The m6A reader SlYTH2 negatively regulates tomato fruit aroma by impeding the translation process.

N6-methyladenosine (m6A) is a fundamentally important RNA modification for gene regulation, whose function is achieved through m6A readers. However, whether and how m6A readers play regulatory roles during fruit ripening and quality formation remains unclear. Here, we characterized SlYTH2 as a tomato m6A reader protein and profiled the binding sites of SlYTH2 at the transcriptome-wide level. SlYTH2 undergoes liquid-liquid phase separation and promotes RNA-protein condensate formation. The target mRNAs of SlYTH2, namely m6A-modified SlHPL and SlCCD1B associated with volatile synthesis, are enriched in SlYTH2-induced condensates. Through polysome profiling assays and proteomic analysis, we demonstrate that knockout of SlYTH2 expedites the translation process of SlHPL and SlCCD1B, resulting in augmented production of aroma-associated volatiles. This aroma enrichment significantly increased consumer preferences for CRISPR-edited fruit over wild type. These findings shed light on the underlying mechanisms of m6A in plant RNA metabolism and provided a promising strategy to generate fruits that are more attractive to consumers.

PoSnf1 affects cellulose utilization through interaction with cellobiose transporter in Pleurotus ostreatus.

Pleurotus ostreatus is one of the most cultivated edible fungi worldwide, but its lignocellulose utilization efficiency is relatively low (<50 %), which eventually affects the biological efficiency of P. ostreatus. Improving cellulase production and activity will contribute to enhancing the lignocellulose-degrading capacity of P. ostreatus. AMP-activated/Snf1 protein kinase plays important roles in regulating carbon and energy metabolism. The Snf1 homolog (PoSnf1) in P. ostreatus was obtained and analyzed using bioinformatics. The cellulose response of PoSnf1, the effect of the phosphorylation level of PoSnf1 on the expression of cellulose degradation-related genes, the putative proteins that interact with the phosphorylated PoSnf1 (P-PoSnf1), the cellobiose transport function of two sugar transporters (STP1 and STP2), and the interactions between PoSnf1 and STP1/STP2 were studied in this research. We found that cellulose treatment improved the phosphorylation level of PoSnf1, which further affected cellulase activity and the expression of most cellulose degradation-related genes. A total of 1, 024 proteins putatively interacting with P-PoSnf1 were identified, and they were enriched mainly in the substances transport and metabolism. Most of the putative cellulose degradation-related protein-coding genes could respond to cellulose. Among the P-PoSnf1-interacting proteins, the functions of two sugar transporters (STP1 and STP2) were further studied, and the results showed that both could transport cellobiose and were indirectly regulated by P-PoSnf1, and that STP2 could directly interact with PoSnf1. The results of this study indicated that PoSnf1 plays an important role in regulating the expression of cellulose degradation genes possibly by affecting cellobiose transport.

Enhanced enzymatic sugar production from corn stover by combination of water extraction and glycerol-assisted instant catapult steam explosion.

Glycerol-assisted instant catapult steam explosion (ICSE) of lignocellulose is an effective pretreatment method for enhancing sugar production compared to glycerol-free ICSE. In this study, glycerol-assisted ICSE of corn stover was studied in order to understand the reaction mechanisms and further optimize the process. Results showed that water extraction of corn stover prior to ICSE reduced pseudo-lignin formation. The combination of water extraction and glycerol-assisted ICSE led to the formation of lignin with a lower molecular weight (Mw) of 2851 g/mol than 3521 g/mole of that from the combination of water extraction and glycerol-free ICSE. 1H-13C NMR analysis revealed that glycerol likely reacted with lignin carboxylic OHs through esterification while etherification of aliphatic OHs was not observed in ICSE. These lignin analyses indicated that glycerol protected lignin from condensation/repolymerization during glycerol-assisted ICSE. Enzymatic hydrolysis results showed that without water extraction increasing glycerol usage from 0.2 kg/kg stover to 0.4 kg/kg stover improved glucan digestibility to 78% but further increase to 0.5 kg/kg stover reduced glucan digestibility. In addition, at the glycerol usage of 0.2-0.4 kg/kg stover, washing of pretreated stover for removal of glycerol and other biomass-derived compounds did not improve glucan digestibility compared to unwashed ones. Combination of water extraction and glycerol-assisted ICSE led to a high glucan digestibility of 89.7% and a total glucose yield of 25.5 g glucose/100 g stover, which were 30.1% and 7.5 g/100 g stover higher than those derived from glycerol-free ICSE of stover, respectively. Since glycerol is a low-cost carbon source, the resulting enzymatic hydrolysate that contained both glucose and glycerol may be directly used to produce bioproducts by microbial fermentation.

