TAF1B depletion leads to apoptotic cell death by inducing nucleolar stress and activating p53-miR-101 circuit in hepatocellular carcinoma.

Background: TAF1B (TATA Box Binding Protein (TBP)-Associated Factor) is an RNA polymerase regulating rDNA activity, stress response, and cell cycle. However, the function of TAF1B in the progression of hepatocellular carcinoma (HCC) is unknown. Objective: In this study, we intended to characterize the crucial role and molecular mechanisms of TAF1B in modulating nucleolar stress in HCC. Methods: We analyzed the differential expression and prognostic value of TAF1B in hepatocellular carcinoma based on The Cancer Genome Atlas (TCGA) database, tumor and paraneoplastic tissue samples from clinical hepatocellular carcinoma patients, and typical hepatocellular carcinoma. We detected cell proliferation and apoptosis by lentiviral knockdown of TAF1B expression levels in HepG2 and SMMC-7721 cells using clone formation, apoptosis, and Western blotting (WB) detection of apoptosis marker proteins. Simultaneously, we investigated the influence of TAF1B knockdown on the function of the pre-initiation complex (PIC) by WB, and co-immunoprecipitation (Co-IP) and chromatin immunoprecipitation (ChIP) assays verified the interaction between the complexes and the effect on rDNA activity. Immunofluorescence assays measured the expression of marker proteins of nucleolus stress, fluorescence in situ hybridization (FISH) assays checked the rDNA activity, and qRT-PCR assays tested the pre-rRNA levels. Regarding molecular mechanisms, we investigated the role of p53 and miR-101 in modulating nucleolar stress and apoptosis. Finally, the impact of TAF1B knockdown on tumor growth, apoptosis, and p53 expression was observed in xenograft tumors. Result: We identified that TAF1B was highly expressed in hepatocellular carcinoma and associated with poor prognosis in HCC patients. TAF1B depletion modulated nucleolar stress and apoptosis in hepatocellular carcinoma cells through positive and negative feedback from p53-miR-101. RNA polymerase I transcription repression triggered post-transcriptional activation of miR-101 in a p53-dependent manner. In turn, miR-101 negatively feeds back through direct inhibition of the p53-mediated PARP pathway. Conclusion: These findings broaden our comprehension of the function of TAF1B-mediated nucleolar stress in hepatocellular carcinoma and may offer new biomarkers for exploring prospective therapeutic targets in HCC.

Late-Stage Aryl C-H Bond Cyclopropenylation with Cyclopropenium Cations.

Herein, we disclose the first regio-, site- and chemoselective late-stage (hetero)aryl C-H bond cyclopropenylation with cyclopropenium cations (CPCs). The process is fast, operationally simple and shows an excellent functional group tolerance in densely-functionalized drug molecules, natural products, agrochemicals and fluorescent dyes. Moreover, we discovered that the installation of the cyclopropene ring in drug molecules could not only be used to shield against metabolic instability but also as a synthetic tool to reach medicinally-relevant sp3 -rich scaffolds exploiting the highly-strained nature of the cyclopropene ring with known transformations.

Cinobufacini retards progression of pancreatic ductal adenocarcinoma through targeting YEATS2/TAK1/NF-κB axis.

BACKGROUND: Cinobufacini, a sterilized hot water extract of dried toad skin, had significant effect against several human cancers. However, there are few studies reporting the effect of cinobufacini on pancreatic cancer. PURPOSE: To investigate the effects of cinobufacini on the progress of pancreatic ductal adenocarcinoma and the underlying mechanisms. METHODS: Cell counting, EdU incorporation and flow Cytometry were performed to evaluate the effect of cinobufacini on cell cycle and growth. MIA-PaCa2 cells were implanted into the nude mice to determine whether cinobufacini represses PDAC progression in vivo. Luciferase reporter assay, western blotting and qPCR were carried out to measure the activity of NF-κB pathway and the alteration of YEATS2 and TAK1. Ectopic gene expression introduced by plasmids was used to verify the molecular mechanism. RESULTS: Our results showed that cinobufacini induced cell cycle arrest and inhibited the growth of PDAC cell in vitro, and repressed MIA-derived PDAC in vivo. Cinobufacini inhibited the phosphorylation of IKK, IκB and NF-κB p65 in PDAC cells. Furthermore, cinobufacini decreased the abundance of intracellular YEATS2 and total TAK1 protein in a time- and dose dependent manner. Ectopic expression of YEATS2 re-elevated the level of TAK1 and phosphorylated IKKα/ß, IκBα and p65 after cinobufacini treatment in PANC-1 cells. CONCLUSION: Cinobufacini retards the growth and progression of PDAC in vitro and in vivo through YEATS2/TAK1/NF-κB axis.

