AMPK Attenuation of ß-Adrenergic Receptor-Induced Cardiac Injury via Phosphorylation of ß-Arrestin-1-ser330.

BACKGROUND: ß-adrenergic receptor (ß-AR) overactivation is a major pathological cue associated with cardiac injury and diseases. AMPK (AMP-activated protein kinase), a conserved energy sensor, regulates energy metabolism and is cardioprotective. However, whether AMPK exerts cardioprotective effects via regulating the signaling pathway downstream of ß-AR remains unclear. METHODS: Using immunoprecipitation, mass spectrometry, site-specific mutation, in vitro kinase assay, and in vivo animal studies, we determined whether AMPK phosphorylates ß-arrestin-1 at serine (Ser) 330. Wild-type mice and mice with site-specific mutagenesis (S330A knock-in [KI]/S330D KI) were subcutaneously injected with the ß-AR agonist isoproterenol (5 mg/kg) to evaluate the causality between ß-adrenergic insult and ß-arrestin-1 Ser330 phosphorylation. Cardiac transcriptomics was used to identify changes in gene expression from ß-arrestin-1-S330A/S330D mutation and ß-adrenergic insult. RESULTS: Metformin could decrease cAMP/PKA (protein kinase A) signaling induced by isoproterenol. AMPK bound to ß-arrestin-1 and phosphorylated Ser330 with the highest phosphorylated mass spectrometry score. AMPK activation promoted ß-arrestin-1 Ser330 phosphorylation in vitro and in vivo. Neonatal mouse cardiomyocytes overexpressing ß-arrestin-1-S330D (active form) inhibited the ß-AR/cAMP/PKA axis by increasing PDE (phosphodiesterase) 4 expression and activity. Cardiac transcriptomics revealed that the differentially expressed genes between isoproterenol-treated S330A KI and S330D KI mice were mainly involved in immune processes and inflammatory response. ß-arrestin-1 Ser330 phosphorylation inhibited isoproterenol-induced reactive oxygen species production and NLRP3 (NOD-like receptor protein 3) inflammasome activation in neonatal mouse cardiomyocytes. In S330D KI mice, the ß-AR-activated cAMP/PKA pathways were attenuated, leading to repressed inflammasome activation, reduced expression of proinflammatory cytokines, and mitigated macrophage infiltration. Compared with S330A KI mice, S330D KI mice showed diminished cardiac fibrosis and improved cardiac function upon isoproterenol exposure. However, the cardiac protection exerted by AMPK was abolished in S330A KI mice. CONCLUSIONS: AMPK phosphorylation of ß-arrestin-1 Ser330 potentiated PDE4 expression and activity, thereby inhibiting ß-AR/cAMP/PKA activation. Subsequently, ß-arrestin-1 Ser330 phosphorylation blocks ß-AR-induced cardiac inflammasome activation and remodeling.

TP53-inducible putative long noncoding RNAs encode functional polypeptides that suppress cell proliferation.

Polypeptides encoded by long noncoding RNAs (lncRNAs) are a novel class of functional molecules. However, whether these hidden polypeptides participate in the TP53 pathway and play a significant biological role is still unclear. Here, we discover that TP53-regulated lncRNAs can encode peptides, two of which are functional in various human cell lines. Using ribosome profiling and RNA-seq approaches in HepG2 cells, we systematically identified more than 300 novel TP53-regulated lncRNAs and further confirmed that 15 of these TP53-regulated lncRNAs encode peptides. Furthermore, several peptides were validated by mass spectrometry. Ten of the novel translational lncRNAs are directly inducible by TP53 in response to DNA damage. We show that the TP53-inducible peptides TP53LC02 and TP53LC04, but not their lncRNAs, can suppress cell proliferation. TP53LC04 peptide also has a function associated with cell proliferation by regulating the cell cycle in response to DNA damage. This study shows that TP53-regulated lncRNAs can encode new functional peptides, leading to the expansion of the TP53 tumor-suppressor network and providing novel potential targets for cancer therapy.

Bis-sulfonamido-2-phenylbenzoxazoles Validate the GroES/EL Chaperone System as a Viable Antibiotic Target.