Design, synthesis, and biological evaluation of piperazine derivatives as pan-PPARs agonists for the treatment of liver fibrosis.

Liver fibrosis is commonly occurred in chronic liver diseases, but there is no approved drug for clinical use. The nuclear receptor peroxisome proliferator-activated receptors (PPARs) could not only regulate metabolic homeostasis but also possess anti-inflammatory and antifibrotic effects, and pan-PPARs agonist was considered as a potential anti-liver fibrosis agent. In this study, a series of novel piperazine pan-PPARs agonists were developed, and the preferred compound 12 displayed potent and well-balanced pan-PPARs agonistic activity. Moreover, compound 12 could dose-dependently stimulate the PPARs target genes expression and showed high selectivity over other related nuclear receptors. Importantly, compound 12 exhibited excellent pharmacokinetic profiles and good anti-liver fibrosis effects in vivo. Collectively, compound 12 holds promise for developing an anti-liver fibrosis agent.

Pharmacokinetics, Bioequivalence, and Safety Evaluation of Two Oral Formulations of Calcium Dobesilate Capsules in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

To determine the pharmacokinetics (PK), safety, and bioequivalence profiles of 0.5-g calcium dobesilate capsules in both fasting and fed states for the test drug and reference drug. A randomized-sequence, single-dose, open-label, 2-period crossover study was conducted in fasted and fed healthy Chinese volunteers (Chinese Clinical Trials Registry identifier: CTR202000268-01). The fasting and fed studies, both involving 24 subjects, were conducted. A single dosage of either the reference or the test preparation was given to each eligible subject in a 1:1 ratio, followed by a 7-day rest interval before the administration of the alternative formulation. After taking the capsules, plasma samples were taken for 48 hours, and using liquid chromatography-tandem mass spectrometry, the calcium dobesilate level was determined. The PK parameters evaluated in the study included the maximum serum concentration (Cmax), area under the plasma concentration-time curve (AUC) from time 0 to the last quantifiable concentration, AUC from time 0 to infinity, half-life, time to Cmax, and terminal elimination rate constant. In addition, the safety evaluation encompassed monitoring fluctuations in vitals (temperature, pulse, and blood pressure) and laboratory tests (urinalysis, hepatic function, blood biochemistry, and hematology), as well as recording the emergence of adverse events (AEs). The geometric mean ratio (GMR) of the test/reference medications was used to assess bioequivalence by determining if the 90% confidence intervals of the GMR fell within the predefined range of 80%-125%. AEs were assessed as safety end points. The study included 48 healthy Chinese volunteers (with n = 24 each for the fasting and the fed conditions), and no subjects dropped out for any reason. The differences in the PK metrics for the test and reference drugs for both conditions were insignificant (P > .05). For bioequivalence, irrespective of whether the food was consumed or not, the range of the 90% confidence intervals of the GMR for Cmax, AUC from time 0 to the last quantifiable concentration, and AUC from time 0 to infinity was between 80% and 125%. In the experiment, no serious AEs were recorded. Our findings revealed that the calcium dobesilate capsules used as the reference and the test drugs were both bioequivalent. Irrespective of whether the healthy Chinese volunteers consumed food or not, the PK and safety profiles were comparable.

An RNA Methylation-Sensitive AIEgen-Aptamer Reporting System for Quantitatively Evaluating m6A Methylase and Demethylase Activities.

