Ubiquitin specific protease 38 aggravates pathological cardiac remodeling by stabilizing phospho-TBK1.

Chronic pressure overload can cause pathological cardiac remodeling and eventually heart failure. The ubiquitin specific protease (USP) family proteins play a prominent role in regulating substrate protein degradation and cardiac structural and functional homeostasis. Although USP38 is expressed in the heart, uncertainty exists regarding the function of USP38 in pathological cardiac remodeling. We constructed and generated cardiac specific USP38 knockout mice and cardiac specific USP38 overexpression mice to assess the role of USP38 in pathological cardiac remodeling. Furthermore, we used co-immunoprecipitation (Co-IP) assays and western blot analysis to identify the molecular interaction events. Here, we reported that the expression of USP38 is significantly elevated under a hypertrophic condition in vivo and in vitro. USP38 deletion significantly mitigates cardiomyocyte enlargement in vitro and hypertrophic effect induced by pressure overload, while overexpression of USP38 markedly aggravates cardiac hypertrophy and remodeling. Mechanistically, USP38 interacts with TANK-binding kinase 1 (TBK1) and removes K48-linked polyubiquitination of TBK1, stabilizing p-TBK1 and promoting the activation of its downstream mediators. Overexpression of TBK1 in the heart of cardiac specific USP38 knockout mice partially counteracts the benefit of USP38 deletion on pathological cardiac remodeling. The TBK1 inhibitor Amlexanox significantly alleviates pressure overload induced-cardiac hypertrophy and myocardial fibrosis in mice with USP38 overexpression. Our results demonstrate that USP38 serves as a positive regulator of pathological cardiac remodeling and suggest that targeting the USP38-TBK1 axis is a promising treatment strategy for hypertrophic heart failure.

Comparative analysis of the fecal microbiota of healthy and injured common kestrel (Falco tinnunculus) from the Beijing Raptor Rescue Center.

The gut microbiota is a complex ecosystem that interacts with many other factors to affect the health and disease states of the host. The common kestrel (Falco tinnunculus) is protected at the national level in China. However, the available sequencing data of the gut microbiota from the feces of wild common kestrels, especially for being rescued individuals by professional organization, remains limited. In the present study, we characterized the fecal bacterial communities of healthy and injured common kestrels, and compared the structure of their fecal microbiota by analyzing the V3-V4 region of the 16S rRNA gene using high-throughput sequencing technology with the Illumina MiSeq platform. We found that Firmicutes, Proteobacteria and Actinobacteria were the most predominant phyla in common kestrels. Further, the beta diversity analysis showed that changes in gut microbes were associated with injuries to the common kestrel. The Bacteroides/Firmicutes ratio was significantly lower in the injured group. At the genus level, Glutamicibacter showed significant difference in the two groups. The aim of our current study was to characterize the basic bacterial composition and community structure in the feces of healthy common kestrels, and then compare the differences in the fecal microbiota between healthy and injured individuals. Patescibacteria, Spirochaetes, and Glutamicibacter may be studied as potential biomarkers for certain diseases in raptors. The results could provide the basic data for additional research on the fecal microbiota of common kestrels and contribute to the rescue of wild raptors in the future.

Treatment of infected placenta accreta in the uterine horn by transabdominal temporary occlusion of internal iliac arteries: A case report and literature review.

RATIONALE: This case report aims to describe the treatment of infected placenta accreta in the uterine horn by transabdominal temporary occlusion of internal iliac arteries. PATIENT CONCERNS: A 29-year-old female patient had a history of retained placenta for 28 days after labor induction in the second trimester of pregnancy because of fetal malformation. DIAGNOSES: Placenta accreta in the uterine horn was diagnosed by 3-dimensional ultrasound and magnetic resonance imaging, and the diagnosis was confirmed during the operation. INTERVENTIONS: Laparotomy was performed to remove the placenta and repair the uterine defect after temporary occlusion of both internal iliac arteries. OUTCOMES: Body temperature and inflammatory markers were elevated at admission but returned to normal on the second day after surgery. Normal menstruation resumed approximately 1 month postoperatively. Ultrasound examination showed that the shape of the uterine cavity was normal. No postoperative complications were observed. LESSONS: Temporary occlusion of the internal iliac artery can help effectively manage infected placenta accreta in the uterine horn.

