Role of transient receptor potential channels in the regulation of vascular tone.

Vascular tone is a major element in the control of hemodynamics. Transient receptor potential (TRP) channels conducting monovalent and/or divalent cations(e.g. Na+ and Ca2+) are expressed in the vasculature. Accumulating evidence suggests that TRP channels participate in regulating vascular tone by regulating intracellular Ca2+ signaling in both vascular smooth muscle cells (VSMCs) and endothelial cells (ECs). Aberrant expression/function of TRP channels in the vasculature is associated with vascular dysfunction in systemic/pulmonary hypertension and metabolic syndromes. This review intends to summarize our current knowledge of TRP-mediated regulation of vascular tone in both physiological and pathophysiological conditions and to discuss potential therapeutic approaches to tackle abnormal vascular tone due to TRP dysfunction.

Adenosine kinase inhibits ß-cell proliferation by upregulating DNA methyltransferase 3A expression.

AIM: To investigate the effects of adenosine kinase (ADK), a key enzyme in determining intracellular adenosine levels, on ß cells, and their underlying mechanism. METHODS: Genetic animal models and transgenic immortalized cells were applied to study the effect of ADK on islet beta-cell proliferation and function. The beta-cell mass and response to glucose were measured in vivo using mice with beta-cell-specific ADK overexpression, and in vitro using ADK-overexpressed immortalized beta-cell. RESULTS: The expression of ADK in human islets at high abundance, especially in ß cells, was decreased during the process of ß-cell proliferation. Additionally, a transgenic mouse model (ADKtg/tg /Mip-Cre) was generated wherein the mouse Insulin1 gene promoter specifically overexpressed ADK in pancreatic ß cells. The ADKtg/tg /Mip-Cre model exhibited impaired glucose tolerance, decreased fasting plasma insulin, loss of ß-cell mass, and inhibited ß-cell proliferation. Proteomic analysis revealed that ADK overexpression inhibited the expression of several proteins that promote cell proliferation and insulin secretion. Upregulating ADK in the ß-cell line inhibited the expression of ß-cell related regulatory molecules, including FoxO1, Appl1, Pxn, Pdx-1, Creb and Slc16a3. Subsequent in vitro experiments indicated that the inhibition of ß-cell proliferation and the decreased expression of Pdx-1, Creb and Slc16a3 were rescued by DNA methyltransferase 3A (DNMT3A) knockdown in ß cells. CONCLUSION: In this study, we found that the overexpression of ADK decreased the expression of several genes that regulate ß cells, resulting in the inhibition of ß-cell proliferation and dysfunction by upregulating the expression of DNMT3A.

N-doped 3D carbon encapsulating nickel selenide nanoarchitecture with cation defect engineering: An ultrafast and long-life anode for sodium-ion batteries.

Transition metal chalcogenides (TMCs) hold great potential for sodium-ion batteries (SIBs) owing to their multielectron conversion reactions, yet face challenges of poor intrinsic conductivity, sluggish diffusion kinetics, severe phase transitions, and structural collapse during cycling. Herein, a self-templating strategy is proposed for the synthesis of a class of metal cobalt-doped NiSe nanoparticles confined within three-dimensional (3D) N-doped macroporous carbon matrix nanohybrids (Co-NiSe/NMC). The cation defect engineering within the developed Co-NiSe and 3D N-doped carbon plays a crucial role in enhancing intrinsic conductivity, reinforcing structural stability, and reducing the barrier to sodium ion diffusion, which are verified by a series of electrochemical kinetic analyses and density functional theory calculations. Significantly, such cation defect engineering not only reduces overpotential but also accelerates conversion reaction kinetics, ensuring both exceptional high-rate capability and extended durability. Consequently, the optimally engineered Co-NiSe/NMC demonstrates a remarkable rate performance, delivering 390 mAh g-1 at 10 A g-1. Moreover, it exhibits an unprecedented lifespan, maintaining a remarkable capacity of 403 mAh g-1 after 1400 cycles and 318 mAh g-1 after 4000 cycles, even at high rates of 1.0 and 2.0 A g-1, respectively. This work marks a substantial advancement in achieving both high performance and prolonged cycle life in sodium-ion batteries.