N6-Methyladenosine (m6A) chemical modification determines the fate of the mammalian cellular mRNA to modulate crucial physiological and pathological processes. Dysregulations of m6A methylase and demethylase have been linked to cancer diseases. Therefore, evaluations of enzyme mutants' activities and related inhibitors for discovery of targeted therapeutic strategies are very necessary. Here, we report an RNA methylation-sensitive fluorescent aptamer reporting assay to measure the catalytic activities of m6A enzymes under various conditions. The rationale is that when an RNA aptamer, named A-Pepper, is methylated at a specific adenosine position to generate m6A-Pepper, the latter displays stronger fluorescence than the former upon binding the ligand, which is an aggregation-induced emission-active luminogen. The fluorescence signal enhancement is linearly proportional to the RNA methylation extent, which is equivalent to the methylase activity. On the contrary, the m6A demethylase activity is measured through calculating the fluorescence signal decrease caused by the switching from m6A-Pepper to A-Pepper. The assay has been successfully applied to quantitatively evaluate the mutation and inhibitor effects on the activities of m6A methylases METTL3/METTL14 and demethylase FTO, and the obtained results are well-consistent with those quantified by the expensive and time-consuming golden standard LC-MS/MS. Our work provides a simple tool capable of detecting m6A enzymes' activities and screening their inhibitors in a rapid, quantitative, cost-effective, and high-throughput manner.

Application of graph frequency attention convolutional neural networks in depression treatment response.

Depression, a prevalent global mental health disorder, necessitates precise treatment response prediction for the improvement of personalized care and patient prognosis. The Graph Convolutional Neural Networks (GCNs) have emerged as a promising technique for handling intricate signals and classification tasks owing to their end-to-end neural architecture and nonlinear processing capabilities. In this context, this article proposes a model named the Graph Frequency Attention Convolutional Neural Network (GFACNN). Primarily, the model transforms the EEG signals into graphs to depict the connections between electrodes and brain regions, while integrating a frequency attention module to accentuate brain rhythm information. The proposed approach delves into the application of graph neural networks in the classification of EEG data, aiming to evaluate the response to antidepressant treatment and discern between treatment-resistant and treatment-responsive cases. Experimental results obtained from an EEG dataset at Peking University People's Hospital demonstrate the notable performance of GFACNN in distinguishing treatment responses among depression patients, surpassing deep learning methodologies including CapsuleNet and GoogLeNet. This highlights the efficacy of graph neural networks in leveraging the connections within EEG signal data. Overall, GFACNN exhibits potential for the classification of depression EEG signals, thereby potentially aiding clinical diagnosis and treatment.

Whole genome sequencing and analysis of selenite-reducing bacteria Bacillus paralicheniformis SR14 in response to different sugar supplements.

The biosynthetic process of selenium nanoparticles (SeNPs) by specific bacterial strain, whose growth directly affects the synthesis efficiency, has attracted great attentions. We previously reported that Bacillus paralicheniformis SR14, a SeNPs-producing bacteria, could improve intestinal antioxidative function in vitro. To further analyze the biological characteristics of SR14, whole genome sequencing was used to reveal the genetic characteristics in selenite reduction and sugar utilization. The results reviewed that the genome size of SR14 was 4,448,062 bp, with a GC content of 45.95%. A total of 4300 genes into 49 biological pathways was annotated to the KEGG database. EC: 1.1.1.49 (glucose-6-phosphate 1-dehydrogenase) and EC: 5.3.1.9 (glucose-6-phosphate isomerase), were found to play a potential role in glucose degradation and EC:2.7.1.4 (fructokinase) might be involved in the fructose metabolism. Growth profile and selenite-reducing ability of SR14 under different sugar supplements were determined and the results reviewed that glucose had a better promoting effect on the reduction of selenite and growth of bacteria than fructose, sucrose, and maltose. Moreover, RT-qPCR experiment proved that glucose supplement remarkably promoted the expressions of thioredoxin, fumarate reductase, and the glutathione peroxidase in SR14. Analysis of mRNA expression showed levels of glucose-6-phosphate dehydrogenase and fructokinase significantly upregulated under the supplement of glucose. Overall, our data demonstrated the genomic characteristics of SR14 and preliminarily determined that glucose supplement was most beneficial for strain growth and SeNPs synthesis.

Metal-organic framework derived CdSe wrapped with rGO for enhanced lithium storage performance.

Considering the advantages of MOF-based, CdSe-based, and rGO-based materials, CdSe nanoparticles encapsulated with rGO (CdSe@rGO) were synthesized by a metal-organic framework derived method. CdSe nanoparticles encapsulated with rGO can effectively tolerate volume expansion and improve electrical conductivity, leading to excellent cycling stability (396 mAh g-1at 0.3 A g-1after 200 cycles, 311 mAh g-1at 0.5 A g-1after 500 cycles), and rate performance (562 mAh g-1at 0.1 A g-1and 122.2 mAh g-1at 4 A g-1) for lithium-ion storage. This strategy for preparing metal selenides protected by carbon layers can be extended to the design of other high-performance materials.