Dysregulated hepatic lipid metabolism and gut microbiota associated with early-stage NAFLD in ASPP2-deficiency mice.

Background: Growing evidence indicates that lipid metabolism disorders and gut microbiota dysbiosis were related to the progression of non-alcoholic fatty liver disease (NAFLD). Apoptosis-stimulating p53 protein 2 (ASPP2) has been reported to protect against hepatocyte injury by regulating the lipid metabolism, but the mechanisms remain largely unknown. In this study, we investigate the effect of ASPP2 deficiency on NAFLD, lipid metabolism and gut microbiota using ASPP2 globally heterozygous knockout (ASPP2+/-) mice. Methods: ASPP2+/- Balb/c mice were fed with methionine and choline deficient diet for 3, 10 and 40 day to induce an early and later-stage of NAFLD, respectively. Fresh fecal samples were collected and followed by 16S rRNA sequencing. HPLC-MRM relative quantification analysis was used to identify changes in hepatic lipid profiles. The expression level of innate immunity-, lipid metabolism- and intestinal permeability-related genes were determined. A spearman's rank correlation analysis was performed to identify possible correlation between hepatic medium and long-chain fatty acid and gut microbiota in ASPP2-deficiency mice. Results: Compared with the WT control, ASPP2-deficiency mice developed moderate steatosis at day 10 and severe steatosis at day 40. The levels of hepatic long chain omega-3 fatty acid, eicosapentaenoic (EPA, 20:5 n-3) and docosahexaenoic (DHA, 22:6 n-3), were decreased at day 10 and increased at day 40 in ASPP+/- mice. Fecal microbiota analysis showed significantly increased alpha and beta diversity, as well as the composition of gut microbiota at the phylum, class, order, family, genus, species levels in ASPP2+/- mice. Moreover, ASPP-deficiency mice exhibited impaired intestinal barrier function, reduced expression of genes associated with chemical barrier (REG3B, REG3G, Lysozyme and IAP), and increased expression of innate immune components (TLR4 and TLR2). Furthermore, correlation analysis between gut microbiota and fatty acids revealed that EPA was significantly negatively correlated with Bifidobacterium family. Conclusion: Our findings suggested that ASPP2-deficiency promotes the progression of NAFLD, alterations in fatty acid metabolism and gut microbiota dysbiosis. The long chain fatty acid EPA was significantly negatively correlated with Bifidobacterial abundance, which is a specific feature of NAFLD in ASPP2-deficiency mice. Totally, the results provide evidence for a mechanism of ASPP2 on dysregulation of fatty acid metabolism and gut microbiota dysbiosis.

Catalytic Synthesis of Cyclopropenium Cations with Rh-Carbynoids.

Herein, we report the first catalytic one-step synthesis of cyclopropenium cations (CPCs) with readily available alkynes and hypervalent iodine reagents as carbyne sources. Key to the process is the catalytic generation of a novel Rh-carbynoid that formally transfers monovalent cationic carbynes (:+C-R) to alkynes via an oxidative [2+1] cycloaddition. Our process is able to synthesize a new type of CPC substituted with an ester group that underpins the regioselective attack of a broad range of carbon and heteroatomic nucleophiles, thus providing a new platform for the synthesis of valuable cyclopropenes difficult or not possible to make by current methodologies.

Association between the atherogenic index of plasma and major adverse cardiovascular events among non-diabetic hypertensive older adults.