Deep genome skimming reveals the hybrid origin of Pseudosasa gracilis (Poaceae: Bambusoideae).

Pseudosasa gracilis (Poaceae: Bambusoideae) is a temperate woody bamboo species endemic to South-central China with a narrow distribution. Previous phylogenetic studies revealed an unexpected, isolated phylogenetic position of Ps. gracilis. Here we conducted phylogenomic analysis by sampling populations of Ps. gracilis and its sympatric species Ps. nanunica and Sinosasa polytricha reflecting different genomic signals, by deep genome skimming. Integrating molecular evidence from chloroplast genes and genome-wide SNPs, we deciphered the phylogenetic relationships of Ps. gracilis. Both plastid and nuclear data indicate that Ps. gracilis is more closely related to Sinosasa, which is discordant with the taxonomic treatment. To further explore this molecular-morphological conflict, we screened 411 "perfect-copy" syntenic genes to reconstruct phylogenies using both the concatenation and coalescent methods. We observed extensive discordance between gene trees and the putative species tree. A significant hybridization event was detected based on 411 genes from the D subgenome, showing Ps. gracilis was a hybrid descendant between Sinosasa longiligulata and Ps. nanunica, with 63.56% and 36.44% inheritance probabilities of each parent. Moreover, introgression events were detected in the C subgenome between Ps. gracilis and S. polytricha in the same distribution region. Our findings suggest that sympatric hybridization and introgression play a crucial role in the origin of Ps. gracilis. By providing an empirical example of bamboo of hybrid origin using comprehensive analyses based on genomic data from different inheritance systems and morphological characters, our study represents a step forward in understanding of reticulate evolution of bamboos.

Analysis of chloroplast genome characteristics and codon usage bias in 14 species of Annonaceae.

For the study of species evolution, chloroplast gene expression, and transformation, the chloroplast genome is an invaluable resource. Codon usage bias (CUB) analysis is a tool that is utilized to improve gene expression and investigate evolutionary connections in genetic transformation. In this study, we analysed chloroplast genome differences, codon usage patterns and the sources of variation on CUB in 14 Annonaceae species using bioinformatics tools. The study showed that there was a significant variation in both gene sizes and numbers between the 14 species, but conservation was still maintained. It's worth noting that there were noticeable differences in the IR/SC sector boundary and the types of SSRs among the 14 species. The mono-nucleotide repeat type was the most common, with A/T repeats being more prevalent than G/C repeats. Among the different types of repeats, forward and palindromic repeats were the most abundant, followed by reverse repeats, and complement repeats were relatively rare. Codon composition analysis revealed that all 14 species had a frequency of GC lower than 50%. Additionally, it was observed that the proteins in-coding sequences of chloroplast genes tend to end with A/T at the third codon position. Among these species, 21 codons exhibited bias (RSCU > 1), and there were 8 high-frequency (HF) codons and 5 optimal codons that were identical across the species. According to the ENC-plot and Neutrality plot analysis, natural selection had less impact on the CUB of A. muricate and A. reticulata. Based on the PR2-plot, it was evident that base G had a higher frequency than C, and T had a higher frequency A. The correspondence analysis (COA) revealed that codon usage patterns different in Annonaceae.

Ion channel Piezo1 activation aggravates the endothelial dysfunction under a high glucose environment.