Synergistic effect of elevated glucose levels with SARS-CoV-2 spike protein induced NOX-dependent ROS production in endothelial cells.

BACKGROUND: Diabetic patients infected with coronavirus disease 2019 (COVID-19) often have a higher probability of organ failure and mortality. The potential cellular mechanisms through which blood glucose exacerbates tissue damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is still unclear. METHODS AND RESULTS: We cultured endothelial cells within differing glucose mediums with an increasing concentration gradient of SARS-CoV-2 Spike protein (S protein). S protein can cause the reduction of ACE2 and TMPRSS2, and activation of NOX2 and NOX4. A high glucose medium was shown to aggravate the decrease of ACE2 and activation of NOX2 and NOX4 in cultured cells, but had no effect on TMPRSS2. S protein mediated activation of the ACE2-NOX axis induced oxidative stress and apoptosis within endothelial cells, leading to cellular dysfunction via the reduction of NO and tight junction proteins which may collectively be exacerbated by elevated glucose. In addition, the glucose variability model demonstrated activation of the ACE2-NOX axis in a similar manner observed in the high glucose model in vitro. CONCLUSIONS: Our present study provides evidence for a mechanism through which hyperglycemia aggravates endothelial cell injury resulting from S protein mediated activation of the ACE2-NOX axis. Our research thus highlights the importance of strict monitoring and control of blood glucose levels within the context of COVID-19 treatment to potentially improve clinical outcomes.

Design, Synthesis, and Biological Activity of Donepezil: Aromatic Amine Hybrids as Anti-Alzheimerss Drugs.

In this study, benzylpiperidine, the active group of donepezil (DNP), was connected with the neurotransmitter phenylethylamine by square amide, in which the fat chain of phenylethylamine was reduced and the benzene rings were substituted. A series of multifunctional hybrid compounds, including DNP-aniline hybrids (1-8), DNP-benzylamine hybrids (9-14), and DNP-phenylethylamine hybrids (15-21) were obtained and their cholinesterase inhibitory activity and neuroprotection of the SH-SY5Y cell line were determined. Results showed that compound 3 exhibited excellent acetylcholinesterase inhibitory activity with an IC50 value of 4.4 µM, higher than that of positive control DNP and significant neuroprotective effects against H2O2-induced oxidative damage in SH-SY5Y cells with 80.11% viability rate at 12.5 µM, much higher than that of the model group (viability rate = 53.1%). The mechanism of action of compound 3 was elucidated by molecular docking, reactive oxygen species (ROS), and immunofluorescence analysis. The results suggest that compound 3 could be further explored as a lead compound for the treatment of Alzheimer's disease. In addition, molecular docking research indicated that the square amide group formed strong interactions with the target protein. Based on the above analysis, we believe that square amide could be an interesting construction unit in anti-AD agents.

Mediterranean diet lowers all-cause and cardiovascular mortality for patients with metabolic syndrome.

A Mediterranean-style diet (MED) can promote people lengthen the span of life and avoid atherosclerotic cardiovascular disease (ASCVD) in primary prevention. Metabolic syndrome (MetS) can significantly reduce life expectancy and increase the risk of ASCVD. However, few studies have focused on the role of the Mediterranean diet in patients with MetS. Participants in the National Health and Nutrition Examination Survey (NHANES) with MetS (N = 8301) from 2007 to 2018 were examined. A 9-point evaluation scorewas used to measure the degree of adherence to the MED diet. In order to compare the various levels of adherence to the MED diet and the effects of the specific MED diet components on all-cause and cardiovascular mortality, Cox regression models were utilized. Among the 8301 participants with MetS, about 13.0% (1080 of 8301) died after a median follow-up of 6.3 years. In this study, participants with MetS with adherence to high-quality and moderate-quality Mediterranean diet were significantly associated with lower all-cause mortality as well as cardiovascular mortality during the follow-up period. Futhermore, in joint analysis of the Mediterranean diet and sedentary behavior or depression, we found that high-quality or moderate-quality Mediterranean diet could attenuate, even reverse the adverse effects of sedentary behavior and depression on all-cause and cardiovascular mortality in participants with MetS. Among the components of the MED diet, greater intakes of vegetables, legumes, nuts and high MUFA/SFA ratio were significantly associated with lower all-cause mortality and greater vegetables intake was significantly associated with lower cardiovascular mortality, while more red/processed meat intake was significantly associated with higher cardiovascular mortality in participants with MetS.

