Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification.

We report the identification of 67 previously undescribed histone modifications, increasing the current number of known histone marks by about 70%. We further investigated one of the marks, lysine crotonylation (Kcr), confirming that it represents an evolutionarily-conserved histone posttranslational modification. The unique structure and genomic localization of histone Kcr suggest that it is mechanistically and functionally different from histone lysine acetylation (Kac). Specifically, in both human somatic and mouse male germ cell genomes, histone Kcr marks either active promoters or potential enhancers. In male germinal cells immediately following meiosis, Kcr is enriched on sex chromosomes and specifically marks testis-specific genes, including a significant proportion of X-linked genes that escape sex chromosome inactivation in haploid cells. These results therefore dramatically extend the repertoire of histone PTM sites and designate Kcr as a specific mark of active sex chromosome-linked genes in postmeiotic male germ cells.

Dectin-1 Acts as a Non-Classical Receptor of Ang II to Induce Cardiac Remodeling.

BACKGROUND: Cardiac remodeling in heart failure involves macrophage-mediated immune responses. Recent studies have shown that a PRR (pattern recognition receptor) called dectin-1, expressed on macrophages, mediates proinflammatory responses. Whether dectin-1 plays a role in pathological cardiac remodeling is unknown. Here, we identified a potential role of dectin-1 in this disease. METHODS: To model aberrant cardiac remodeling, we utilized mouse models of chronic Ang II (angiotensin II) infusion. In this model, we assessed the potential role of dectin-1 through using D1KO (dectin-1 knockout) mice and bone marrow transplantation chimeric mice. We then used cellular and molecular assays to discover the underlying mechanisms of dectin-1 function. RESULTS: We found that macrophage dectin-1 is elevated in mouse heart tissues following chronic Ang II administration. D1KO mice were significantly protected against Ang II-induced cardiac dysfunction, hypertrophy, fibrosis, inflammatory responses, and macrophage infiltration. Further bone marrow transplantation studies showed that dectin-1 deficiency in bone marrow-derived cells prevented Ang II-induced cardiac inflammation and dysfunction. Through detailed molecular studies, we show that Ang II binds directly to dectin-1, causing dectin-1 homodimerization and activating the downstream Syk (spleen tyrosine kinase)/NF-κB (nuclear factor kappa B) signaling pathway to induce expression of inflammatory and chemoattractant factors. Mutagenesis studies identified R184 in the C-type lectin domain to interact with Ang II. Blocking dectin-1 in macrophages suppresses Ang II-induced inflammatory mediators and subsequent intercellular cross talk with cardiomyocytes and fibroblasts. CONCLUSIONS: Our study has discovered dectin-1 as a new nonclassical receptor of Ang II and a key player in cardiac remolding and dysfunction. These studies suggest that dectin-1 may be a new target for treating hypertension-related heart failure.

Unveiling the hidden role of disulfidptosis in kidney renal clear cell carcinoma: a prognostic signature for personalized treatment.

The role of disulfidptosis in kidney renal clear cell carcinoma (KIRC) remains unknown. This study investigated disulfidptosis-related biomarkers for KIRC prognosis prediction and individualized treatment. KIRC patients were clustered by disulfidptosis profiles. Differential expression analysis, survival models, and machine learning were used to construct the disulfidptosis-related prognostic signature (DRPS). Characterizations of the tumor immune microenvironment, genetic drivers, drug sensitivity, and immunotherapy response were explored according to the DRPS risk stratification. Markers included in the signature were validated using single-cell, spatial transcriptomics, quantitative RT-qPCR, and immunohistochemistry. In the discovery cohort, we unveiled two clusters of KIRC patients that differed significantly in disulfidptosis regulator expressions and overall survival (OS). After multiple feature selection steps, a DRPS prognostic model with four features (CHAC1, COL7A1, FOXM1, SHOX2) was constructed and validated. Combined with clinical factors, the model demonstrated robust performance in the discovery and external validation cohorts (5-year AUC = 0.793 and 0.846, respectively). KIRC patients with high-risk scores are characterized by inferior OS, less tumor purity, and increased infiltrations of fibroblasts, M1 macrophages, and B cells. High-risk patients also have higher frequencies of BAP1 and AHNAK2 mutation. Besides, the correlation between the DRPS score and the chemotherapy-response signature indicated the potential effect of Gefitinib for high-risk patients. Among the signature genes, FOXM1 is highly expressed in cycling tumor cells and exhibits spatial aggregation, while others are expressed sparsely within tumor samples. The DRPS model enables improved clinical management and personalized KIRC therapy. The identified biomarkers and immune characteristics offer new mechanistic insight into disulfidptosis in KIRC.