We recently reported on small-molecule inhibitors of the GroES/GroEL chaperone system as potential antibiotics against Escherichia coli and the ESKAPE pathogens but were unable to establish GroES/GroEL as the cellular target, leading to cell death. In this study, using two of our most potent bis-sulfonamido-2-phenylbenzoxazoles (PBZs), we established the binding site of the PBZ molecules using cryo-EM and found that GroEL was the cellular target responsible for the mode of action. Cryo-EM revealed that PBZ1587 binds at the GroEL ring-ring interface (RRI). A cellular reporter assay confirmed that PBZ1587 engaged GroEL in cells, but cellular rescue experiments showed potential off-target effects. This prompted us to explore a closely related analogue, PBZ1038, which is also bound to the RRI. Biochemical characterization showed potent inhibition of Gram-negative chaperonins but much lower potency of chaperonin from a Gram-positive organism, Enterococcus faecium. A cellular reporter assay showed that PBZ1038 also engaged GroEL in cells and that the cytotoxic phenotype could be rescued by a chromosomal copy of E. faecium GroEL/GroES or by expressing a recalcitrant RRI mutant. These data argue that PBZ1038's antimicrobial action is exerted through inhibition of GroES/GroEL, validating this chaperone system as an antibiotic target.

Subcellular localization and relevant mechanisms of human cancer-related micropeptides.

Rapid advances in high-quality sequencing and bioinformatics have invalidated the argument that noncoding RNAs (ncRNAs) are junk transcripts that do not encode proteins. Increasing evidence suggests that small open reading frames (sORFs) in ncRNAs can encode micropeptides and polypeptides within 100 amino acids in length. Several micropeptides have been characterized and proven to have various functions in human physiology and pathology, particularly in cancer. The present review mainly highlights the latest studies on ncRNA-encoded micropeptides in different cancers and categorizes them based on their subcellular localization, thereby providing a theoretical basis for micropeptide applications in the early diagnosis and prognosis of cancer and as therapeutic targets. However, considering the inherent characteristics of micropeptides and the limitations of the assay technology methods, more detailed information is warranted.

Association of maternal phthalates exposure and metabolic gene polymorphisms with congenital heart diseases: a multicenter case-control study.

BACKGROUND: The majority of congenital heart diseases (CHDs) are thought to result from the interactions of genetics and the environment factors. This study aimed to assess the association of maternal non-occupational phthalates exposure, metabolic gene polymorphisms and their interactions with risk of CHDs in offspring. METHODS: A multicenter case-control study of 245 mothers with CHDs infants and 268 control mothers of health infant was conducted from six hospitals. Maternal urinary concentrations of eight phthalate metabolites were measured by ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS). Twenty single nucleotide polymorphisms (SNPs) in cytochrome P450 family 2 subfamily C member 9 (CYP2C9) and 19 (CYP2C19), uridine diphosphate (UDP) glucuronosyl transferase family 1 member A7 (UGT1A7), family 2 member B7 (UGT2B7) and B15(UGT2B15) genes were genotyped. The multivariate logistic regressions were used to estimate the association between maternal phthalates exposure or gene polymorphisms and risk of CHDs. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-gene and gene-phthalates exposure interactions. RESULTS: There was no significant difference in phthalate metabolites concentrations between the cases and controls. No significant positive associations were observed between maternal exposure to phthalates and CHDs. The SNPs of UGT1A7 gene at rs4124874 (under three models, log-additive: aOR = 1.74, 95% CI:1.28-2.37; dominant: aOR = 1.86, 95% CI:1.25-2.78; recessive: aOR = 2.50, 95% CI: 1.26-4.94) and rs887829 (under the recessive model: aOR = 13.66, 95% CI: 1.54-121) were significantly associated with an increased risk of CHDs. Furthermore, the associations between rs4124874 (under log-additive and dominant models) of UGT1A7 were statistically significant after the false discovery rate correction. No significant gene-gene or gene-phthalate metabolites interactions were observed. CONCLUSIONS: The polymorphisms of maternal UGT1A7 gene at rs4124874 and rs887829 were significantly associated with an increased risk of CHDs. More large-scale studies or prospective study designs are needed to confirm or refute our findings in the future.

Does Increasing the Bend Angle of a Stylet to 90° Increase the Nasotracheal Intubation Success Rate?