Extraction, Purification, and Component Identification of Monoterpene Glycosides from Paeonia suffruticosa Seed Meal.

Paeonia suffruticosa (P. suffruticosa) seed meal is a byproduct of P. suffruticosa seed processing, which contains bioactive substances such as monoterpene glycosides, and has not been effectively utilized at present. In this study, monoterpene glycosides were extracted from P. suffruticosa seed meal using an ultrasound-assisted ethanol extraction process. The monoterpene glycoside extract was then purified by macroporous resin and identified using HPLC-Q-TOF-MS/MS. The results indicated the following optimal extraction conditions: ethanol concentration, 33%; ultrasound temperature, 55 °C; ultrasound power, 400 W; liquid-material ratio, 33:1; and ultrasound time, 44 min. Under these conditions, the yield of monoterpene glycosides was 121.03 mg/g. The purity of the monoterpene glycosides increased from 20.5% (crude extract) to 71.2% (purified extract) when using LSA-900C macroporous resin. Six monoterpene glycosides (oxy paeoniflorin, isomaltose paeoniflorin, albiflorin, 6'-O-ß-D-glucopyranoside albiflorin, paeoniflorin, and Mudanpioside i) were identified from the extract using HPLC-Q-TOF-MS/MS. The main substances were albiflorin and paeoniflorin, and the contents were 15.24 mg/g and 14.12 mg/g, respectively. The results of this study can provide a theoretical basis for the effective utilization of P. suffruticosa seed meal.

An alternative ZnO with large specific surface area: Preparation, physicochemical characterization and effects on growth performance, diarrhea, zinc metabolism and gut barrier function of weaning piglets.

High-dose ZnO is widely used to prevent diarrhea and promote growth of weaning piglets, which has led to serious problems of animal toxicity, bacterial resistance and environmental pollution. In this study, a novel alternative ZnO (AZO) was prepared and its physicochemical properties were characterized. Animal experiments were further conducted to evaluate the effects of the ZnO forms, the dose of AZO and the combinations with AZO on the growth performance, diarrhea, zinc metabolism and gut barrier function of weaning piglets. The results showed that the AZO, compared with ordinary ZnO (OZO), nano ZnO (NZO) and porous ZnO (PZO), had the largest surface area and reduced the release of Zn2+ into the gastric fluid. AZO showed better antibacterial activity on Escherichia coli K88, Staphylococcus aureus and Salmonella enteritidis but lower cytotoxicity on porcine intestinal epithelial cells. Animal experiments suggested that low-dose AZO, NZO and PZO (300 mg/kg) improved growth performance and reduced diarrhea in weaning piglets as well as high-dose OZO (3000 mg/kg). Notably, low-dose AZO had the lowest diarrhea incidence. Additionally, low-dose AZO in combination with probiotics improved digestibility and digestive enzyme activities. Low-dose AZO in combination with probiotics also upregulated the expression of the intestinal zinc transporter proteins ZIP4 and DMT1, increased zinc bioavailability, reduced faecal zinc emissions, and avoided zinc overload in the liver and oxidative damage caused by high-dose ZnO. Moreover, low-dose AZO in combination with probiotics improved the gut barrier function of weaning piglets by promoting the expression of tight junction proteins, mucins and antimicrobial peptides and increasing gut microbiota diversity and beneficial Lactobacillus. This study proposed a novel strategy to replace high-dose ZnO and antibiotics with low-dose AZO and probiotics in weaning piglets, which effectively improved growth performance and prevented diarrhea while reducing animal toxicity, bacterial resistance, heavy metal residues and zinc emission pollution.

Heat stress and excessive maturity of fruiting bodies suppress GABA accumulation by modulating GABA metabolism in Pleurotus ostreatus (Jacq. ex Fr.) P. Kumm.

