Among the secondary metabolites detected, a total of 30 differential ones were screened out and categorized into 4 different classes, including 6 alkaloids (20%), 15 flavonoids (50%), 6 phenolic acids (20%), and 3 terpenoids (10%) between DHX and control groups. Of these, compounds as zarzissine, fagomine, arbutin, p-Hydroxypheny-ß-D-allopyranoside, pimaric acid, kaurenoic acid, and isopimaric acid were more abundant in DHX than control group, with the possibility in serve as key secondary metabolites of DHX rice. Furthermore, arbutin, trigonelline and 6'-O-Feruloyl-D-sucrose were optimized as potential biomarkers for DHX rice discrimination. This study would supply data support for DHX rice authenticity and quality improvement.

Targeting HDAC3 to overcome the resistance to ATRA or arsenic in acute promyelocytic leukemia through ubiquitination and degradation of PML-RARα.

Acute promyelocytic leukemia (APL) is driven by the oncoprotein PML-RARα, which recruits corepressor complexes, including histone deacetylases (HDACs), to suppress cell differentiation and promote APL initiation. All-trans retinoic acid (ATRA) combined with arsenic trioxide (ATO) or chemotherapy highly improves the prognosis of APL patients. However, refractoriness to ATRA and ATO may occur, which leads to relapsed disease in a group of patients. Here, we report that HDAC3 was highly expressed in the APL subtype of AML, and the protein level of HDAC3 was positively associated with PML-RARα. Mechanistically, we found that HDAC3 deacetylated PML-RARα at lysine 394, which reduced PIAS1-mediated PML-RARα SUMOylation and subsequent RNF4-induced ubiquitylation. HDAC3 inhibition promoted PML-RARα ubiquitylation and degradation and reduced the expression of PML-RARα in both wild-type and ATRA- or ATO-resistant APL cells. Furthermore, genetic or pharmacological inhibition of HDAC3 induced differentiation, apoptosis, and decreased cellular self-renewal of APL cells, including primary leukemia cells from patients with resistant APL. Using both cell line- and patient-derived xenograft models, we demonstrated that treatment with an HDAC3 inhibitor or combination of ATRA/ATO reduced APL progression. In conclusion, our study identifies the role of HDAC3 as a positive regulator of the PML-RARα oncoprotein by deacetylating PML-RARα and suggests that targeting HDAC3 could be a promising strategy to treat relapsed/refractory APL.

Novel Grade Classification Tool with Lipidomics for Indica Rice Eating Quality Evaluation.

The eating quality evaluation of rice is raising further concerns among researchers and consumers. This research is aimed to apply lipidomics in determining the distinction between different grades of indica rice and establishing effective models for rice quality evaluation. Herein, a high-throughput ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight (UPLC-QTOF/MS) method for comprehensive lipidomics profiling of rice was developed. Then, a total of 42 significantly different lipids among 3 sensory levels were identified and quantified for indica rice. The orthogonal partial least-squares discriminant analysis (OPLS-DA) models with the two sets of differential lipids showed clear distinction among three grades of indica rice. A correlation coefficient of 0.917 was obtained between the practical and model-predicted tasting scores of indica rice. Random forest (RF) results further verified the OPLS-DA model, and the accuracy of this method for grade prediction was 90.20%. Thus, this established approach was an efficient method for the eating grade prediction of indica rice.

Hierarchical tungsten-doped bimetallic selenides nanosheets arrays/nickel foam composite electrode as efficient gallic acid electrochemical sensor.

The development of effective and accurate gallic acid (GA) electrochemical sensors is critical for food and pharmaceutical industry and health perspectives. Multi-step hydrothermal treatments of bimetallic (Ni/Co) flaky bimetallic hydroxides (NiCo FBHs) were employed to prepare tungsten-doped cobalt-nickel selenides nanosheets arrays (W-Co0.5Ni0.5Se2 NSAs) serving  as the main active substance of GA detection. The morphology and composition of the W-Co0.5Ni0.5Se2 NSAs/NF were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray powder diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The GA electrochemical sensor constructed by the W-Co0.5Ni0.5Se2 NSAs/NF composite electrode exhibits two linear concentration ranges of 1.00-36.2 µM and 36.2-1.00×103 µM for GA electrochemical detection with a limit of detection of  0.120 µM (S/N=3) at the working potential of 0.05 V (vs. SCE). The W-Co0.5Ni0.5Se2 NSAs/NF shows high selectivity, good long-term stability, high recovery in the range 97.9-105%, and a relative standard deviation (RSD) between 0.60 and 2.7%.

Sema7A protects against high-fat diet-induced obesity and hepatic steatosis by regulating adipo/lipogenesis.