BACKGROUND: Video-stylet-guided nasotracheal intubation (NTI) is an effective technique for airway management. However, the impact of the bend angle on the success rate of intubation remains unclear. PURPOSE: Does increasing the bend angle of a stylet to 90° increase NTI success rate?. STUDY DESIGN, SETTING, SAMPLE: This prospective randomized controlled trial was conducted in the operating room of a population-based hospital. Adult patients requiring NTI were recruited. PREDICTOR/EXPOSURE/INDEPENDENT VARIABLE: The primary predictor variable is the choice of stylet bend angle (90° vs 70° bend) in NTI. MAIN OUTCOME VARIABLE(S): The primary outcome variables were success rates of NTI, defined as the proportion of successful intubation cases to total cases. COVARIATES: Demographics, intubation time, the distance from the thyroid prominence to the nostril, additional maneuvers applied during intubation, and cases of epistaxis were recorded. ANALYSES: The student's t-test was used to compare continuous variables between groups. Ordinal data (intubation attempts, head extension, and epistaxis) were analyzed using the Wilcoxon rank-sum test. As appropriate, frequency (external pharyngeal pressure) was analyzed using the χ2 test or Fisher's exact test. A P value of <.05 was considered statistically significant. RESULTS: Of the 103 subjects assessed for eligibility, 98 were enrolled in the study. The mean age (27.0 ± 6.9 years vs 27.0 ± 4.1 years, P = .972) and sex differences (male/female: 9/40 vs 7/42, P = .136) were comparable between groups. The overall success rate in the 70° group was significantly lower than that in the 90° group (91.8 vs 100%, P < .001). The intubation time in the 70° group was significantly longer than that in the 90° group (43.2 ± 15.8 s vs 33.7 ± 7.3 s, P < .001). CONCLUSIONS AND RELEVANCE: A 90° bend angle of the stylet significantly improves the likelihood of successful NTI.

Pancreatic metastasis of extra-skeletal mesenchymal chondrosarcoma diagnosed by ultrasound endoscopy-guided fine-needle aspiration.

A 47-year-old man with a history of ESMC resection of the left chest wall seven years ago was admitted to our hospital due to mid-upper abdominal pain and jaundice for more than 10 days. Laboratory tests showed elevated direct bilirubin, alanine aminotransferase, gamma-glutamyltranspeptidase, and alkaline phosphatase. Computed tomography (CT) of the abdomen revealed soft tissue mass in the head and body of the pancreas with irregularly shaped calcifications, and an enhanced scan showed heterogeneous enhancement. Combined with the patient's past medical history, the possibility of pancreatic metastasis of ESMC was considered. After anti-inflammatory, hepatoprotective, and cholagogical treatment jaundice improved, and ultrasound endoscopy-guided fine-needle aspiration (EUS-FNA) was performed to clarify the nature of the mass, which showed a 4.1*4.2 cm mixed echogenic area with internal calcification in the head of the pancreas. Aspiration pathology showed proliferation of short spindle and round cells into nests, the immunohistochemistry stain showed CD99 (+); CD34, CD117, Dog-1, and S-100 were negative. Pancreatic metastasis of ESMC was diagnosed. Four months later, endoscopic biliary metal stent drainage (EMBD) was performed when the patient developed obstructive jaundice again due to lesion progression. PET/CT at a 2-year follow-up showed multiple high-density calcifications and abnormally increased FDG metabolism throughout the body.

Bridging polyp in an anastomosis resected by endoscopic submucosal dissection (ESD).

A 60-year-old man was admitted to our hospital for routine postoperative review of colon cancer. He underwent a colonoscopy, which showed a bridge-like polyp located 13 cm from the anal verge, with the base of the polyp located 1.5 cm above the anastomosis and the head of it located on the anastomosis and fusion growth with the anastomosiz. The patient accepted ESD to remove the lesion. During the ESD procedure, the basal of the polyp was incised using an insulated-tip knife, when the polyp tip located at the anastomosis was gradually dissected with a hook knife, severe fibrosis and three staples was found in the submucosal. We carefully separated the scar tissue and pulled out staples with hook knife in electrocision mode. Finally, we removed the lesion completely.

A regioselective [3 + 2] cycloaddition reaction of 2-benzylidene-1-indenones with functional olefins to access indanone-fused 2D/3D skeletons.