BACKGROUND: Vasculopathy is the most common complication of diabetes. Endothelial cells located in the innermost layer of blood vessels are constantly affected by blood flow or vascular components; thus, their mechanosensitivity plays an important role in mediating vascular regulation. Endothelial damage, one of the main causes of hyperglycemic vascular complications, has been extensively studied. However, the role of mechanosensitive signaling in hyperglycemic endothelial damage remains unclear. METHODS: Vascular endothelial-specific Piezo1 knockout mice were generated to investigate the effects of Piezo1 on Streptozotocin-induced hyperglycemia and vascular endothelial injury. In vitro activation or knockdown of Piezo1 was performed to evaluate the effects on the proliferation, migration, and tubular function of human umbilical vein endothelial cells in high glucose. Reactive oxygen species production, mitochondrial membrane potential alternations, and oxidative stress-related products were used to assess the extent of oxidative stress damage caused by Piezo1 activation. RESULTS: Our study found that in VECreERT2;Piezo1flox/flox mice with Piezo1 conditional knockout in vascular endothelial cells, Piezo1 deficiency alleviated streptozotocin-induced hyperglycemia with reduced apoptosis and abscission of thoracic aortic endothelial cells, and decreased the inflammatory response of aortic tissue caused by high glucose. Moreover, the knockout of Piezo1 showed a thinner thoracic aortic wall, reduced tunica media damage, and increased endothelial nitric oxide synthase expression in transgenic mice, indicating the relief of endothelial damage caused by hyperglycemia. We also showed that Piezo1 activation aggravated oxidative stress injury and resulted in severe dysfunction through the Ca2+-induced CaMKII-Nrf2 axis in human umbilical vein endothelial cells. In Piezo1 conditional knockout mice, Piezo1 deficiency partially restored superoxide dismutase activity and reduced malondialdehyde content in the thoracic aorta. Mechanistically, Piezo1 deficiency decreased CaMKII phosphorylation and restored the expression of Nrf2 and its downstream molecules HO-1 and NQO1. CONCLUSION: In summary, our study revealed that Piezo1 is involved in high glucose-induced oxidative stress injury and aggravated endothelial dysfunction, which have great significance for alleviating endothelial damage caused by hyperglycemia.

Bioinspired Mechanochromic Liquid Crystal Materials: from Fundamentals to Functionalities and Applications.

Inspired by intriguing color changeable ability of natural animals, the design and fabrication of artificial mechanochromic materials capable of changing colors upon stretching or pressing have attracted intense scientific interest. Liquid crystal (LC) is a self-organized soft matter with anisotropic molecular alignment. Due to the sensitivity to various external stimulations, LC has been considered as an emerging and appealing responsive building block to construct intelligent materials and advanced devices. Recently, mechanochromic LC materials have becoming a hot topic in multi fields from flexible artificial skins to visualized sensors and smart biomimetic devices. In this review, the recent progress of mechanochromic LCs is comprehensively summarized. Firstly, the mechanism and functionalities of mechanochromic LC is introduced, followed by preparation of various functional materials based on mechanochromic LCs. Then the applications of mechanochromic LCs are provided. Finally, the conclusion and outlooks of this field is given. This overview is hoped to provide inspiration in fabrication of advanced functional soft materials for scientists and engineers from multidisciplines including materials science, elastomers, chemistry and physical science. This article is protected by copyright. All rights reserved.

Copper-Catalyzed Difunctionalization of Propargylic Carbonates through Tandem Nucleophilic Substitution/Boroprotonation.

Highly functionalized organic molecules are in high demand, but their preparation is challenging. Copper-catalyzed transformation of alkynyl- and allenyl-containing substrates has emerged as a powerful tool to achieve this objective. Herein, an efficient copper-catalyzed difunctionalization of propargylic carbonates through tandem nucleophilic substitution/boroprotonation has been developed, affording the formation of thiol-, selenium-, and boron-functionalized alkenes with high yield and stereoselectivity. Two distinct catalytic mechanisms involving a single reaction without any requirement of catalyst change were successfully demonstrated.

Hyperglycemia activates FGFR1 via TLR4/c-Src pathway to induce inflammatory cardiomyopathy in diabetes.

Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs-NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.

Preservation of the celiac branch of the vagus nerve reduces the incidence of postoperative diarrhea in gastric cancer: a cohort study.