GABA is a health-promoting bioactive substance. Here, the GABA biosynthetic pathways were investigated, and then the dynamic quantitative changes in GABA and the expression levels of genes related to GABA metabolism under heat stress or at different developmental stages of fruiting bodies in Pleurotus ostreatus (Jacq. ex Fr.) P. Kumm were determined. We found that the polyamine degradation pathway was the main route of GABA production under growth normal condition. The accumulation of GABA and the expression of most genes related to GABA biosynthesis, including genes encoding glutamate decarboxylase (PoGAD-2), polyamine oxidase (PoPAO-1), diamine oxidase (PoDAO) and aminoaldehyde dehydrogenase (PoAMADH-1 and PoAMADH-2), were significantly suppressed by heat stress and the excessive maturity of fruiting bodies. Finally, the effects of GABA on the mycelial growth, heat tolerance and the morphogenesis and development of fruiting bodies were studied, the results showed that the deficiency of endogenous GABA inhibited the mycelial growth and primordial formation and aggravated heat damage, whereas exogenous application of GABA could improve thermotolerance and promote the development of fruiting bodies.

Effects of Weight Gain During Pregnancy in Normal-Weight Women on Changes in the Gut Microbiota of Pregnant Women in the Third Trimester.

With the improvement of living standards and the lack of nutrition awareness during pregnancy, the phenomenon of excessive weight gain (EWG) of pregnancy is increasing. EWG during pregnancy has profound effects on the health of mother and offspring. The role of intestinal flora in regulating metabolic diseases has gradually attracted attention in recent years. The study explored the effect of EWG during pregnancy on gut microbiota, and analyzed the diversity and composition of gut microbiota in pregnant women in third trimester. Fecal samples were collected and divided into: insufficient weight gain (IWG) during pregnancy (group A1, N = 4), and appropriate weight gain (AWG) during pregnancy (group A2, N = 9), and EWG during pregnancy (N = 9 in A3 group). MiSeq high-throughput sequencing technology and bioinformatics analysis were introduced to investigate relationship of gestational weight gain and maternal gut microbiota. General data analysis showed that gestational weight gain and delivery mode have significant differences among the three groups. The overall level and diversity of intestinal microbiota in A1 and A3 group were increased. Composition of gut microbiota has no difference among three groups at the phylum level, but species of gut microbiota were different. Alpha diversity index analysis showed that the richness of A3 group was increased versus A2 group. EWG during pregnancy affects the abundance and proportion of gut microbiota in the third trimester. Therefore, maintaining moderate weight gain during pregnancy helps to maintain intestinal homeostasis.

Dynamic changes of inulin utilization associated with longitudinal development of gut microbiota.

Inulin is a typical kind of fermentable polysaccharide and has emerged as a promising dietary supplement due to its multiple health-promoting effects. This study aimed to unveil the dynamic change pattern of inulin utilizability as a fermentation substrate during gut microbiota development and illuminate its potential association with gut microbiota in Chinese Jinhua native pig models via longitudinal analyses. Herein, fresh feces were collected at one week pre- and post-weaning as well as 3rd month post-weaning, respectively. Targeted metabolomics and in vitro simulated fermentation revealed increasing concentrations of fecal short-chain fatty acids (SCFAs) and elevating utilizability of inulin as a fermentation substrate. Microbiomic analyses demonstrated the conspicuous longitudinal alteration in gut microbial composition and a significant rise in microbial community diversity during gut microbiota development. Furthermore, gut microbial functional analyses showed a remarkable increase in the relative abundances of carbohydrate metabolism pathways, including pentose phosphate pathway, galactose metabolism pathway, butanoate metabolism pathway as well as fructose and mannose metabolism pathway. Notably, relative abundances of bacterial genera Bifidobacterium, Roseburia, Faecalibacterium and Enterococcus displayed significantly positive correlations with the production of microbial fermentation-derived SCFAs. Collectively, these findings offer novel insights into understanding inulin utilizability variations from the perspective of gut microbiota development.

Cell-Permeable PROTAC Degraders against KEAP1 Efficiently Suppress Hepatic Stellate Cell Activation through the Antioxidant and Anti-Inflammatory Pathway.