The Invasive Anemone Condylactis sp. of the Coral Reef as a Source of Sulfur- and Nitrogen-Containing Metabolites and Cytotoxic 5,8-Epidioxy Steroids.

The Condylactis-genus anemones were examined for their proteinaceous poisons over 50 years ago. On the other hand, the current research focuses on isolating and describing the non-proteinaceous secondary metabolites from the invasive Condylactis anemones, which help take advantage of their population outbreak as a new source of chemical candidates and potential drug leads. From an organic extract of Condylactis sp., a 1,2,4-thiadiazole-based alkaloid, identified as 3,5-bis(3-pyridinyl)-1,2,4-thiadiazole (1), was found to be a new natural alkaloid despite being previously synthesized. The full assignment of NMR data of compound 1, based on the analysis of 2D NMR correlations, is reported herein for the first time. The proposed biosynthetic precursor thionicotinamide (2) was also isolated for the first time from nature along with nicotinamide (3), uridine (5), hypoxanthine (6), and four 5,8-epidioxysteroids (7-10). A major secondary metabolite (-)-betonicine (4) was isolated from Condylactis sp. and found for the first time in marine invertebrates. The four 5,8-epidioxysteroids, among other metabolites, exhibited cytotoxicity (IC50 3.5-9.0 µg/mL) toward five cancer cell lines.

New Verticillene Diterpenoids, Eudesmane Sesquiterpenoids, and Hydroperoxysteroids from the Further Chemical Investigation of a Taiwanese Soft Coral Cespitularia sp.

An investigation of the chemical composition of a Formosan soft coral Cespitularia sp. led to the discovery of one new verticillene-type diterpenoid, cespitulactam M (1); one new eudesmane sesquiterpenoid, cespilamide F (2); and three new hydroperoxysteroids (3-5) along with twelve known analogous metabolites (6-17). In addition, one new derivative, cespitulactam M-6,2'-diacetate (1a), was prepared from compound 1. The structures were determined by detailed spectroscopic analyses, particularly HRESIMS and NMR techniques. Moreover, the in vitro cytotoxicity, anti-inflammatory, and antibacterial activity of 1-17 and 1a were evaluated.

Isosarcophytoxide Derivatives with a 2,5-Dihydrofuran Moiety from the Soft Coral Sarcophyton cinereum.

The present chemical investigation on the organic extract of the soft coral Sarcophyton cinereum has contributed to the isolation of four new cembranoids: 16ß- and 16α-hydroperoxyisosarcophytoxides (1 and 2), 16ß- and 16α-methoxyisosarcophytoxides (3 and 4), and a known cembranoid, lobocrasol (5). The structures of all isolates were elucidated by detailed spectroscopic analysis. Their structures were characterized by a 2,5-dihydrofuran moiety, of which the relative configuration was determined by DU8-based calculation for long-range coupling constants (4JH,H). The cytotoxicity and immunosuppressive activities of all isolates were evaluated in this study.