Photo/Mechanical/Acidic Multi-Stimuli Responses and Information Encryption Design of Acylhydrazone Derivative.

Stimuli-responsive crystalline materials have received much attention for being potential candidates of smart materials. However, the occurrence of polymorphism-driven stimuli responses in crystalline materials remains interesting but rare. Herein, three polymorphs of an acylhydrazone derivative, N'-[(E)-(1-benzofuran-2-yl) methylidene] pyridine -4-carbohydrazide (BFMP) were prepared. Form-1 undergoes a photomechanical response via E→Z photoisomerization under UV irradiation, accompanied by a decrease in fluorescence intensity and a change from colorless to yellow. Two types of Z→E thermal isomerization mechanisms with significant differences in conversion rate were observed at different temperatures in form-1. The solid-melt-solid transition has a faster conversion rate compared to the solid-solid transition due to freedom from lattice confinement. The transition from form-2 to form-3 can be achieved under grinding, coupled with a significant decrease in fluorescence intensity. The similar molecular stacking pattern of form-2 and form-3 provides a structural basis for the grinding-induced crystalline transition behavior. In addition, the presence of the pyridine moiety imparts an acidochromic property. The combination of photochromism and acidochromism explores the possible applications of acylhydrazone derivatives in information encryption.

A novel single-base deletional mutation of MIP impairs protein distribution and cell-to-cell adhesion in autosomal dominant cataracts in a Chinese family.

Congenital cataracts are the leading cause of irreversible visual disability in children, and genetic factors play an important role in their development. In this study, targeted exome sequencing revealed a novel single-base deletional mutation of MIP (c.301delG; p.Ala101Profs*16) segregated with congenital punctate cataract in a Chinese family. The hydrophobic properties, and secondary and tertiary structures for truncated MIP were predicted to affect the function of protein by bioinformatics analysis. When MIP-WT and MIP-Ala101fs expression constructs were singly transfected into HeLa cells, it was found that the mRNA level showed no significant difference, while the protein level of the mutant was remarkably reduced compared to that of the wild-type MIP. Immunofluorescence images showed that the MIP-WT was principally localized to the plasma membrane, whereas the MIP-Ala101fs protein was aberrantly trapped in the cytoplasm. Furthermore, the cell-to-cell adhesion capability and the cell-to-cell communication property were both significantly reduced for MIP-Ala101fs compared to the MIP-WT (all *p < 0.05). This is the first report of the c.301delG mutation in the MIP gene associated with autosomal dominant congenital cataracts. We propose that the cataract is caused by the decreased protein expression and reduced cell-to-cell adhesion by the mutant MIP. The impaired trafficking or instability of the mutant protein, as well as compromised intercellular communication is probably a concurrent result of the mutation. The results expand the genetic and phenotypic spectra of MIP and help to better understand the molecular basis of congenital cataracts.

13,14-seco withaphysalins from Physalis minima and their inhibitory effects on NLRP3 inflammasome activation.

Seven new 13,14-seco withaphysalins including two new skeletons (1 and 9) were isolated from the whole plants of Physalis minima, together with three known analogues (6-8). Among them, compound 1 was an extremely rare steroid with a 6, 8-cyclo ring. Their structures were established by extensive analysis of spectroscopic data, experimental electronic circular dichroism measurements, and single-crystal X-ray crystallographic analysis. In Raw264.7 cells, compounds 1-3, 5, 6, and 8 demonstrated potent ability to reduce the NLRP3-dependent caspase-1 activation. Among these compounds, 1 and 2 showed a superior potential, consistently concentration-dependent downregulating NLRP3-dependent proinflammatory cytokine IL-1ß production in macrophage. Mechanistically, compounds 1 and 2 reduced the cleavage of caspase-1 and GSDMD, and exhibited no obvious impact both on the NF-κB activation and the expression of NLRP3 and IL-1ß, suggesting that the compounds target the activation of the NLRP3 pathway mainly by inhibiting the NLRP3 inflammasome activation step rather than the priming step.