The regioselective [3 + 2] cycloaddition reaction of 2-benzylidene-1-indenones with functional olefins was established with DABCO as a base under mild conditions. Using this approach, a series of diversely substituted indanone-fused cyclopentane polycycles with highly crowded multiple substituents were synthesized in high yields.

Regio- and diastereoselective synthesis of diverse spirocyclic indenes by cyclization with indene-dienes as two carbon building blocks.

We report a base-promoted cyclization with indene-dienes as two carbon building blocks toward diverse spirocyclic indene scaffolds including hexacyclic spiroindenes bearing benzo pyran motifs and pentacyclic spiroindenes containing oxindole units in high yields with excellent diastereoselectivities.

Clinical observation of dexmedetomidine nasal spray in the treatment of sleep disorders on the first night after undergoing maxillofacial surgery: a single-center double-blind randomized controlled study.

Purpose: Dexmedetomidine exerts a sedative effect by promoting the sleep pathway endogenously and producing a state similar to N2 sleep. This study aimed to study the efficacy and safety of dexmedetomidine nasal spray in the treatment of postoperative sleep disturbance. Methods: This study enrolled 120 participants [men and women; age, 18-40 years; American Society of Anesthesiologists grade, I or II] who underwent maxillofacial surgery under general anesthesia through nasotracheal intubation. The participants were randomly divided into three groups: blank control group (BC group), 1.0 µg/kg dexmedetomidine group (1.0 Dex group), and 1.5 µg/kg dexmedetomidine group (1.5 Dex group), with 40 patients allocated to each group. At 21:30 on the night after the operation, the intervention groups were administered their corresponding doses of dexmedetomidine nasal spray. The Pittsburgh Sleep Quality Index (PSQI) scale was used to evaluate the baseline sleep status of participants 1 month preoperatively and on the night after the operation. Polysomnography (PSG) was used to record the sleep status on the night after the operation. We recorded the rescue times of sedative and analgesic drugs on the first night after surgery, adverse reactions, total hospital stay duration, and total costs. Results: Compared with patients in the BC group, those in 1.0 Dex and 1.5 Dex groups had longer N2 sleep duration, were awake for a shorter time after dose administration, woke up less often, and had significantly improved sleep efficiency (p < 0.05). Compared with the BC group, the PSQI scores of 1.0 Dex and 1.5 Dex groups were significantly lower on the night after operation, and the proportion of PSQI > 5 was significantly lower (p < 0.05). Compared with patients in the BC group and the 1.0 Dex group, those in the 1.5 Dex group had significantly prolonged N3 sleep, reduced frequency of requiring sufentanil rescue, lower incidence of sore throat after surgery, and shorter average length of hospital stay (all, p < 0.05). Conclusion: The sleep quality of participants on the night after having undergone maxillofacial surgery was safely and effectively improved by 1.0-1.5 µg/kg dexmedetomidine atomized nasal sprays. Notably, only the latter could prolong N3 sleep. Level of Evidence II: Evidence was obtained from at least one properly designed randomized controlled trial.

The changing epidemiology of syndactyly in Chinese newborns: a nationwide surveillance-based study.

BACKGROUND: Little is known about the epidemiologic features of syndactyly (SD) in Chinese newborns. METHODS: Using 2007-2019 data from the Chinese Birth Defects Monitoring Network, we conducted a prevalence analysis on overall, isolated and associated syndactyly according to birth year, maternal age, maternal residence, geographic region and infant sex, with special interests in time trends, perinatal outcomes and clinical phenotypes. RESULTS: A total of 13,611 SD cases were identified among 24,157,719 births in the study period, yielding the prevalence of 5.63, 4.66 and 0.97 per 10,000 for overall, isolated, and associated SD, respectively. The prevalence of each type of SD exhibited an upward trend over the period. The prevalence of overall SD varied significantly by maternal residence (urban vs. rural, 6.69/10,000 vs. 4.35/10,000), maternal age (< 20 years, 5.43/10,000; 20-24 years, 5.03/10,000; 25-29 year, 5.65/10,000; 30-34 years, 6.07/10,000; ≥ 35 years, 5.76/10,000), geographic region (central, 5.07/10,000; east, 6.75/10,000; west, 5.12/10,000), and infant sex (male vs. female, 6.28/10,000 vs. 4.86/10,000). Newborns with associated SD were more likely to be born prematurely (29.2% vs. 10.6%) or with low birthweight (30.5% vs.9.8%) than those with isolated SD. The bilaterally, and unilaterally affected cases accounted for 18.4% and 76.7%, respectively. The feet were more frequently involved (64.3%) in those bilaterally affected cases, while right side preference (right vs left: 53.8% vs 46.2%) and upper limbs preference (hand vs foot: 50.8% vs 48.0%) were found in unilateral cases. CONCLUSIONS: The prevalence of syndactyly in China is on the rise and notably higher than that in other Asian and European countries, highlighting the importance of investigating the etiology, epidemiology, and clinical implications of this condition in the Chinese population.