BACKGROUND: To investigate the short-term and long-term outcomes of preserving the celiac branch of the vagus nerve during laparoscopic distal gastrectomy. METHODS: A total of 149 patients with prospective diagnosis of gastric cancer who underwent laparoscopic-assisted distal gastrectomy (LADG) combined with Billroth-II anastomosis and D2 lymph node dissection between 2017 and 2018 were retrospectively analyzed. The patients were divided into the preserved LADG group (P-LADG, n = 56) and the resected LADG group (R-LADG, n = 93) according to whether the vagus nerve celiac branch was preserved. We selected 56 patients (P-LADG, n = 56) with preservation of the celiac branch of the vagus nerve and 56 patients (R-LADG, n = 56) with removal of the celiac branch of the vagus nerve by propensity-matched score method. Postoperative nutritional status, weight change, short-term and long-term postoperative complications, and gallstone formation were evaluated in both groups at 5 years of postoperative follow-up. The status of residual gastritis and bile reflux was assessed endoscopically at 12 months postoperatively. RESULTS: The incidence of diarrhea at 5 years postoperatively was lower in the P-LADG group than in the R-LADG group (p < 0.05). In the multivariate logistic analysis, the removal of vagus nerve celiac branch was an independent risk factor for the occurrence of postoperative diarrhea (odds ratio = 3.389, 95% confidential interval = 1.143-10.049, p = 0.028). In the multivariate logistic analysis, the removal of vagus nerve celiac branch was an independent risk factor for the occurrence of postoperative diarrhea (odds ratio = 4.371, 95% confidential interval = 1.418-13.479, p = 0.010). CONCLUSIONS: Preservation of the celiac branch of the vagus nerve in LADG reduced the incidence of postoperative diarrhea postoperatively in gastric cancer. TRIAL REGISTRATION: This study was registered with the Ethics Committee of the First Affiliated Hospital of Dalian Medical University in 2014 under the registration number: LCKY2014-04(X).

Gut microbiota and risk of coronary heart disease: a two-sample Mendelian randomization study.

Background: The relationship between gut microbiota composition and coronary heart disease (CHD) has been recently reported in several observational studies. However, the causal effect of gut microbiota on coronary heart disease is uncharted. Objective: This study attempted to investigate the effect of gut microbiota on coronary heart disease by Mendelian randomization (MR) analysis. Methods: Through the two-sample MR method, single-nucleotide polymorphisms relevant to gut microbiota were selected as instrument variables to evaluate the causal association between gut microbiota and the risk of CHD. Results: According to the selection criteria of the inverse variance-weighted average method, Class Actinobacteria, Class Lentisphaeria, Family Clostridiales vadinBB60group, Genus Clostridium innocuum group, Genus Bifidobacterium, Genus Butyricicoccus, Genus Oxalobacter, Genus Turicibacter, and Order Victivallales, presented a suggestive association with coronary heart disease. Conclusion: This two-sample Mendelian randomization study found that gut microbiota was causally associated with coronary heart disease. Further randomized controlled trials are needed to clarify the protective effect of probiotics on coronary heart disease and their specific protective mechanisms.

Dehydroxylative radical N-glycosylation of heterocycles with 1-hydroxycarbohydrates enabled by copper metallaphotoredox catalysis.

N-Glycosylated heterocycles play important roles in biological systems and drug development. The synthesis of these compounds heavily relies on ionic N-glycosylation, which is usually constrained by factors such as labile glycosyl donors, precious metal catalysts, and stringent conditions. Herein, we report a dehydroxylative radical method for synthesizing N-glycosides by leveraging copper metallaphotoredox catalysis, in which stable and readily available 1-hydroxy carbohydrates are activated for direct N-glycosylation. Our method employs inexpensive photo- and copper- catalysts and can tolerate some extent of water. The reaction exhibits a broad substrate scope, encompassing 76 examples, and demonstrates high stereoselectivity, favoring 1,2-trans selectivity for furanoses and α-selectivity for pyranoses. It also exhibits high site-selectivity for substrates containing multiple N-atoms. The synthetic utility is showcased through the late-stage functionalization of bioactive compounds and pharmaceuticals like Olaparib, Axitinib, and Metaxalone. Mechanistic studies prove the presence of glycosyl radicals and the importance of copper metallaphotoredox catalysis.

Association of preoperative and recurrent serum carcinoembryonic antigen and outcome of colorectal cancer patients with metastatic relapse.