BACKGROUND: Literature on the association between the atherogenic index of plasma (AIP) and the risk of major adverse cardiovascular events (MACEs) among non-diabetic hypertensive older adults is quite limited. METHODS: A post-hoc analysis of data obtained from the Systolic Blood Pressure Intervention Trial was performed. The predictive value of AIP on the risk of MACEs among non-diabetic hypertensive older adults was assessed to evaluate whether the benefit of intensive blood pressure (BP) control in preventing MACEs is consistent in different AIP subgroups. RESULTS: In this study, 9323 participants with AIP were included, out of which 561 (6.02%) had composite cardiovascular outcomes during a median of 3.22 years of follow-up. Patients in the highest AIP quartile had a significantly increased risk of the primary outcome. In the fully adjusted Model 3, the adjusted hazard ratios (HRs) of the primary outcome for participants in Q2, Q3, and Q4 of AIP were 1.32 (1.02, 1.72), 1.38 (1.05, 1.81), and 1.56 (1.17, 2.08) respectively. Consistently, the trend test for the association between AIP quartiles and the primary outcome showed that a higher AIP quartile was associated with a significantly higher risk of the primary outcome (adjusted HR (95%CI) in model 3:1.14 (1.04, 1.25), P = 0,004). However, within each AIP quartile, absolute event rates were lower in the intensive treatment group. No evidence was found for the interaction between intensive BP control and AIP for the risk of the primary outcome (P for interaction = 0.932). CONCLUSION: This study found that elevated AIP was independently and positively associated with the risk of MACEs among non-diabetic hypertensive older adults. The benefits of intensive BP control in managing cardiovascular events were consistent in different AIP subgroups.

Celastrol inhibits TXNIP expression to protect pancreatic ß cells in diabetic mice.

BACKGROUND: Celastrol (CEL) has a great potential in the treatment of a wide variety of metabolic diseases. However, whether CEL protects pancreatic ß cells and its underlying mechanism are not yet clear. PURPOSE: This study investigates to determine the effects of CEL on the pathogenesis of pancreatic ß cells damage. METHODS: C57BLKS/Leprdb (db/db) mice and rat insulinoma INS-1 cell line or mouse J774A.1 cell line were used as in vivo and in vitro models for investigating the protective effect of CEL on pancreatic ß cells under high glucose environment and the related mechanism. The phenotypic changes were evaluated by immunofluorescence, immunohistochemical staining, flow cytometry and the measurement of biochemical indexes. The molecular mechanism was explored by biological techniques such as western blotting, qPCR, ChIP-qPCR, co-immunoprecipitation and lentivirus infection. RESULTS: Our results showed that CEL at the high dose (CEL-H, 0.2 mg/kg) protects db/db mice against increased body weight and blood glucose. CEL-H inhibits pancreatic ß cell apoptosis in db/db mice and high glucose-induced INS-1 cells. CEL-H also reduced IL-1ß production in islet macrophages. The further study found that CEL suppressed TXNIP expression and NLRP3 inflammasome activation in pancreatic ß cells and islet macrophages. Importantly, the inhibitory effect of CEL on pancreatic ß cell apoptosis and IL-1ß production was also dependent on TXNIP. Mechanically, CEL inhibits Txnip transcription by promoting the degradation of ChREBP. CONCLUSION: Celastrol inhibits TXNIP expression to protect pancreatic ß cells in vivo and in vitro. Our research pointed out another mechanism by which celastrol functions under the condition leptin signaling is ineffective.

Association Between the Frailty and New-Onset Atrial Fibrillation/Flutter Among Elderly Hypertensive Patients.

Background: Frailty was found to be common in patients with atrial fibrillation/flutter (AF), but there was still a lack of evidence regarding the relationship between frailty and new-onset AF. Methods: We performed a post hoc analysis of data from the Systolic Blood Pressure Intervention Trial (SPRINT). In addition, we evaluated the relationship between baseline frailty status and new-onset AF in older adult patients with hypertension. Results: In total, 7,316 participants were included in our analysis, and a total of 115 new-onset AF occurred during an average of 3.54 years of follow-up. Using SPRINT frailty index criteria, 1,535 fit, 4,041 less fit, and 1,740 frailty were enrolled. Compared with other groups, the incidence of new-onset AF in the frailty group was significantly higher. We constructed three Cox models to assess the relationship between the frailty status (fit group as reference) and new-onset AF. Participants with frailty had a significantly higher risk of new-onset AF compared with the fit group in all the models we used. We combined the fit group and the less fit group into a no frailty group to assess the impact of frailty on new-onset AF in various subgroups. After full adjustment (Model 3), frailty remained associated with the increased risk of new-onset AF compared with the no frailty group [hazard ratio [HR] = 2.09, 95% CI:(1.41, 3.09), p < 0.001]. Additionally, we examined the frailty index as continuous variable to assess the relationship between the frailty index and new-onset AF. The smooth curve showed that log HR appeared to increase linearly. And there was a significant interaction between baseline systolic blood pressure (SBP) categories and frailty on the risk of new-onset AF (p for interaction = 0.030). Conclusion: This study found baseline frailty status was a strong independent risk factor for new-onset AF among older adult patients with hypertension. Screening for frailty should be considered in older adult patients with hypertension to prevent new-onset AF.