Macrophage Dectin-1 mediates Ang II renal injury through neutrophil migration and TGF-ß1 secretion.

Macrophage activation has been shown to play an essential role in renal fibrosis and dysfunction in hypertensive chronic kidney disease. Dectin-1 is a pattern recognition receptor that is also involved in chronic noninfectious diseases through immune activation. However, the role of Dectin-1 in Ang II-induced renal failure is still unknown. In this study, we found that Dectin-1 expression on CD68 + macrophages was significantly elevated in the kidney after Ang II infusion. We assessed the effect of Dectin-1 on hypertensive renal injury using Dectin-1-deficient mice infused by Angiotensin II (Ang II) at 1000 ng/kg/min for 4 weeks. Ang II-induced renal dysfunction, interstitial fibrosis, and immune activation were significantly attenuated in Dectin-1-deficient mice. A Dectin-1 neutralizing antibody and Syk inhibitor (R406) were used to examine the effect and mechanism of Dectin-1/Syk signaling axle on cytokine secretion and renal fibrosis in culturing cells. Blocking Dectin-1 or inhibiting Syk significantly reduced the expression and secretion of chemokines in RAW264.7 macrophages. The in vitro data showed that the increase in TGF-ß1 in macrophages enhanced the binding of P65 and its target promotor via the Ang II-induced Dectin-1/Syk pathway. Secreted TGF-ß1 caused renal fibrosis in kidney cells through Smad3 activation. Thus, macrophage Dectin-1 may be involved in the activation of neutrophil migration and TGF-ß1 secretion, thereby promoting kidney fibrosis and dysfunction.

Insights into the Understanding of the Nickel-Based Pre-Catalyst Effect on Urea Oxidation Reaction Activity.

Nickel-based catalysts are regarded as the most excellent urea oxidation reaction (UOR) catalysts in alkaline media. Whatever kind of nickel-based catalysts is utilized to catalyze UOR, it is widely believed that the in situ-formed Ni3+ moieties are the true active sites and the as-utilized nickel-based catalysts just serve as pre-catalysts. Digging the pre-catalyst effect on the activity of Ni3+ moieties helps to better design nickel-based catalysts. Herein, five different anions of OH-, CO32-, SiO32-, MoO42-, and WO42- were used to bond with Ni2+ to fabricate the pre-catalysts ß-Ni(OH)2, Ni-CO3, Ni-SiO3, Ni-MoO4, and Ni-WO4. It is found that the true active sites of the five as-fabricated catalysts are the same in situ-formed Ni3+ moieties and the five as-fabricated catalysts demonstrate different UOR activity. Although the as-synthesized five catalysts just serve as the pre-catalysts, they determine the quantity of active sites and activity per active site, thus determining the catalytic activity of the catalysts. Among the five catalysts, the amorphous nickel tungstate exhibits the most superior activity per active site and can catalyze UOR to reach 158.10 mA·cm-2 at 1.6 V, exceeding the majority of catalysts. This work makes for a deeper understanding of the pre-catalyst effect on UOR activity and helps to better design nickel-based UOR catalysts.

The combination of allantoin, bisabolol, D-panthenol and dipotassium glycyrrhizinate mitigates UVB-induced PGE2 synthesis by keratinocytes.