Accumulating evidence indicates that oxidative stress and inflammation are involved in the physiopathology of liver fibrogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor, which regulates the expression of redox regulators to establish cellular redox homeostasis. The Nrf2 modulator can serve as a primary cellular defense against the cytotoxic effects of oxidative stress. We designed a chimeric Keap1-Keap1 peptide (KKP1) based on the proteolysis-targeting chimera technology. The KKP1 peptide not only can efficiently penetrate into the rat hepatic stellate cell line (HSC-T6) cells but also can induce Keap1 protein degradation by the ubiquitination-proteasome degradation pathway, which releases Nrf2 and promotes the transcriptional activity of the Nrf2/antioxidant response element pathway. It then activates the protein expression of the downstream antioxidant factors, the glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 (HO-1). Finally, Keap1 protein degradation inhibits the nuclear factor-kappaB inflammatory signal pathway, the downstream inflammatory factor tumor necrosis factor alpha, and the interleukin-1beta protein expression and further inhibits the expression of the fibrosis biomarker gene. The current research suggests that our designed KKP1 may provide a new avenue for the future treatment of liver fibrosis.

Clinical Efficacy of Blood Ultrafiltration Therapy in Patients with Acute Decompensated Chronic Heart Failure Running Title: Blood Ultrafiltration Therapy for Heart Failure.

In this study, we investigated the clinical effects of blood ultrafiltration therapy in patients with acute decompensated chronic heart failure. We enrolled 78 patients with acute decompensated chronic heart failure who were admitted to a hospital from September 2017 to December 2021, and divided them into two groups based on the digital randomization method. The FQ-16 heart failure ultrafiltration dehydrating device blood ultrafiltration therapy was administered to the observation group (39 patients) for 8-16 hours, while the control group (39 patients) received the stepped drug therapy. Echocardiography was used to assess the changes in cardiac function of the patients in both groups before and after treatment. The changes in urine volume, N-terminal pro-B-type natriuretic peptide (NT-proBNP), plasma renin, and serum creatinine levels were measured before and after the treatment to compare the overall response rate of the patients in both groups. The differences in left ventricular end-systolic dimension and left ventricular end-diastolic dimension and the ejection fraction between the groups before treatment were not statistically significant (P > 0.05), however, the left ventricular end-diastolic dimension in the observation group was significantly lower and the ejection fraction was significantly higher (P < 0.05) compared with that before treatment; the urine volume, N-terminal pro-B-type natriuretic peptide (NT-proBNP), plasma renin, and serum creatinine were significantly improved in both groups after treatment compared with that before treatment. All indexes in the observation group were better than those in the control group (P < 0.05), 74.36%. The overall response rate of the observation group was 94.87%, x2 = 4.843 and the difference between groups was statistically significant (P < 0.05). Blood ultrafiltration therapy for patients with acute decompensated chronic heart failure can improve their cardiac and renal functions, reduce NT-proBNP, reduce volume load, and enhance efficacy while ensuring high safety.

AKAP8L enhances the stemness and chemoresistance of gastric cancer cells by stabilizing SCD1 mRNA.

Gastric cancer (GC) remains the third leading cause of cancer-related deaths. Chemoresistance is the major determinant of GC treatment failure. To explore the molecular mechanisms of GC chemoresistance, mass spectrometry was performed to detect the genes altered in expression between chemoresistant and chemosensitive GC. PRKA kinase anchor protein 8L (AKAP-8L) was identified as one of the top upregulated genes in chemoresistant GC tissues. Moreover, the higher AKAP-8L expression was associated with the lower survival rate in GC patients. Overexpression of AKAP-8L enhanced the GC cell stemness and chemoresistance of oxaliplatin in vivo and in vitro. AKAP-8L deficiency obtained the opposite results. Mechanistically, AKAP-8L interacted with Stearoyl-CoA desaturase 1 (SCD1) mRNA and IGF2BP1 protein, and regulated SCD1 mRNA stability via IGF2BP1-dependent manner. SCD1 played a critical role in mediating the function of AKAP-8L in GC cell stemness and chemoresistance. Clinically, AKAP-8L and SCD1 protein levels was positively associated with human GC chemoresistance. Taken together, our results demonstrated that AKAP-8L facilitates GC chemoresistance via regulating SCD1-mediated stemness of GC cells. AKAP8L may represent a novel therapeutic target to overcome GC chemoresistance.