Limonin, an AMPK Activator, Inhibits Hepatic Lipid Accumulation in High Fat Diet Fed Mice.

NAFLD is the most prevalent liver disease in human history. The treatment is still limited yet. In the current study, we reported that limonin inhibited hepatic lipid accumulation and fatty acid synthesis in HFD fed mice. Using AMPK inhibitor and AMPK deficient C. elegans, we revealed the effect was dependent on the activation of AMPK. We found that limonin activated AMPK through inhibition of cellular energy metabolism and increasing ADP:ATP ratio. Furthermore, the treatment of limonin induced AMPK mediated suppression of the transcriptional activity of SREBP1/2. Our study suggests that limonin may a promising therapeutic agent for the treatment of NAFLD.

Diverse diterpenoids with α-glucosidase and ß-glucuronidase inhibitory activities from Euphorbia milii.

Four undescribed regular rosane-type diterpenoids euphominoids M-P and three undescribed rearranged rosane-type diterpenoids euphomilones C-E were isolated from the whole plants of Euphorbia milii Des Moul., along with nine known compounds. Their structures were elucidated by detailed interpretation of the NMR and mass spectroscopy. The absolute configurations were established by single-crystal X-ray diffraction experiments, as well as comparative analyses of calculated and experimental ECD spectra. Euphominoid M featured a highly oxygenated ring A and a rare four-membered oxygen ring while euphomilones C-E possessed 7/5/6 or 5/7/6 fused ring systems, which were rarely occurring in rosane-type diterpenoids. In the in-vitro bioassays, 19-norrosa-1,3,5(10),15-tetraene-2,3-diol and antiquorin showed more potent α-glucosidase inhibitory activity than the positive control acarbose while euphominoid C exhibited significant inhibitory activity against both α-glucosidase and ß-glucuronidase. To the best of our knowledge, it was the first time that rosane-type diterpenoids were reported as ß-glucuronidase inhibitors.

Dibenzocyclooctadiene lignans from the stems of Schisandra sphaerandra.

Chemical investigation into the stems of the medicinal plant Schisandra sphaerandra led to the isolation and identification of a new dibenzocyclooctadiene lignan sphaerandrin A (1) and 11 known ones gomisin B (2), schirubrisin B (3), kadsuphilin B (4), schizandrin (5), benzoylgomisin Q (6), angeloylgomisin Q (7), gomisin G (8), schisanwilsonin O (9), isogomisin O (10), schisantherin D (11), and wuweizisu C (12). The structure of the new compound was elucidated by comprehensive spectroscopic methods including 1 D/2D NMR, HRESIMS, and CD spectrometry. To the best of our knowledge, compounds 2 - 11 were obtained from this species for the first time. All the compounds were evaluated for the cytotoxic activity against the triple-negative breast cancer cell lines MDA-MB-231 and HCC-1937.

Anthrahydroquinone-2,6-disulfonate alleviates paraquat-induced kidney injury via the apelin-APJ pathway in rats