OBJECTIVE: Erythema, characterized by the redness of the skin, is a common skin reaction triggered by various endogenous and exogenous factors. This response is often a result of the activation of underlying inflammatory mechanisms within the skin. The objective of this study is to investigate the potential benefits of applying a combination of skincare ingredients, namely allantoin, bisabolol, D-panthenol and dipotassium glycyrrhizinate (AB5D), in the modulation of inflammatory factors associated with erythema. Additionally, the study aims to elucidate the mechanisms by which these ingredients exert their combined actions to alleviate erythema-associated inflammation. METHODS: Human epidermal keratinocytes were exposed to UVB and subsequently treated with AB5D. Transcriptomics profiling was performed to analyse the dose-response effect of AB5D treatment on keratinocytes. The quantitation of inflammatory mediators, including PGE2 , IL-1α, IL-6, IL-8, IL-1RA and TNFα, was performed on cultured media. Additionally, the oxygen radical absorbance capacity (ORAC) assay was carried out to evaluate the total antioxidant capacity of both individual ingredients and the AB5D combination. To assess the in-vitro antioxidant effects of AB5D against UVB-induced oxidative stress in hTERT keratinocytes, real-time quantitation of mitochondrial superoxide was measured through live-cell imaging. RESULTS: The application of AB5D to UVB-exposed keratinocytes downregulated gene sets associated with inflammatory responses, highlighting the anti-inflammatory properties of AB5D. Specifically, AB5D effectively reduced the production of PGE2 , leading to the downregulation of inflammatory cytokines. Moreover, our findings indicate that AB5D exhibits antioxidative capabilities, functioning as both an antioxidant agent and a regulator of antioxidant enzyme expression to counteract the detrimental effects of cellular oxidative stress. CONCLUSION: We demonstrated that AB5D can reduce UVB-induced PGE2 , IL-1α, IL-6, IL-8, IL-1RA and TNFα as well as mitochondrial superoxide. These findings suggest that AB5D may alleviate erythema by modulating inflammation via PGE2 and through antioxidation mechanisms.

L'érythème, caractérisé par une rougeur sur la peau, est une réaction cutanée fréquente déclenchée par divers facteurs endogènes et exogènes. Il s'agit d'une réponse qui résulte souvent de l'activation des mécanismes inflammatoires sous-jacents dans la peau. OBJECTIF: cette étude vise à étudier les bénéfices potentiels de l'application d'une association d'ingrédients de soins cutanés, à savoir l'allantoïne, le bisabolol, le D-panthénol et le glycyrrhizinate dipotassique (AB5D) dans la modulation des facteurs inflammatoires associés à l'érythème. En outre, l'étude vise à élucider les mécanismes par lesquels ces ingrédients exercent leurs actions combinées pour soulager l'inflammation associée à l'érythème. MÉTHODES: les kératinocytes épidermiques humains ont été exposés aux UVB et traités par la suite par AB5D. Un profilage transcriptomique a été effectué pour analyser l'effet dose-réponse du traitement par AB5D sur les kératinocytes. La quantification des médiateurs inflammatoires, y compris PGE2, IL-1α, IL-6, IL-8, IL-1RA et TNFα, a été effectuée sur des milieux de culture. En outre, le dosage de la capacité d'absorption des radicaux oxygénés (Oxygen Radical Absorbance Capacity, ORAC) a été effectué pour évaluer la capacité antioxydante totale des deux ingrédients individuels et de l'association AB5D. Pour évaluer les effets antioxydants in vitro de l'AB5D contre le stress oxydatif induit par les UVB dans les kératinocytes hTERT, on a mesuré la quantification en temps réel du superoxyde mitochondrial par des tests d'imagerie des cellules vivantes. RÉSULTATS: l'application de l'AB5D aux ensembles de gènes régulés à la baisse exposés aux kératinocytes UVB associés à des réponses inflammatoires, a mis en évidence les propriétés anti-inflammatoires de l'AB5D. Plus précisément, l'AB5D a efficacement réduit la production de PGE2, entraînant une régulation négative des cytokines inflammatoires. En outre, nos résultats indiquent que l'AB5D présente des capacités antioxydantes. Il fonctionne à la fois comme un agent antioxydant et comme un régulateur de l'expression enzymatique antioxydante pour contrer les effets néfastes du stress oxydatif cellulaire. CONCLUSION: nous avons montré que l'AB5D pouvait réduire la PGE2 induite par les UVB, l'IL-1α, l'IL-6, IL-8, IL-1RA et le TNFα, ainsi que le superoxyde mitochondrial. Ces résultats suggèrent que l'AB5D pourrait soulager l'érythème en modulant l'inflammation via la PGE2 et via des mécanismes d'antioxydation.

Enzymatic Synthesis of Noncanonical α-Amino Acids Containing γ-Tertiary Alcohols.