Dapagliflozin reduces pulmonary vascular damage and susceptibility to atrial fibrillation in right heart disease.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have made considerable progress in the field of heart failure, but their application in arrhythmia remains to be in-depth. Right heart disease (RHD) often leads to right heart dysfunction and is associated with atrial fibrillation (AF). Here, we explored the possible electrophysiologic effect of dapagliflozin (a type of SGLT2is) in the development of AF in rats with RHD. METHODS AND RESULTS: Rats in the experimental group were intraperitoneally injected with a single dose of 60 mg/kg monocrotaline (MCT group, n = 32) on the first day of the experiment, whereas rats in the control group were injected with vehicle (CTL group, n = 32). Rats in the treatment subgroup were treated with dapagliflozin solution orally (MCT + DAPA and CTL + DAPA groups) for a total of 4 weeks, whereas rats in the rest of subgroups were given sterile drinking water. After 4 weeks, echocardiography demonstrated that MCT group rats developed obvious pulmonary arterial hypertension and right heart dysfunction. In addition, there were also obvious inflammatory infiltration, fibrosis, and muscularization in right atrial and pulmonary arteries. The P-wave duration (17.00 ± 0.53 ms, vs. 14.43 ± 0.57 ms in CTL; 14.00 ± 0.65 ms in CTL + DAPA; 14.57 ± 0.65 ms in MCT + DAPA; P < 0.05), RR interval (171.60 ± 1.48 ms, vs. 163.10 ± 1.10 ms in CTL; 163.30 ± 1.19 ms in CTL + DAPA; 163.10 ± 1.50 ms in MCT + DAPA; P < 0.05), Tpeak-Tend interval (65.93 ± 2.55 ms, vs. 49.55 ± 1.71 ms in CTL; 48.27 ± 3.08 ms in CTL + DAPA; P < 0.05), and corrected QT interval (200.90 ± 2.40 ms, vs. 160.00 ± 0.82 ms in CTL; 160.40 ± 1.36 ms in CTL + DAPA; 176.6 ± 1.57 ms in MCT + DAPA; P < 0.01) were significantly prolonged in the MCT group after 4 weeks, whereas P-wave amplitude (0.07 ± 0.0011 mV, vs. 0.14 ± 0.0009 mV in CTL; 0.14 ± 0.0011 mV in CTL + DAPA; 0.08 ± 0.0047 mV in MCT + DAPA; P < 0.05) and T-wave amplitude (0.04 ± 0.002 mV, vs. 0.13 ± 0.003 mV in CTL; 0.13 ± 0.003 mV in CTL + DAPA; P < 0.01) were decreased, and atrial 90% action potential duration (47.50 ± 0.93 ms, vs. 59.13 ± 2.1 ms in CTL; 59.75 ± 1.13 ms in CTL + DAPA; 60.63 ± 1.07 ms in MCT + DAPA; P < 0.01) and effective refractory periods (41.14 ± 0.88 ms, vs. 62.86 ± 0.99 ms in CTL; 63.14 ± 0.67 ms in CTL + DAPA; 54.86 ± 0.70 ms in MCT + DAPA; P < 0.01) were shortened. Importantly, the inducibility rate (80%, vs. 0% in CTL; 10% in CTL + DAPA; 40% in MCT + DAPA; P < 0.05) and duration of AF (30.85 ± 22.90 s, vs. 0 ± 0 s in CTL; 0.24 ± 0.76 s in CTL + DAPA; 5.08 ± 7.92 s in MCT + DAPA; P < 0.05) were significantly increased, whereas the expression levels of cardiac ion channels and calcium-handling proteins such as potassium/calcium channels and calmodulin were decreased. Mechanistically, 'NACHT, LRR, and PYD domain-containing protein 3' inflammasome-related pathway was significantly activated in the MCT group. Nevertheless, in the MCT + DAPA group, the above abnormalities were significantly improved. CONCLUSIONS: Dapagliflozin reduces pulmonary vascular damage and right heart dysfunction, as well as the susceptibility to AF in RHD rats.

Modulating the electrocatalytic activity of mononuclear nickel complexes toward water oxidation by tertiary amine group.

Water oxidation is the bottleneck of water splitting, which is a promising strategy for hydrogen production. Therefore, it is significant to develop efficient water oxidation catalysts. Herein, electrochemical water oxidation catalyzed by three nickel complexes, namely [Ni(bptn)(H2O)](ClO4)2 (1), [Ni(mbptn)(CH3CN)](ClO4)2 (2), and [Ni(tmbptn)(H2O)](ClO4)2 (3) (bptn = 1,9-bis(2-pyridyl)-2,5,8-triazanonane, mbptn = 5-methyl-1,9-bis(2-pyridyl)-2,5,8-triazanonane, and tmbptn = 1,9-bis(2-pyridyl)-2,5,8-triazanonane), is studied under near-neutral condition (pH 9.0). Meanwhile, the homogeneous catalytic behaviors of the three mononuclear nickel complexes were investigated and confirmed by scanning electron microscopy, energy dispersive spectrometry, X-ray photoelectron spectroscopy and electrochemical method. Complex 1 stabilized by a pentadentate ligand with three N-H fragments homogeneously catalyzes water oxidation to oxygen with the lowest onset overpotential. Complex 2 stabilized by a similar ligand with two N-H groups and one N-CH3 group exhibits relatively higher onset overpotential but higher catalytic current and turnover frequency. However, complex 3 with three N-CH3 coordination environment shows the highest onset overpotential and the highest catalytic current at higher potential. Comparison of catalytic behaviors and ligand structure of the three complexes reveals that the methyl group on the polypyridine amine ligand affects the water oxidation activity of the complexes obviously. The electronic effect of N-CH3 coordination environment leads to higher redox potential of the metal center and potential demand for water oxidation, while it leads to higher reaction activity of high-valent intermediates, which account for higher catalytic current and efficiency of water oxidation. This work reveals that electrocatalytic water oxidation performance of nickel complexes can be finely modulated by constructing suitable N-CH3 coordination.