Background: Seldom have the associations of preoperative CEA (p-CEA) and recurrent CEA (r-CEA) levels as well as changes in p-CEA and r-CEA with survival in patients with stage I-III colorectal cancer (CRC) who have experienced metastatic relapse, been thoroughly examined. Methods: 241 consecutive patients with stage I-III CRC who experienced metastatic relapse at Fudan University Shanghai Cancer Center (FUSCC) between January 2008 and January 2016 were investigated. The influence of p-CEA, r-CEA and CEA alteration on the overall survival (OS) and relapse-to-death survival (RDS) was evaluated. The restricted cubic spline regression model was employed to explore the optimal cut-off value of CEA. Results: All 241 patients were categorized into four groups built on their CEA alteration patterns as follows: A, patients presenting elevated p-CEA levels but normal r-CEA levels (P-N); B, patients displaying normal levels of both p-CEA and r-CEA (N-N); C, patients exhibiting elevated levels of both p-CEA and r-CEA (P-P); D, patients with normal p-CEA levels but elevated r-CEA levels (N-P). The correlation between p-CEA and OS (P = 0.3266) and RDS (P = 0.2263) was insignificant. However, r-CEA exhibited a significant association with both OS (P = 0.0005) and RDS (P = 0.0002). Group A demonstrated the longest OS and RDS, whereas group D exhibited the poorest OS and RDS outcomes. For both OS and RDS, the CEA alteration groups served as an independent prognostic indicator. The optimal cut-off threshold for CEA was determined to be 5.1 ng/ml via the restricted cubic spline regression model. Conclusion: r-CEA has a stronger correlation with OS and RDS in individuals with stage I-III CRC who have experienced metastatic relapse.The change between p-CEA and r-CEA could further indicate post-relapse survival, thereby facilitating the assessment of mortality risk stratification in stage I-III CRC patients experiencing metastatic relapse.

Comparative analysis of codon usage patterns in the chloroplast genomes of nine forage legumes.

Leguminosae is one of the three largest families of angiosperms after Compositae and Orchidaceae. It is widely distributed and grows in a variety of environments, including plains, mountains, deserts, forests, grasslands, and even waters where almost all legumes can be found. It is one of the most important sources of starch, protein and oil in the food of mankind and also an important source of high-quality forage material for animals, which has important economic significance. In our study, the codon usage patterns and variation sources of the chloroplast genome of nine important forage legumes were systematically analyzed. Meanwhile, we also constructed a phylogenetic tree based on the whole chloroplast genomes and protein coding sequences of these nine forage legumes. Our results showed that the chloroplast genomes of nine forage legumes end with A/T bases, and seven identical high-frequency (HF) codons were detected among the nine forage legumes. ENC-GC3s mapping, PR2 analysis, and neutral analysis showed that the codon bias of nine forage legumes was influenced by many factors, among which natural selection was the main influencing factor. The codon usage frequency showed that the Nicotiana tabacum and Saccharomyces cerevisiae can be considered as receptors for the exogenous expression of chloroplast genes of these nine forage legumes. The phylogenetic relationships of the chloroplast genomes and protein coding genes were highly similar, and the nine forage legumes were divided into three major clades. Among the clades Melilotus officinalis was more closely related to Medicago sativa, and Galega officinalis was more closely related to Galega orientalis. This study provides a scientific basis for the molecular markers research, species identification and phylogenetic studies of forage legumes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01421-0.

Surface wettability control and electron transport regulation in zerovalent iron for enhanced removal of emerging polystyrene microplastics-heavy metal contaminants.

Emerging microplastics-heavy metal (MPs-HM) contaminants in wastewaters pose an emerging health and environmental risk due to their persistence and increasing ecological risks (e.g., "Trojan horse" effect). Hence, removing MPs in solution and preventing secondary releases of HM has become a key challenge when tackling with MPs pollution. Leveraging the hydrophobic nature of MPs and the electron transfer efficiency from Fe0 to HM, we demonstrate an alkylated and sulfidated nanoscale zerovalent iron (AS-nZVI) featuring a delicate "core-shell-hydrophobic film" nanostructure. Exemplified by polystyrene (PS) MPs-Pb(II) removal, the three nanocomponents offer synergistic functions for the rapid separation of MPs, as well as the reduction and stabilization of Pb(II). The outmost hydrophobic film of AS-nZVI greatly improves the anticorrosion performance of nanoscale zerovalent iron and the enrichment abilities of hydrophobic MPs, achieving a maximum removal capacity of MPs to 2725.87 mgMPs·gFe-1. This MPs enrichment promotes the subsequent reductive removal of Pb(II) through the electron transfer from the iron core of AS-nZVI to Pb(II), a process further strengthened by the introduced sulfur. When considering the inevitable aging of MPs in wastewaters due to mechanical wear or microbial degradation, our study concurrently examines the efficiencies and behaviors of AS-nZVI in removing virgin-MPs-Pb(II) and aged-MPs-Pb(II). The batch results reveal that AS-nZVI has an exceptional ability to remove above 99.6 % Pb(II) for all reaction systems. Overall, this work marks a pioneering effort in highlighting the importance of MPs-toxin combinations in dealing with MPs contamination and in demonstrating the utility of nZVI techniques for MPs-contaminated water purification.