Noncanonical amino acids (ncAAs) containing tertiary alcohols are valuable as precursors of natural products and active pharmaceutical ingredients. However, the assembly of such ncAA scaffolds from simple material by C-C bond formation remains a challenging task due to the presence of multiple stereocenters and large steric hindrance. In this study, we present a novel solution to this problem through highly selective enzymatic decarboxylative aldol addition. This method allows for the streamlined assembly of multifunctionalized ncAAs with γ-tertiary alcohols from readily available materials, such as L -aspartatic acid and isatins, vicinal diones and keto esters. The modularity of electrophiles furnished four classes of ncAAs with decent efficiency as well as excellent site and stereocontrol. Computational modeling was employed to gain detailed insight into the catalytic mechanism and to provide a rationale for the observed selectivities. The method offers a single-step approach to producing multifunctionalized ncAAs, which can be directly utilized in peptide synthesis and bioactivity assessment.

Building Block Extractor: An MS/MS Data Mining Tool for Targeted Discovery of Natural Products with Specified Features.

The utilization of a building-block-based molecular network is an efficient approach to investigate the unknown chemical space of natural products. However, structure-based automated MS/MS data mining remains challenging. This study introduces building block extractor, a user-friendly MS/MS data mining program that automatically extracts user-defined specified features. In addition to the characteristic product ions and neutral losses, this program integrates the abundance of the product ions and sequential neutral loss features as building blocks for the first time. The discovery of nine undescribed sesquiterpenoid dimers from Artemisia heptapotamica highlights the power of this tool. One of these dimers, artemiheptolide I (9), exhibited in vitro inhibition of influenza A/Hongkong/8/68 (H3N2) with an IC50 of 8.01 ± 6.19 µM. Furthermore, two known guaianolide derivatives (16 and 17) possessed remarkable antiviral activity against influenza A/Puerto Rico/8/1934 H1N1, H3N2, and influenza B/Lee/40 with IC50 values ranging from 3.46 to 11.77 µM. In addition to the efficient discovery of novel natural products, this strategy can be generally applied to grab derivatives with specific fragments and enhance the annotation power of LC-MS/MS analysis.

Investigating the prognostic and predictive value of the type II cystatin genes in gastric cancer.

BACKGROUND: Accumulating evidence indicates that type II cystatin (CST) genes play a pivotal role in several tumor pathological processes, thereby affecting all stages of tumorigenesis and tumor development. However, the prognostic and predictive value of type II CST genes in GC has not yet been investigated. METHODS: The present study evaluated the expression and prognostic value of type II CST genes in GC by using The Cancer Genome Atlas (TCGA) database and the Kaplan-Meier plotter (KM plotter) online database. The type II CST genes related to the prognosis of GC were then screened out. We then validated the expression and prognostic value of these genes by immunohistochemistry. We also used Database for Annotation, Visualization, and Integrated Discovery (DAVID), Gene Multiple Association Network Integration Algorithm (GeneMANIA), Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), nomogram, genome-wide co-expression analysis, and other bioinformatics tools to analyze the value of type II CST genes in GC and the underlying mechanism. RESULTS: The data from the TCGA database and the KM plotter online database showed that high expression of CST2 and CST4 was associated with the overall survival (OS) of patients with GC. The immunohistochemical expression analysis showed that patients with high expression of CST4 in GC tissues have a shorter OS than those with low expression of CST4 (HR = 1.85,95%CI: 1.13-3.03, P = 0.015). Multivariate Cox regression analysis confirmed that the high expression level of CST4 was an independent prognostic risk factor for OS. CONCLUSIONS: Our findings suggest that CST4 could serve as a tumor marker that affects the prognosis of GC and could be considered as a potential therapeutic target for GC.

Effects of Dietary Phytochemicals on DNA Damage in Cancer Cells.

With the increasing incidence of cancer worldwide, the prevention and treatment of cancer have garnered considerable scientific attention. Traditional chemotherapeutic drugs are highly toxic and associated with substantial side effects; therefore, there is an urgent need for developing new therapeutic agents. Dietary phytochemicals are important in tumor prevention and treatment because of their low toxicity and side effects at low concentrations; however, their exact mechanisms of action remain obscure. DNA damage is mainly caused by physical or chemical factors in the environment, such as ultraviolet light, alkylating agents and reactive oxygen species that cause changes in the DNA structure of cells. Several phytochemicals have been shown inhibit the occurrence and development of tumors by inducing DNA damage. This article reviews the advances in phytochemical research; particularly regarding the mechanisms related to DNA damage and provide a theoretical basis for future chemoprophylaxis research.