OBJECTIVE: Obesity and related diseases are becoming a growing risk for public health around the world due to the westernized lifestyle. Sema7A, an axonal guidance molecule, has been known to play a role in neurite growth, bone formation, and immune regulation. Whether Sema7A participates in obesity and metabolic diseases is unknown. As several SNPs in SEMA7A and its receptors were found to correlate with BMI and metabolic parameters in the human population, we investigated the potential role of Sema7A in obesity and hepatic steatosis. METHODS: GWAS and GEPIA database was used to analyze SNPs in SEMA7A and the correlation of Sema7A expression with lipid metabolism related genes. Sema7A-/- mice and recombinant Sema7A (rSema7A) were used to study the role of Sema7A in HFD-induced obesity and hepatic steatosis. Adipose tissue-derived mesenchymal stem cells (ADSCs) were used to examine the role of Sema7A in adipogenesis, lipogenesis and downstream signaling. RESULTS: Deletion of Sema7A aggravated HFD-induced obesity. Sema7A deletion enhanced adipogenesis in both subcutaneous and visceral ADSCs, while the addition of rSema7A inhibited adipogenesis of ADSCs and lipogenesis of differentiated mature adipocytes. Sema7A inhibits adipo/lipogenesis potentially through its receptor integrin ß1 and downstream FAK signaling. Importantly, administration of rSema7A had protective effects against diet-induced obesity in mice. In addition, deletion of Sema7A led to increased hepatic steatosis and insulin resistance in mice. CONCLUSIONS: Our findings reveal a novel inhibitory role of Sema7A in obesity and hepatic steatosis, providing a potential new therapeutic target for obesity and metabolic diseases.

Deep eutectic solvent-based dispersive liquid-liquid microextraction followed by smartphone digital image colorimetry for the determination of carbofuran in water samples.

A detection method of carbofuran (CBF) in water samples was reported using deep eutectic solvent (DES)-based dispersive liquid-liquid microextraction (DLLME) combined with digital image colorimetry (DIC), which was environmentally friendly, solvent-saving, rapid, and convenient. Under alkaline conditions, the green and multifunctional extractant DESs dissociated into linalool and heptanoic acid, and CBF was hydrolyzed to 2,3-dihydro-2,2-dimethyl-7-benzofuranol and further coupled with fast blue BB salt to form an azo derivative. Heptanoic acid led to the dispersion of linalool to extract the orange-red azo derivative; DIC was used for quantitative analysis using a smartphone with its associated ease of data-acquisition. This experiment optimized the types, molar ratios, and volumes of DESs and the amounts of sodium carbonate and sodium chloride. Under optimal conditions, the limits of detection (LOD) and quantitation (LOQ) were 0.024-0.032 mg L-1 and 0.081-0.108 mg L-1, respectively. The extraction recoveries in real samples (tap, pond, and river water) were 92.4-101.0% with a relative standard deviation below 4.6%. This method has successfully analyzed CBF in different water samples and shows prospects for the monitoring and control of CBF residues in other environmental samples.

Plasma-Methylated SEPT9 for the Noninvasive Diagnosis of Gastric Cancer.

BACKGROUND: Gastric cancer (GC) is one of the most prevalent cancers globally. This study was designed to evaluate the potential performance of plasma SEPT9 methylation (mSEPT9) as a noninvasive biomarker for the diagnosis of GC. METHODS: A total of 182 participants, i.e., 60 patients with GC, 39 with chronic superficial gastritis (CSG), 27 with chronic atrophic gastritis (CAG), 30 with gastric ulcer (GU), and 26 with gastric polys (GP), were recruited. The mSEPT9 level was measured using real-time polymerase chain reaction. RESULTS: As a diagnostic target, mSEPT9 (1/3 algorithm) had a sensitivity of 48.33 (95% confidence interval (CI): 35.40-61.48%) and a specificity of 86.89% (95% CI: 79.28-92.09%), and mSEPT9 (2/3 algorithm) had a sensitivity of 33.33 (95% CI: 22.02-46.79%) and a specificity of 98.36% (95% CI: 93.61-99.72%). The area under the receiver operating characteristic curve (ROC) curve of mSEPT9 was 0.698 (95% CI: 0.609-0.787) for the differentiation of GC from benign gastric diseases. The effectiveness of mSEPT9 (1/3 algorithm) was superior to that of CEA, CA19-9, and CA72-4. mSEPT9 was positively correlated with T, N, M, and the clinical stage of GC. CONCLUSIONS: Plasma mSEPT9 might serve as a useful and noninvasive biomarker for the diagnosis of GC.

Plasma Methylated RNF180 for Noninvasive Diagnosis of Gastric Cancer.

Background: RNF180 is a tumor suppressor gene involved in cell development, proliferation, and apoptosis. Methylation of RNF180 (mRNF180) leads to low expression of RNF180, which is closely related to the occurrence and development of gastric cancer (GC). This study was designed to evaluate the potential performance of plasma mRNF180 as noninvasive biomarker for the diagnosis of GC. Methods: A total of 156 participants, including 60 patients with GC, 39 with chronic superficial gastritis (CSG), 27 with chronic atrophic gastritis (CAG), and 30 with gastric ulcer (GU) were recruited for this study. Plasma mRNF180 level was measured using real-time polymerase chain reaction. Results: As a diagnostic target, mRNF180 had a sensitivity of 71.67% (95% CI: 58.36%-82.18%) and specificity of 59.38% (95% CI: 48.85%-69.14%). The area under the ROC curve value of mRNF180 was 0.731 (95% CI: 0.648%-0.813%) for differentiation of GC from benign gastric diseases (BGD). The effectiveness of mRNF180 was superior to that of CEA, CA199, and CA724. mRNF180 was positively correlated with age, tumor size, T stage, N stage, M stage, and clinical stage of patients with GC. Conclusions: Plasma mRNF180 might serve as a useful and noninvasive biomarker for the diagnosis of GC and can be used to evaluate its prognosis.