Objective: To explore the protective effects of anthrahydroquinone-2,6-disulfonate (AH 2 QDS) on the kidneys of paraquat (PQ) poisoned rats via the apelin-APJ pathway. Methods: Male Sprague Dawley rats were divided into four experimental groups: control, PQ, PQ+sivelestat, and PQ+AH 2 QDS. The PQ+sivelestat group served as the positive control group. The model of poisoning was established via intragastric treatment with a 20% PQ pesticide solution at 200 mg/kg. Two hours after poisoning, the PQ+sivelestat group was treated with sivelestat, while the PQ+AH 2 QDS group was given AH 2 QDS. Six rats were selected from each group on the first, third, and seventh days after poisoning and dissected after anesthesia. The PQ content of the kidneys was measured using the sodium disulfite method. Hematoxylin-eosin staining of renal tissues was performed to detect pathological changes. Apelin expression in the renal tissues was detected using immunofluorescence. Western blotting was used to detect the expression levels of the following proteins in the kidney tissues: IL-6, TNF-α, apelin-APJ (the apelin-Angiotensin receptor), NF-κB p65, caspase-1, caspase-8, glucose-regulated protein 78 (GRP78), and the C/EBP homologous protein (CHOP). In in vitro study, a PQ toxicity model was established using human tubular epithelial cells treated with standard PQ. Twenty-four hours after poisoning, sivelestat and AH 2 QDS were administered. The levels of oxidative stress in human renal tubular epithelial cells were assessed using a reactive oxygen species fluorescence probe. Results: The PQ content in the kidney tissues of the PQ group was higher than that of the PQ+AH 2 QDS group. Hematoxylin-eosin staining showed extensive hemorrhage and congestion in the renal parenchyma of the PQ group. Vacuolar degeneration of the renal tubule epithelial cells, deposition of crescent-like red staining material in renal follicles, infiltration by a few inflammatory cells, and a small number of cast formation were also observed. However, these pathological changes were less severe in the PQ+sivelestat group and the PQ+AH 2 QDS group (P<0.05). On the third day after poisoning, immunofluorescence assay showed that the level of apelin in the renal tissues was significantly higher in the PQ+AH 2 QDS group than in the PQ group. Western blotting analysis results showed that IL-6, TNF-α, NF-κB p65, caspase-1, caspase-8, GRP78, and CHOP protein levels in the PQ group were higher than in the PQ+AH 2 QDS group (P<0.05). The expression of apelin-APJ proteins in the PQ+AH 2 QDS group was higher than in the PQ+sivelestat and PQ groups (P<0.05); this difference was significant on Day 3 and Day 7. The level of oxidative stress in the renal tubular epithelial cells of the PQ+AH 2 QDS group and the PQ+sivelestat group was significantly lower than in the PQ group (P<0.05). Conclusions: This study confirms that AH 2 QDS has a protective effect on PQ-poisoned kidneys and its positive effect is superior to that of sivelestat. The mechanism of the protective effects of AH 2 QDS may be linked to reduction in cellular oxidative stress, PQ content of renal tissue, inflammatory injury, endoplasmic reticulum stress, and apoptosis. AH 2 QDS may play a role in the treatment of PQ poisoning by upregulating the expression of the apelin-APJ.

YEATS2 regulates the activation of TAK1/NF-κB pathway and is critical for pancreatic ductal adenocarcinoma cell survival.

The prognosis of pancreatic ductal adenocarcinoma (PDAC) is poor despite diagnostic progress and new chemotherapeutic regimens. Constitutive activation of NF-κB is frequently observed in PDAC. In this study, we found that YEATS2, a scaffolding protein of ATAC complex, was highly expressed in human PDAC. Depletion of YEATS2 reduced the growth, survival, and tumorigenesis of PDAC cells. The binding of YEATS2 is crucial for maintaining TAK1 activation and NF-κB transcriptional activity. Of importance, our results reveal that YEATS2 promotes NF-κB transcriptional activity through modulating TAK1 abundance and directly interacting with NF-κB as a co-transcriptional factor.

Cardiac resynchronization performed by LBBaP-CRT in patients with cardiac insufficiency and left bundle branch block.

OBJECTIVE: To evaluate the efficacy and safety of left bundle branch area pacing (LBBaP) in patients with heart failure and left bundle branch block (LBBB), and to compare the clinical effects with traditional cardiac resynchronization therapy (CRT). METHODS: Thirty-two patients with dilated cardiomyopathy complicated by cardiac insufficiency and left bundle branch block were divided into CRT group and LBBaP group. Parameters including pacing threshold, R-wave amplitude, pacing impedance and operation time, and X-ray exposure time were recorded. The left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), and left ventricular end-systolic diameter (LVESD) were examined by echocardiography. The changes of QRS complex before and after operation were compared. RESULTS: Compared with CRT group, the LBBaP group spent less time on total operation time and X-ray exposure time and had stable electrode parameters including pacing threshold, R-wave amplitude, and lead impedance after 12-month follow-up. In addition, LBBaP can achieve narrow QRS complex (117.15 ± 9.91) ms immediately than that in CRT group (130.32 ± 12.41) ms. The change of QRS between LBBaP is (50.30 ± 23.79) ms and CRT group is (33.15 ± 20.22) ms. After 6 months' follow-up in LBBaP group, EF was higher than that before operation. Followed up for 12 months after operation, EF and LVEDD in LBBaP group were significantly improved compared with those before operation. CONCLUSION: Left bundle branch area pacing is a safe and effective resynchronization method for patients with cardiac insufficiency and asynchronization, which can achieve same clinical effects to CRT.