Oxidation/Alkylation of Amino Acids with α-Bromo Carbonyls Catalyzed by Copper and Quick Access to HDAC Inhibitor.

A facile and efficient method was reported for Cu-catalyzed selective α-alkylation processes of amino acids/peptides and α-bromo esters/ketones through a radical-radical coupling pathway. The reaction displays an excellent functional group tolerance and broad substrate scope, allowing access to desired products in moderate to excellent yields. Notably, this method is distinguished by site-specificity and exhibits total selectivity for aryl glycine motifs over other amino acid units. Furthermore, the practicality of this strategy is certified by the efficient synthesis of the novel SAHA phenylalanine-containing analogue (SPACA).

Alkenyl Thioetherification Enabled by Nickel Catalysis.

This paper describes an efficient strategy to promote alkenyl thioetherifications via the Ni-catalyzed cross-coupling of inactivated or ß-aryl-substituted (E)-alkenyl halides with thio-alcohols/phenols. The present strategy with easy-to-operate reaction conditions represents one of the most effective alkenyl C(sp2)-S bond-forming methods via readily accessible nickel catalysis. Notably, the mildly basic conditions employed facilitate access to a broad scope including protected amino acids, saccharides, and heterocycles. Moreover, this work presents its attractive usefulness by the application in late-stage modifications of several structurally complex natural products and pharmaceuticals.

Microwave-assisted rapid synthesis of chiral oxazolines.

Chiral oxazoline compounds play an extremely important role in asymmetric synthesis and drug discovery. Herein a simpler, greener and more efficient microwave-assisted protocol to rapidly access chiral oxazolines is developed using aryl nitriles or cyano-containing compounds and chiral ß-amino alcohols as starting materials. The reaction proceeds smoothly in the presence of a recoverable heterogeneous catalyst in either concentrated solution or under solvent-free conditions. The advantages of this method include rapidness, convenience, environmental protection, high atom economy, and excellent yields. The protocol should find wider application in the community in the future.

Bisabolane-Type Sesquiterpenoids with a Tetrahydrofuran or Tetrahydropyran Ring from Vernonia solanifolia.

Phytochemical investigation of the aerial parts of Vernonia solanifolia resulted in the isolation of 23 new highly oxidized bisabolane-type sesquiterpenoids (1-23). Structures were determined by interpretation of spectroscopic data, single-crystal X-ray diffraction analysis, and time-dependent density functional theory electronic circular dichroism calculations. Most compounds possess a rare tetrahydrofuran (1-17) or tetrahydropyran ring (18-21). Compounds 1/2 and 11/12 are pairs of epimers isomerized at C-10, while compounds 9/10 and 15/16 are isomerized at C-11 and C-2, respectively. The anti-inflammatory effect in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages was evaluated for pure compounds. Compound 9 inhibited LPS-stimulated NO production at the concentration of 80 µM. It showed an anti-inflammatory effect by suppressing the activation of the NF-κB signaling pathway.

The effectiveness and feasibility of using multi-lead ECG monitoring combined with a programmed intracavitary ECG to complete left bundle branch area pacing.

BACKGROUND: Left bundle branch area pacing (LBBaP) as an alternative method for delivering physiological pacing, is difficult for many primary hospitals that lack the electrophysiological multichannel recorder to carry out. We hope to find a simple and feasible method that combines the multi-lead surface electrocardiogram (ECG) monitoring and the intracavity ECG of the pacing programmer to achieve LBBaP. METHODS: A total of 50 patients with bradycardia indications who attempted permanent pacemaker implantation were included in this study. We referred to multi-lead surface ECG monitoring and pacing system analyzer (PSA), combined with the nine-zone pacing method of the LBBaP, to complete LBBaP. We assessed multiple parameters to verify whether the LBBaP was successfully achieved and used univariable analysis of variance for repeated measures to judge the feasibility and effectiveness of LBBaP without the electrophysiological multichannel recorder. RESULTS: LBBaP was successfully archived without the electrophysiological multichannel recorder in 44 of 50 patients (88%). In the study, paced QRS duration and the stimulus to peak left ventricular activation time (Sti-LVAT) were 117.04 ± 10.34 ms and 71.10 ± 7.91 ms and had no significant changes in the 3-month follow-up. The unipolar pacing threshold and R-wave amplitudes were 0.85 ± 0.32 V and 10.36 ± 5.24 mV at baseline respectively, which also showed stability during the 1-month and 3-month follow-up. During the 3-month follow-up, no lead-related complication was recorded. CONCLUSION: It is effective and feasible to achieve LBBaP combining the multi-lead ECG monitoring and the intracavitary ECG of PSA without the electrophysiological multichannel recorder, which could be an alternative to perform LBBaP.