The ciliary protein Spef2 stimulates acinar Ampkα/Sirt1 signaling and ameliorates acute pancreatitis and associated lung injury.

Background: Pancreatic acinar cells are susceptible to nuclear factor kappa B (NF-κB)-mediated inflammation and resulting cell necrosis during early acute pancreatitis. As adenosine monophosphate-activated protein kinase alpha (Ampkα)/sirtuin 1 (Sirt1) pathway activity attenuates NF-κB activity, we examined whether the Ampkα/Sirt1 axis affects the progression of acute pancreatitis and associated lung injury in vivo. Furthermore, we explored the role of the ciliary protein sperm flagellar 2 (Spef2, Kpl2) in regulating Ampkα/Sirt1 activity in vitro and in vivo. Methods: Pancreatic injury, oxidative stress, acinar cell necrosis and apoptosis, acinar levels of Ampkα/Sirt1/NF-κB signaling activity, NF-kB-mediated inflammatory markers, and markers of associated lung injury were measured in rat models of acute pancreatitis following pharmacological Ampkα activation with A769662 or self-complementary recombinant adeno-associated virus serotype 6 (scAAV6)-mediated Spef2 overexpression. Additional in vivo rescue studies involving Ampkα silencing and/or constitutively active (CA)-Sirt1 overexpression were performed in acute pancreatitis rats. In vitro immunoblotting and Ampkα activity assays were conducted in the pancreatic acinar cell line AR42J. Results: Pharmacological Ampkα activation or Spef2 overexpression reduced acute pancreatitis severity, oxidative stress, necrosis, apoptosis, NF-kB-mediated inflammatory markers, and the degree of associated lung injury. Spef2 overexpression in AR42J cells in vitro promoted AmpkαThr172 phosphorylation and Ampkα activity. In vivo rescue studies revealed that Spef2's suppressive effect on acute pancreatitis and associated lung injury is mediated via the Ampkα/Sirt1 axis. Conclusions: This study established the existence of a Spef2/Ampkα/Sirt1 axis in pancreatic acinar cells that is involved in the regulation of NF-κB-mediated acinar cell inflammation and resulting cell necrosis during acute pancreatitis.

ERF4 interacts with and antagonizes TCP15 in regulating endoreduplication and cell growth in Arabidopsis.

Endoreduplication is prevalent during plant growth and development, and is often correlated with large cell and organ size. Despite its prevalence, the transcriptional regulatory mechanisms underlying the transition from mitotic cell division to endoreduplication remain elusive. Here, we characterize ETHYLENE-RESPONSIVE ELEMENT BINDING FACTOR 4 (ERF4) as a positive regulator of endoreduplication through its function as a transcriptional repressor. ERF4 was specifically expressed in mature tissues in which the cells were undergoing expansion, but was rarely expressed in young organs. Plants overexpressing ERF4 exhibited much larger cells and organs, while plants that lacked functional ERF4 displayed smaller organs than the wild-type. ERF4 was further shown to regulate cell size by controlling the endopolyploidy level in the nuclei. Moreover, ERF4 physically associates with the class I TEOSINTE BRANCHED 1/CYCLOIDEA/PCF (TCP) protein TCP15, a transcription factor that inhibits endoreduplication by activating the expression of a key cell-cycle gene, CYCLIN A2;3 (CYCA2;3). A molecular and genetic analysis revealed that ERF4 promotes endoreduplication by directly suppressing the expression of CYCA2;3. Together, this study demonstrates that ERF4 and TCP15 function as a module to antagonistically regulate each other's activity in regulating downstream genes, thereby controlling the switch from the mitotic cell cycle to endoreduplication during leaf development. These findings expand our understanding of how the control of the cell cycle is fine-tuned by an ERF4-TCP15 transcriptional complex.

Lethal and sublethal effects of chlorantraniliprole on the migratory moths Agrotis ipsilon and A. segetum: New perspectives for pest management strategies.