3D printed double-network alginate hydrogels containing polyphosphate for bioenergetics and bone regeneration.

Low mechanical strength, poor processability, and low bioactivity of hydrogels limit their application in bone tissue engineering severely. Herein, a new 3D-printable, osteoinductive, and bioenergetic-active double-network (DN) hydrogel containing sodium alginate (SA), poly (ethylene glycol) diacrylate (PEGDA), and sodium polyphosphate (PolyP) was developed via a two-step method. The synergy of the covalent cross-linking network and the ionic cross-linking network improves the mechanical properties of the hydrogel. And the pre-gel with Ca2+ has better 3D printing performance to print complex tissue engineering scaffolds than common hydrogels. In addition, the incorporation of PolyP into DN hydrogel matrix significantly improves the bioactivity of hydrogels. The bioenergetic effect of PolyP improves adenosine triphosphate content of cells significantly to promote cell activities such as migration. The in vitro osseointegration investigation suggests that the orthophosphate monomer units, which are degradation fragments of PolyP, provide enough phosphoric acid units for the formation of calcium phosphate and accelerate the osteogenic differentiation of cells greatly. Therefore, the proposed printable, bioenergetic-active, osteoinductive DN hydrogel is potential to solve the problems of complex tissue engineering scaffolds and be applied in energy-crucial bone tissue regeneration.

Comparison of efficacy and safety of His-Purkinje system pacing versus cardiac resynchronisation therapy in patients with pacing-induced cardiomyopathy: protocol for a randomised controlled trial.

INTRODUCTION: Recent studies have shown that the His-Purkinje system pacing (HPSP) can achieve electrocardiomechanical synchronisation, and thus improve cardiac function. For patients with pacing-induced cardiomyopathy (PICM) who should be treated with pacemaker upgrade, the HPSP is a viable alternative to cardiac resynchronisation therapy (CRT). However, no randomised controlled trial has been performed to evaluate the efficacy and safety of HPSP in patients with PICM. The present study compared the efficacy and safety of HPSP with that of traditional CRT in the treatment of patients with PICM. METHODS AND ANALYSIS: This study is a single-centre, randomised controlled non-inferiority trial. This trial was carried out at the cardiac centre of Beijing Anzhen Hospital. A total of 46 patients with PICM who needed pacemaker upgrade treatment between January 2022 and December 2023 will be enrolled in this study. Patients will be randomised into an investigational group (HPSP) and a control group (CRT) at a 1:1 ratio. The primary outcome is the duration of QRS complex (QRS width), and the secondary outcomes are NT-proBNP (N terminal pro B type natriuretic peptide), C reactive protein, the number of antibiotics used, left ventricular ejection fraction, end systolic volume, end diastolic volume, the hospitalisation duration, the incidence of postoperative infection, pacemaker parameters (threshold, sensing and impedance), the 6-minute walking test, and quality of life (36-Item Short Form Survey scale), all-cause mortality, cardiovascular death, heart failure-related rehospitalisation rate, other rehospitalisation rates, major complication rates and procedure costs. ETHICS AND DISSEMINATION: This study has been approved by the Beijing Anzhen Hospital Medical Ethics Committee (No. 2020043X). TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR2000034265).

Nobiletin Alleviates Non-alcoholic Steatohepatitis in MCD-Induced Mice by Regulating Macrophage Polarization.