Cardiovascular imaging in conduction system pacing: What does the clinician need?

Permanent pacemakers are used for symptomatic bradycardia and biventricular pacing (BVP)-cardiac resynchronization therapy (BVP-CRT) is established for heart failure (HF) patients traditionally. According to guidelines, patients' selection for CRT is based on QRS duration (QRSd) and morphology by surface electrocardiogram (ECG). Cardiovascular imaging techniques evaluate cardiac structure and function as well as identify pathophysiological substrate changes including the presence of scar. Cardiovascular imaging helps by improving the selection of candidates, guiding left ventricular (LV) lead placement, and optimization devices during the follow-up. Conduction system pacing (CSP) includes His bundle pacing (HBP) and left bundle branch pacing (LBBP) which is screwed into the interventricular septum. CSP maintains and restores ventricular synchrony in patients with native narrow QRSd and left bundle branch block (LBBB), respectively. LBBP is more feasible than HBP due to a wider target area. This review highlights the role of multimodality cardiovascular imaging including fluoroscopy, echocardiography, cardiac magnetic resonance (CMR), myocardial scintigraphy, and computed tomography (CT) in the pre-procedure assessment for CSP, better selection for CSP candidates, the guidance of CSP lead implantation, and the optimization of devices programming after the procedure. We also compare the different characteristics of multimodality imaging and discuss their potential roles in future CSP implantation.

14-Deoxygarcinol improves insulin sensitivity in high-fat diet-induced obese mice via mitigating NF-κB/Sirtuin 2-NLRP3-mediated adipose tissue remodeling.

Interleukin (IL)-1ß is a culprit of adipose tissue inflammation, which in turn causes systematic inflammation and insulin resistance in obese individuals. IL-1ß is mainly produced in monocytes and macrophages and marginally in adipocytes, through cleavage of the inactive pro-IL-1ß precursor by caspase-1, which is activated via the NLRP3 inflammasome complex. The nuclear factor-κB (NF-κB) transcription factor is the master regulator of inflammatory responses. Brindle berry (Garcinia cambogia) has been widely used as health products for treating obesity and related metabolic disorders, but its active principles remain unclear. We previously found a series of polyisoprenylated benzophenones from brindle berry with anti-inflammatory activities. In this study we investigated whether 14-deoxygarcinol (DOG), a major polyisoprenylated benzophenone from brindle berry, alleviated adipose tissue inflammation and insulin sensitivity in high-fat diet fed mice. The mice were administered DOG (2.5, 5 mg · kg-1 · d-1, i.p.) for 4 weeks. We showed that DOG injection dose-dependently improved insulin resistance and hyperlipidemia, but not adiposity in high-fat diet-fed mice. We found that DOG injection significantly alleviated adipose tissue inflammation via preventing macrophage infiltration and pro-inflammatory polarization of macrophages, and adipose tissue fibrosis via reducing the abnormal deposition of extracellular matrix. In LPS plus nigericin-stimulated THP-1 macrophages, DOG (1.25, 2.5, 5 µM) dose-dependently suppressed the activation of NLRP3 inflammasome and NF-κB signaling pathway. We demonstrated that DOG bound to and activated the deacetylase Sirtuin 2, which in turn deacetylated and inactivated NLRP3 inflammasome to reduce IL-1ß secretion. Moreover, DOG (1.25, 2.5, 5 µM) dose-dependently mitigated inflammatory responses in macrophage conditioned media-treated adipocytes and suppressed macrophage migration toward adipocytes. Taken together, DOG might be a drug candidate to treat metabolic disorders through modulation of adipose tissue remodeling.