Advancements in culture technology of adipose-derived stromal/stem cells: implications for diabetes and its complications.

Stem cell-based therapies exhibit considerable promise in the treatment of diabetes and its complications. Extensive research has been dedicated to elucidate the characteristics and potential applications of adipose-derived stromal/stem cells (ASCs). Three-dimensional (3D) culture, characterized by rapid advancements, holds promise for efficacious treatment of diabetes and its complications. Notably, 3D cultured ASCs manifest enhanced cellular properties and functions compared to traditional monolayer-culture. In this review, the factors influencing the biological functions of ASCs during culture are summarized. Additionally, the effects of 3D cultured techniques on cellular properties compared to two-dimensional culture is described. Furthermore, the therapeutic potential of 3D cultured ASCs in diabetes and its complications are discussed to provide insights for future research.

Advanced Hollow Cubic FeCo-N-C Cathode Electrocatalyst for Ultrahigh-Power Aluminum-Air Battery.

The exploration of electrocatalysts toward oxygen reduction reaction (ORR) is pivotal in the development of diverse batteries and fuel cells that rely on ORR. Here, a FeCo-N-C electrocatalyst (FeCo-HNC) featuring with atomically dispersed dual metal sites (Fe-Co) and hollow cubic structure is reported, which exhibits high activity for electrocatalysis of ORR in alkaline electrolyte, as evidenced by a half-wave potential of 0.907 V, outperforming that of the commercial Pt/C catalyst. The practicality of such FeCo-HNC catalyst is demonstrated by integrating it as the cathode catalyst into an alkaline aluminum-air battery (AAB) paring with an aluminum plate serving as the anode. This AAB demonstrates an unprecedented power density of 804 mW cm-2 in ambient air and an impressive 1200 mW cm-2 in an oxygen-rich environment. These results not only establish a new benchmark but also set a groundbreaking record for the highest power density among all AABs reported to date. Moreover, they stand shoulder to shoulder with state-of-the-art H2-O2 fuel cells. This AAB exhibits robust stability with continuous operation for an impressive 200 h. This groundbreaking achievement underscores the immense potential and forward strides that the present work brings to the field.

Personalized circulating tumor DNA monitoring improves recurrence surveillance and management after curative resection of colorectal liver metastases: a prospective cohort study.

BACKGROUND: Approximately 60% of patients with colorectal liver metastases (CRLM) experience relapse within 2 years after radical resection, previous studies have proven that repeat local treatment (LT) could prolong survival, however, it is difficult to seize the window for LT due to the lack of a high-sensitive surveillance method. In this study, the authors aim to examine the value of longitudinal circulating tumor DNA (ctDNA) in guiding adjuvant chemotherapy, optimizing clinical surveillance strategy, and thereby improving CRLM outcomes. MATERIALS AND METHODS: The authors conducted a prospective clinical trial using a personalized, tumor-informed ctDNA assay to monitor 60 CRLM patients undergoing resection with curative intent. Formalin-fixed paraffin-embedded tumor samples were collected after surgery. Blood samples were collected before surgery, 30 days after surgery (post-OP), and every third month until relapse or up to 2 years. RESULTS: A total of 394 plasma samples from 60 eligible patients were analyzed, with a median follow-up time of 31.3 months. Landmark analyses revealed that detectable ctDNA at post-OP (HR, 4.8), postadjuvant chemotherapy (HR, 6.0), and end-of-treatment (HR, 5.6) were associated with higher recurrence risk ( P <0.001). Post-OP ctDNA positivity served as the only independent prognostic marker in the multivariant analysis (HR, 5.1; P <0.001). Longitudinal ctDNA analysis identified relapsed patients at both sensitivity and specificity of 100%. Most (75%) patients were found with radiological relapse within 6 months after the first detectable ctDNA with a median lead time of 3.5 months. In relapsed patients, 73.2% had oligometastatic disease and 61% were liver-restricted, of which 72.0% received repeat LTs, and 60.0% achieved a secondary no evidence of disease status. CONCLUSIONS: Longitudinal ctDNA monitoring assists in early prediction of relapse, and thereby improves survival of CRLM patients by increased secondary resection rate and secondary no evidence of disease rate.