Epidemiology and prevalence of pulmonary sequestration in Chinese population, 2010-2019.

BACKGROUND: Pulmonary sequestration (PS) is the second common congenital lung malformation and has been known for over 150 years. However, there is a scarcity of epidemiological studies on it. This study aimed to characterize the epidemiology of pulmonary sequestration in Chinese population in the recent decade by using a nationwide database. METHODS: Using data from the Chinese Birth Defects Monitoring Network during 2010-2019, the prevalence rates for PS were calculated by birth year, maternal age, residence area, geographical region, and infant sex. Variations in prevalence and changes over time were further examined. Other variables of interest for analysis included the pregnancy outcomes of affected infants, the prenatal diagnosis, and the co-occurring anomalies of PS cases. RESULTS: During the study period, we identified an average prevalence rate of 0.31, 0.11, and 0.42 per 10,000 live and still births for the isolated, non-isolated, and overall PS, respectively. An upward trend was observed for each category of PS. The prevalence rates varied significantly by maternal age (< 20 years, 0.34/10,000; 20-24 years, 0.33/10,000; 25-29 years, 0.45/10,000; 30-34 years, 0.46/10,000; ≥ 35 years, 0.36/10,000), residence area (urban vs. rural, 0.51/10,000 vs. 0.30/10,000), geographical region (western, 0.33/10,000; eastern, 0.49/10,000; central, 0.43/10,000), and by infant sex (male vs. female, 0.45/10,000 vs. 0.38/10,000). Non-isolated PS cases were more likely born prematurely than isolated cases (15.29% vs. 7.83%). 40.28% and 33.80% of non-isolated cases were accompanied by additional respiratory, and circulatory system malformations, respectively. CONCLUSIONS: The study presents for the first time the prevalence of pulmonary sequestration in Chinese population. The rising prevalence and relatively poor perinatal outcome of affected fetuses or newborns indicate the necessity to improve perinatal management of PS.

Clinical characteristics of patients with prenatal hydronephrosis in early postnatal period: a single center retrospective study.

BACKGROUND: The study aims to investigate the clinical characteristics of early postnatal period in children with prenatal hydronephrosis (HN) in our single center for 8 years. STUDY DESIGN: The clinical data of 1137 children with prenatal HN from 2012 to 2020 were retrospectively analyzed in our center. Variables of our study mainly included different malformations and urinary tract dilation (UTD) classification, and main outcomes were recurrent hospitalization, urinary tract infection (UTI), jaundice, and surgery. RESULTS: Among the 1137 children with prenatal HN in our center, 188 cases (16.5%) were followed-up in early postnatal period, and 110 cases (58.5%) were found malformations. The incidence of recurrent hospitalization (29.8%) and UTI (72.5%) were higher in malformation, but the incidence of jaundice (46.2%) was higher in non-malformation(P < 0.001). Furthermore, UTI and jaundice were higher in vesicoureteral reflux (VUR) than those in uretero-pelvic junction obstruction (UPJO) (P < 0.05). Meanwhile, Children with UTD P2 and UTD P3 were prone to recurrent UTI, but UTD P0 was prone to jaundice (P < 0.001). In addition, 30 cases (16.0%) of surgery were all with malformations, and the surgical rates of UTD P2 and UTD P3 were higher than those of UTD P0 and UTD P1 (P < 0.001). Lastly, we concluded that the first follow-up should be less than 7 days, the first assessment should be 2 months, and the follow up should be at least once every 3 months. CONCLUSION: Children with prenatal HN have been found many malformations in early postnatal period, and with high-grade UTD were more prone to recurrent UTI, even to surgery. So, prenatal HN with malformations and high-grade UTD should be followed up in early postnatal period regularly.