Non-alcoholic steatohepatitis (NASH) is an inflammatory disorder that is characterized by chronic activation of the hepatic inflammatory response and subsequent liver damage. The regulation of macrophage polarization in liver is closely related to the progression of NASH. The orphan nuclear receptor retinoic-acid-related orphan receptor α (RORα) and Krüppel-like factor 4 (KLF4) are key regulators which promote hepatic macrophages toward M2 phenotype and protect against NASH in mice. Nobiletin (NOB), a natural polymethoxylated flavone, is previously reported as a RORα regulator in diet-induced obese mice. However, it is still unclear whether NOB has the protective effect on NASH. In this study, we investigated the role of NOB in NASH using a methionine and choline deficient (MCD)-induced NASH mouse model. Our results showed that NOB ameliorated hepatic damage and fibrosis in MCD fed mice. NOB treatment reduced the infiltration of macrophages and neutrophils in the liver in MCD-fed mice. Of importance, NOB significantly increased the proportion of M2 macrophages and the expression of anti-inflammatory factors in vivo and in vitro. Meanwhile, NOB also decreased the population of M1 macrophages and the expression of proinflammatory cytokines. Mechanistically, NOB elevated KLF4 expression in macrophages. Inhibition of KLF4 abolished NOB regulated macrophage polarization. Furthermore, the regulation of NOB in KLF4 expression was dependent on RORα.

Study on the Curative Effect and Safety of Radiofrequency Catheter Ablation of Paroxysmal Atrial Fibrillation via Zero-Fluoroscopy Transseptal Puncture under the Dual Guidance of Electroanatomical Mapping and Intracardiac Echocardiography.

AIMS: 3D electroanatomical mapping combined with intracardiac echocardiography- (EAM-ICE-) guided transseptal puncture has been proven safe and effective during the radiofrequency catheter ablation (RFCA) procedure used to treat paroxysmal atrial fibrillation (PAF). In this study, we aimed to compare the curative effect and safety of RFCA via F (fluoroscopy) and zero-fluoroscopy transseptal puncture guided by EAM-ICE in patients with PAF. METHODS AND RESULTS: A prospective study in which 110 patients with PAF were included and assigned to two groups was conducted. Fifty-five (50%) patients were enrolled in the EAM-ICE group, whereas the other 55 (50%) patients were enrolled in the F group. There were no significant differences in baseline characteristics between the two groups. The transseptal duration time was longer in the EAM-ICE group (19.8 ± 3.0 min vs. 8.6 ± 1.2 min, p ≤ 0.01); however, fluoroscopy was not used in the EAM-ICE group compared with the F group (0 mGy vs. 109.1 ± 57.9 mGy). Similarly, there was also no significant difference in the recurrence rate of atrial fibrillation between the EAM-ICE and F groups (25.5% vs. 18.2%, p=0.356). CONCLUSION: RFCA via EAM-ICE-guided zero-fluoroscopy transseptal puncture in patients with PAF is safe and effective for long-term follow-up.

Efficacy and safety of left bundle branch area pacing versus right ventricular apex pacing in patients with atrioventricular block: study protocol for a randomised controlled trial.

INTRODUCTION: Left bundle branch area pacing (LBBaP) is a relatively new approach for physiologic pacing. A limited number of retrospective clinical studies, featuring small sample sizes, have shown that compared with right ventricular apex pacing (RVAP), the QRS duration of postoperative ECG in LBBaP patients is narrower and the cardiac systolic function is improved. However, there have been no randomised controlled trials (RCTs) evaluating the efficacy and safety of LBBaP in patients with atrioventricular block (AVB). Therefore, the current study intends to address the paucity in RCT data evaluating LBBaP versus RVAP in AVB patients. ANALYSIS AND METHODS: This study is a single-centre, randomised controlled superiority trial to be conducted at the Cardiac Centre of Beijing Anzhen Hospital. From January 2021 to December 2023, 210 consecutive AVB patients meeting the inclusion criteria and receiving pacemaker implantation will be enrolled. Participants will be randomly divided into an experimental group (LBBaP) and a control group (RVAP) at a 1:1 ratio. The primary outcome is left ventricular ejection fraction (LVEF), which will be assessed by echocardiography. The secondary outcomes in this study are synchrony of left ventricular systole, NT-proBNP, LVEDD, the 6-min walk distance, quality of life (SF-36 scale), all-cause mortality, cardiovascular death events, rehospitalisation rate and major complication rate. ETHICS AND DISSEMINATION: This study was approved by the Medical Ethics Committee of Beijing Anzhen Hospital (No. 2020021X). The results of the trial will be presented at national and international conferences. We hypothesise that compared with RVAP, LBBaP will be superior for treating patients with AVB. This trial will provide evidence-based suggestion for the majority of electrophysiologists in pacing implantation. TRIAL REGISTRATION: ChiCTR2000034335.