Compound SJ-12 attenuates streptozocin-induced diabetic cardiomyopathy by stabilizing SERCA2a.

Heart failure (HF) is one of the major causes of death among diabetic patients. Although studies have shown that curcumin analog C66 can remarkably relieve diabetes-associated cardiovascular and kidney complications, the role of SJ-12, SJ-12, a novel curcumin analog, in diabetic cardiomyopathy and its molecular targets are unknown. 7-week-old male C57BL/6 mice were intraperitoneally injected with single streptozotocin (STZ) (160 mg/kg) to develop diabetic cardiomyopathy (DCM). The diabetic mice were then treated with SJ-12 via gavage for two months. Body weight, fast blood glucose, cardiac utrasonography, myocardial injury markers, pathological morphology of the heart, hypertrophic and fibrotic markers were assessed. The potential target of SJ-12 was evaluated via RNA-sequencing analysis. The O-GlcNAcylation levels of SP1 were detected via immunoprecipitation. SJ-12 effectively suppressed myocardial hypertrophy and fibrosis, thereby preventing heart dysfunction in mice with STZ-induced heart failure. RNA-sequencing analysis revealed that SJ-12 exerted its therapeutic effects through the modulation of the calcium signaling pathway. Furthermore, SJ-12 reduced the O-GlcNAcylation levels of SP1 by inhibiting O-linked N-acetylglucosamine transferase (OGT). Also, SJ-12 stabilized Sarcoplasmic/Endoplasmic Reticulum Calcium ATPase 2a (SERCA2a), a crucial regulator of calcium homeostasis, thus reducing hypertrophy and fibrosis in mouse hearts and cultured cardiomyocytes. However, the anti-fibrotic effects of SJ-12 were not detected in SERCA2a or OGT-silenced cardiomyocytes, indicating that SJ-12 can prevent DCM by targeting OGT-dependent O-GlcNAcylation of SP1.These findings indicate that SJ-12 can exert cardioprotective effects in STZ-induced mice by reducing the O-GlcNAcylation levels of SP1, thus stabilizing SERCA2a and reducing myocardial fibrosis and hypertrophy. Therefore, SJ-12 can be used for the treatment of diabetic cardiomyopathy.

Targeting type I PRMTs as promising targets for the treatment of pulmonary disorders: Asthma, COPD, lung cancer, PF, and PH.

Pulmonary disorders, including asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (PF), pulmonary hypertension (PH), and lung cancer, seriously impair the quality of lives of patients. A deeper understanding of the occurrence and development of the above diseases may inspire new strategies to remedy the scarcity of treatments. Type I protein arginine methyltransferases (PRMTs) can affect processes of inflammation, airway remodeling, fibroblast proliferation, mitochondrial mass, and epithelial dysfunction through substrate methylation and non-enzymatic activity, thus affecting the occurrence and development of asthma, COPD, lung cancer, PF, and PH. As potential therapeutic targets, inhibitors of type I PRMTs are developed, moreover, representative compounds such as GSK3368715 and MS023 have also been used for early research. Here, we collated structures of type I PRMTs inhibitors and compared their activity. Finally, we highlighted the physiological and pathological associations of type I PRMTs with asthma, COPD, lung cancer, PF, and PH. The developing of type I PRMTs modulators will be beneficial for the treatment of these diseases.