Exercise Training Attenuates Acute ß-Adrenergic Receptor Activation-Induced Cardiac Inflammation via the Activation of AMP-Activated Protein Kinase.

Exercise has proven cardiac benefits, but the underlying mechanisms of exercise that protect the heart from acute sympathetic stress injuries remain unknown. In this study, adult C57BL/6J mice and their AMP-activated protein kinase α2 knockout (AMPKα2-/-) littermates were either subjected to 6 weeks of exercise training or housed under sedentary conditions and then treated with or without a single subcutaneous injection of the ß-adrenergic receptor (ß-AR) agonist isoprenaline (ISO). We investigated the differences in the protective effects of exercise training on ISO-induced cardiac inflammation in wild-type (WT) and AMPKα2-/- mice using histology, enzyme-linked immunosorbent assay (ELISA) and Western blotting analyses. The results indicated that exercise training alleviated ISO-induced cardiac macrophage infiltration, chemokines and the expression of proinflammatory cytokines in wild-type mice. A mechanism study showed that exercise training attenuated the ISO-induced production of reactive oxygen species (ROS) and the activation of NLR Family, pyrin domain-containing 3 (NLRP3) inflammasomes. In cardiomyocytes, the ISO-induced effects on these processes were inhibited by AMP-activated protein kinase (AMPK) activator (metformin) pretreatment and reversed by the AMPK inhibitor (compound C). AMPKα2-/- mice showed more extensive cardiac inflammation following ISO exposure than their wild-type littermates. These results indicated that exercise training could attenuate ISO-induced cardiac inflammation by inhibiting the ROS-NLRP3 inflammasome pathway in an AMPK-dependent manner. Our findings suggested the identification of a novel mechanism for the cardioprotective effects of exercise.

Ligation-assisted endoscopic mucosal resection for duodenal neuroendocrine tumor.

Endoscopic treatment has become a preferred method for neuroendocrine tumors (NETs) of the gastrointestinal tract.Here we report a 72-year-old female with a duodenal neuroendocrine tumor treated by ligation-assisted endoscopic mucosal resection. This treatment was effectively used to cure the duodenal NETs and ensured complete resection without residual positive margins. This case report is rare.

Cyanotoxins, biosynthetic gene clusters, and factors modulating cyanotoxin biosynthesis.

Cyanobacterial harmful algal blooms (CHABs) are a global environmental concern that encompasses public health issues, water availability, and water quality owing to the production of various secondary metabolites (SMs), including cyanotoxins in freshwater, brackish water, and marine ecosystems. The frequency, extent, magnitude, and duration of CHABs are increasing globally. Cyanobacterial species traits and changing environmental conditions, including anthropogenic pressure, eutrophication, and global climate change, together allow cyanobacteria to thrive. The cyanotoxins include a diverse range of low molecular weight compounds with varying biochemical properties and modes of action. With the application of modern molecular biology techniques, many important aspects of cyanobacteria are being elucidated, including aspects of their diversity, gene-environment interactions, and genes that express cyanotoxins. The toxicological, environmental, and economic impacts of CHABs strongly advocate the need for continuing, extensive efforts to monitor cyanobacterial growth and to understand the mechanisms regulating species composition and cyanotoxin biosynthesis. In this review, we critically examined the genomic organization of some cyanobacterial species that lead to the production of cyanotoxins and their characteristic properties discovered to date.

Fabrication of Pillar-Cage Fluorinated Anion Pillared Metal-Organic Frameworks via a Pillar Embedding Strategy and Efficient Separation of SO2 through Multi-Site Trapping.