BACKGROUND: Agrotis ipsilon and A. segetum are major migratory pests of many crops in China, and frequent regional outbreaks cause severe yield losses. Use of food attractants is one of the most promising control methods against adult lepidoptera, notably through the attract-and-kill strategy. Chlorantraniliprole's acute toxicity and sublethal effects on both moths were evaluated. RESULTS: Chlorantraniliprole showed high activity against both adults of both species, with LC20 and LC50 values of 0.08 and 0.21 mg L-1 (A. ipsilon), and 0.14 and 0.51 mg L-1 (A. segetum). The fecundity, effective oviposition rate, and egg hatching rate of both species in dual-sex exposure treatments were all significantly reduced compared with the control, and the population growth coefficients in the LC50 ♀ × LC50 ♂ treatments were only 0.32% (A. ipsilon) and 3.35% (A. segetum) that of the control. Furthermore, the flight distance was significantly suppressed from 6.67 km (control) to 0.01 km (LC50 ) for A. ipsilon, and from 7.39 km (control) to 0.78 km (LC50 ) for A. segetum. The proportions of robust- and medium-flight individuals of A. ipsilon and A. segetum in exposure treatments were greatly reduced. CONCLUSIONS: Low lethal concentration exposures to chlorantraniliprole can drastically reduce the reproduction and flight performance of A. ipsilon and A. segetum, while inhibiting the production of offspring, suggesting chlorantraniliprole would be an excellent compound for use in combination with food attractants. Chlorantraniliprole has good potential for management of the two long-range migratory pests tested using an attract-and-kill strategy. © 2022 Society of Chemical Industry.

Computationally Assisted Structural Elucidation of Cembranoids from the Soft Coral Sarcophyton tortuosum.

A persistent study on soft coral Sarcophyton tortuosum resulted in the characterization of two new cembranolides, tortuolides A and B (1 and 2), and a new related diterpene, epi-sarcophytonolide Q. Their structures were determined not only by extensive spectroscopic analysis but also by DFT calculations of ECD and NMR data, the latter of which was combined with statistical analysis methods, e.g., DP4+ and J-DP4 approaches. Anti-inflammatory and cytotoxicity activities were evaluated in this study.

A new species of anthothelid octocoral (Cnidaria, Alcyonacea) discovered on an algal reef of Taiwan.

A molecular phylogenetic analysis of 132 octocoral species reveals a close relationship between specimens collected from the intertidal pools of the Datan Algal Reef, Taoyuan, Taiwan, and Erythropodiumcaribaeorum (Duchassaing & Michelotti, 1860), but the two species have distinct morphological features. On the basis of morphological differences in polyps and sclerites, we identify and describe a new Erythropodium species: E.taoyuanensis sp. nov. The distinct identifying features of E.taoyuanensis sp. nov. include the upright contractile polyps from thin encrusting membranes and abundant 6-radiate sclerites. Using an integrative approach, we present the findings of morphological comparisons and molecular phylogenetic analyses to demonstrate that E.taoyuanensis sp. nov. is distinct from other Erythropodium species. Our study contributes to the knowledge of octocoral biodiversity in marginal habitats.

Safety and Efficacy of Systemic Anti-Scg3 Therapy to Treat Oxygen-Induced Retinopathy.

BACKGROUND: To circumvent possible systemic side effects, anti-angiogenic drugs targeting vascular endothelial growth factor (VEGF) for ocular neovascular diseases in adults are approved only for intravitreal administration. However, intravitreal injection itself can elicit injection-related adverse effects, and premature eyes of infants with retinopathy of prematurity (ROP) may be particularly susceptible to intravitreal injection. Therefore, an unmet clinical need is to develop safe systemic anti-angiogenic therapies for ROP. We recently reported that secretogranin III (Scg3) is a disease-restricted angiogenic factor and that systemic anti-Scg3 mAb alleviates ROP in animal models with minimal side effects on developing eyes and organs. The aim of this study is to investigate the safety and efficacy of a humanized anti-Scg3 antibody via systemic administration. METHODS: We analyzed the safety and efficacy of a humanized anti-Scg3 antibody Fab fragment (hFab) delivered by intraperitoneal injection in oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP. RESULTS: The results showed that systemic anti-Scg3 hFab effectively alleviated pathological retinal neovascularization in OIR mice with similar efficacy to the anti-VEGF drug aflibercept. Systemic aflibercept conferred significant adverse side effects in neonatal mice, including reduced body weight, abnormalities in retinal and renal development, and retarded physiological neovascularization, whereas systemic anti-Scg3 hFab elicited no such side effects. CONCLUSIONS: The findings suggest that systemic anti-Scg3 hFab is a safe and effective therapy for OIR and support further development for ROP treatment.