Flue gas desulfurization is crucial for both human health and ecological environments. However, developing efficient SO2 adsorbents that can break the trade-off between adsorption capacity and selectivity is still challenging. In this work, a new type of fluorinated anion-pillared metal-organic frameworks (APMOFs) with a pillar-cage structure is fabricated through pillar-embedding into a highly porous and robust framework. This type of APMOFs comprises smaller tetrahedral cages and larger icosahedral cages interconnected by embedded [NbOF5 ]2- and [TaOF5 ]2- anions acting as pillars. The APMOFs exhibits high porosity and density of fluorinated anions, ensuring exceptional SO2 adsorption capacity and ultrahigh selectivity for SO2 /CO2 and SO2 /N2 gas mixtures. Furthermore, these two structures demonstrate excellent stability towards water, acid/alkali, and SO2 adsorption. Cycle dynamic breakthrough experiments confirm the excellent separation performance of SO2 /CO2 gas mixtures and their cyclic stability. SO2 -loaded single-crystal X-ray diffraction, Grand canonical Monte Carlo (GCMC) simulations combined with density functional theory (DFT) calculations reveal the preferred adsorption domains for SO2 molecules. The multiple-site host-guest and guest-guest interactions facilitate selective recognition and dense packing of SO2 in this hybrid porous material. This work will be instructive for designing porous materials for flue gas desulfurization and other gas-purification processes.

IMM-H007 attenuates isoprenaline-induced cardiac fibrosis through targeting TGFß1 signaling pathway.

Upon chronic stress, ß-adrenergic receptor activation induces cardiac fibrosis and leads to heart failure. The small molecule compound IMM-H007 has demonstrated protective effects in cardiovascular diseases via activation of AMP-activated protein kinase (AMPK). This study aimed to investigate IMM-H007 effects on cardiac fibrosis induced by ß-adrenergic receptor activation. Because adenosine analogs also exert AMPK-independent effects, we assessed AMPK-dependent and -independent IMM-H007 effects in murine models of cardiac fibrosis. Continual subcutaneous injection of isoprenaline for 7 days caused cardiac fibrosis and cardiac dysfunction in mice in vivo. IMM-H007 attenuated isoprenaline-induced cardiac fibrosis, diastolic dysfunction, α-smooth muscle actin expression, and collagen I deposition in both wild-type and AMPKα2-/- mice. Moreover, IMM-H007 inhibited transforming growth factor ß1 (TGFß1) expression in wild-type, but not AMPKα2-/- mice. By contrast, IMM-H007 inhibited Smad2/3 signaling downstream of TGFß1 in both wild-type and AMPKα2-/- mice. Surface plasmon resonance and molecular docking experiments showed that IMM-H007 directly interacts with TGFß1, inhibits its binding to TGFß type II receptors, and downregulates the Smad2/3 signaling pathway downstream of TGFß1. These findings suggest that IMM-H007 inhibits isoprenaline-induced cardiac fibrosis via both AMPKα2-dependent and -independent mechanisms. IMM-H007 may be useful as a novel TGFß1 antagonist.

Glibenclamide alleviates ß adrenergic receptor activation-induced cardiac inflammation.

ß-Adrenergic receptor (ß-AR) overactivation is a major pathological factor associated with cardiac diseases and mediates cardiac inflammatory injury. Glibenclamide has shown anti-inflammatory effects in previous research. However, it is unclear whether and how glibenclamide can alleviate cardiac inflammatory injury induced by ß-AR overactivation. In the present study, male C57BL/6J mice were treated with or without the ß-AR agonist isoprenaline (ISO) with or without glibenclamide pretreatment. The results indicated that glibenclamide alleviated ISO-induced macrophage infiltration in the heart, as determined by Mac-3 staining. Consistent with this finding, glibenclamide also inhibited ISO-induced chemokines and proinflammatory cytokines expression in the heart. Moreover, glibenclamide inhibited ISO-induced cardiac fibrosis and dysfunction in mice. To reveal the protective mechanism of glibenclamide, the NLRP3 inflammasome was further analysed. ISO activated the NLRP3 inflammasome in both cardiomyocytes and mouse hearts, but this effect was alleviated by glibenclamide pretreatment. Furthermore, in cardiomyocytes, ISO increased the efflux of potassium and the generation of ROS, which are recognized as activators of the NLRP3 inflammasome. The ISO-induced increases in these processes were inhibited by glibenclamide pretreatment. Moreover, glibenclamide inhibited the cAMP/PKA signalling pathway, which is downstream of ß-AR, by increasing phosphodiesterase activity in mouse hearts and cardiomyocytes. In conclusion, glibenclamide alleviates ß-AR overactivation-induced cardiac inflammation by inhibiting the NLRP3 inflammasome. The underlying mechanism involves glibenclamide-mediated suppression of potassium efflux and ROS generation by inhibiting the cAMP/PKA pathway.