Neurovascular abnormalities in retinopathy of prematurity and emerging therapies.

Blood vessels in the developing retina are formed in concert with neural growth, resulting in functional neurovascular network. Disruption of the neurovascular coordination contributes to the pathogenesis of retinopathy of prematurity (ROP), a potentially blinding retinal neovascular disease in preterm infants that currently lacks an approved drug therapy in the USA. Despite vasculopathy as predominant clinical manifestations, an increasing number of studies revealed complex neurovascular interplays among neurons, glial cells and blood vessels during ROP. Coordinated expression of glia-derived vascular endothelial growth factor (VEGF) in spatio-temporal gradients is pivotal to the formation of well-organized vascular plexuses in the healthy retina, whereas uncoordinated VEGF expression triggers pathological angiogenesis with disorganized vascular tufts in ROP. In contrast with VEGF driving both pathological and physiological angiogenesis, neuron-derived angiogenic factor secretogranin III (Scg3) stringently regulates ROP but not healthy retinal vessels in animal models. Anti-VEGF and anti-Scg3 therapies confer similar high efficacies to alleviate ROP in preclinical studies but are distinct in their disease selectivity and safety. This review discusses neurovascular communication among retinal blood vessels, neurons and glial cells during retinal development and ROP pathogenesis and summarizes the current and emerging therapies to address unmet clinical needs for the disease.

Cembranolides and Related Constituents from the Soft Coral Sarcophyton cinereum.

In an attempt to explore the bioactive metabolites of the soft coral Sarcophyton cinereum, three new cembranolides, cinerenolides A-C (1-3), and 16 known compounds were isolated and identified from the EtOAc extract. The structures of the new cembranolides were elucidated on the basis of spectroscopic analysis, and the NOE analysis of cinerenolide A (1) was performed with the assistance of the calculated lowest-energy molecular model. The relative configuration of cinerenolide C (3) was determined by the quantum chemical NMR calculation, followed by applying DP4+ analysis. In addition, the cytotoxic assays disclosed that some compounds exhibited moderate to potent activities in the proliferation of P388, DLD-1, HuCCT-1, and CCD966SK cell lines.

Secretogranin III stringently regulates pathological but not physiological angiogenesis in oxygen-induced retinopathy.

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized Scg3 binding exclusively to disease-related disorganized retinal neovessels and neovascular tufts, whereas VEGF bound to both disorganized and well-organized neovessels. Homozygous deletion of the Scg3 gene showed undetectable effects on physiological retinal neovascularization but markedly reduced the severity of OIR-induced pathological angiogenesis. Furthermore, anti-Scg3 humanized antibody Fab (hFab) inhibited pathological angiogenesis with similar efficacy to anti-VEGF aflibercept. Aflibercept dose-dependently blocked physiological angiogenesis in neonatal retinas, whereas anti-Scg3 hFab was without adverse effects at any dose and supported a therapeutic window at least 10X wider than that of aflibercept. Therefore, Scg3 stringently regulates pathological but not physiological angiogenesis, and anti-Scg3 hFab satisfies essential criteria for development as a safe and effective disease-targeted anti-angiogenic therapy for ROP.

Protective effects of Dapagliflozin on the vulnerability of ventricular arrhythmia in rats with pulmonary artery hypertension induced by monocrotaline.

Monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) has been reported to cause right heart failure (RHF). Moreover, Right heart diseases have been determined to cause ventricular arrhythmia (VA). So we can conclude that MCT-induced PAH increases the incidence of VA. In addition, Previous studies have determined the benefits of Dapagliflozin (DA) on the cardiac system, but the responses of MCT-induced RHF to DA are not fully reported. So the present study sought to evaluate the effects of DA on the MCT-induced PAH. A dose intraperitoneal injection of MCT (60 mg/kg) was carried out to induce a rat model with PAH. DA (60 mg/l) was administered for 4 weeks following MCT injection. Echocardiography, body weight, blood pressure, blood glucose, electrophysiological study, and Western blot were performed. Four weeks after the MCT injection, MCT-treated rats decreased body weight, blood glucose and blood pressure. In addition, MCT caused the formation of PAH and RHF. Moreover, MCT-induced PAH rats increased the incidence of VA, prolonged action potential duration (APD), and shortened effective refractory period (ERP). Additionally, PAH rats significantly prevented the activated expressions of Ion channel proteins such as potassium channel (Kv1.5, Kv2.1, Kv4.2, Kv4.3) and L-type Ca channel (Cav1.2). As we expected, these changes above in PAH rats were reversed when DA was administered. Mechanistically, DA significantly reduced the levels of toll-like receptor (TLR4), the nuclear factor kappa B (NF-κB) in MCT-treated rats. In conclusion, these findings determine that DA reduces the vulnerability of VA in PAH rats through the TLR4/NF-κB signaling pathway.

Inhibition of ferroptosis reduces susceptibility to frequent excessive alcohol consumption-induced atrial fibrillation.

Both long-term and short-term alcohol consumption can cause internal homeostasis imbalance, and they have been proved to be related to the initiation and development of atrial fibrillation (AF). Ferroptosis is an iron-dependent form of non-apoptotic oxidative death which also regulate the cell death homeostasis, but whether it involves in AF induced by alcohol consumption remains unclear. Here, we report a study on the effect of ferroptosis on susceptibility to AF at different alcohol consumption frequencies. We divided the mice into single or frequent excessive alcohol consumption group which given sterile drinking water or alcohol by gavage at different frequencies. Meanwhile, the experimental group was given an intraperitoneal injection of ferroptosis inhibitor (Fer-1) before alcohol drinking. It was found that once exposure to 5 g/kg/d frequent excessive alcohol consumption, compared with the single excessive alcohol consumption group, the mice serum non-heme iron concentration, accumulation of iron and oxidative stress reaction in atrial tissues were increased, while the body weight, heart weight and heart weight to tibia length (HW/TL) ratio were decreased. In addition, the inducibility rate of AF increased, while RR interval, effective refractory periods (ERPs) and 90 % action potential duration (APD90) shortened, as well as QTc interval prolonged. Furthermore, the protein and mRNA expression levels of GPx4, FTL, FTH1, Kv1.5, Kv2.1, Kv4.3, Cav1.2, Serca2α, p-PLB were down-regulated, while PTGS2 was up-regulated. Most of the changes can be partially or completely reversed by Fer-1. These results suggest that frequent excessive alcohol consumption activates ferroptosis and increases the inducibility rate of AF. Nevertheless, inhibition of ferroptosis can balance iron overload disorders and reduce the generation of reactive oxygen species (ROS), eventually decrease the susceptibility to AF. Our results highlight the importance of guidance and warnings for unhealthy alcohol-abuse lifestyle.

Ferroportin-mediated ferroptosis involved in new-onset atrial fibrillation with LPS-induced endotoxemia.

Sepsis is a known risk factor for new-onset atrial fibrillation (AF), and previous studies have demonstrated that ferroptosis participates in sepsis-induced organ injury development. Nevertheless, the role of ferroptosis in new-onset AF with sepsis remains largely unknown. This study aims to investigate the underlying mechanisms linking ferroptosis and AF caused by sepsis. LPS-induced endotoxemia is often used to model the acute inflammatory response associated with sepsis. Herein, we reported that ferroptosis was significantly activated in LPS-induced endotoxemia rat model. We also observed that ferroportin (Fpn), the only identified mammalian non-heme iron exporter, was downregulated in the atrium of endotoxemia model. Vulnerability to AF was also significantly increased in a endotoxemia rat model. Additionally, Fpn knockdown by shFpn further increased intracellular iron concentration and oxidative stress and exaggerated the AF vulnerability, which was alleviated by ferroptosis inhibition. Mechanistically, silencing Fpn worsened the alterations in calcium handling proteins expression in a endotoxemia rat model. These findings suggest that Fpn-mediated ferroptosis is involved in the new-onset AF with LPS-induced endotoxemia via worsening the calcium handling proteins dysregulation and provides a novel and promising strategy for preventing AF development in sepsis.