Prostaglandin I2 signaling prevents angiotensin II-induced atrial remodeling and vulnerability to atrial fibrillation in mice.

Atrial fibrillation (AF) is the most common arrhythmia, and atrial fibrosis is a pathological hallmark of structural remodeling in AF. Prostaglandin I2 (PGI2) can prevent the process of fibrosis in various tissues via cell surface Prostaglandin I2 receptor (IP). However, the role of PGI2 in AF and atrial fibrosis remains unclear. The present study aimed to clarify the role of PGI2 in angiotensin II (Ang II)-induced AF and the underlying molecular mechanism. PGI2 content was decreased in both plasma and atrial tissue from patients with AF and mice treated with Ang II. Treatment with the PGI2 analog, iloprost, reduced Ang II-induced AF and atrial fibrosis. Iloprost prevented Ang II-induced atrial fibroblast collagen synthesis and differentiation. RNA-sequencing analysis revealed that iloprost significantly attenuated transcriptome changes in Ang II-treated atrial fibroblasts, especially mitogen-activated protein kinase (MAPK)-regulated genes. We demonstrated that iloprost elevated cAMP levels and then activated protein kinase A, resulting in a suppression of extracellular signal-regulated kinase1/2 and P38 activation, and ultimately inhibiting MAPK-dependent interleukin-6 transcription. In contrast, cardiac fibroblast-specific IP-knockdown mice had increased Ang II-induced AF inducibility and aggravated atrial fibrosis. Together, our study suggests that PGI2/IP system protects against atrial fibrosis and that PGI2 is a therapeutic target for treating AF.The prospectively registered trial was approved by the Chinese Clinical Trial Registry. The trial registration number is ChiCTR2200056733. Data of registration was 2022/02/12.

Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis.

BACKGROUND: Myocardial ischemia-reperfusion (I/R) injury causes cardiac dysfunction to myocardial cell loss and fibrosis. Prevention of cell death is important to protect cardiac function after I/R injury. The process of reperfusion can lead to multiple types of cardiomyocyte death, including necrosis, apoptosis, autophagy, and ferroptosis. However, the time point at which the various modes of cell death occur after reperfusion injury and the mechanisms underlying ferroptosis regulation in cardiomyocytes are still unclear. METHODS: Using a left anterior descending coronary artery ligation mouse model, we sought to investigate the time point at which the various modes of cell death occur after reperfusion injury. To discover the key molecules involved in cardiomyocyte ferroptosis, we performed a metabolomics study. Loss/gain-of-function approaches were used to understand the role of 15-lipoxygenase (Alox15) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Pgc1α) in myocardial I/R injury. RESULTS: We found that apoptosis and necrosis occurred in the early phase of I/R injury, and that ferroptosis was the predominant form of cell death during the prolonged reperfusion. Metabolomic profiling of eicosanoids revealed that Alox15 metabolites accumulated in ferroptotic cardiomyocytes. We demonstrated that Alox15 expression was specifically increased in the injured area of the left ventricle below the suture and colocalized with cardiomyocytes. Furthermore, myocardial-specific knockout of Alox15 in mice alleviated I/R injury and restored cardiac function. 15-Hydroperoxyeicosatetraenoic acid (15-HpETE), an intermediate metabolite derived from arachidonic acid by Alox15, was identified as a trigger for cardiomyocyte ferroptosis. We explored the mechanism underlying its effects and found that 15-HpETE promoted the binding of Pgc1α to the ubiquitin ligase ring finger protein 34, leading to its ubiquitin-dependent degradation. Consequently, attenuated mitochondrial biogenesis and abnormal mitochondrial morphology were observed. ML351, a specific inhibitor of Alox15, increased the protein level of Pgc1α, inhibited cardiomyocyte ferroptosis, protected the injured myocardium, and caused cardiac function recovery. CONCLUSIONS: Together, our results established that Alox15/15-HpETE-mediated cardiomyocyte ferroptosis plays an important role in prolonged I/R injury.

RHO OF PLANT proteins are essential for pollen germination in Arabidopsis.

Pollen germination is a process of polarity establishment, through which a single and unique growth axis is established. Although most of the intracellular activities associated with pollen germination are controlled by RHO OF PLANTs (ROPs) and increased ROP activation accompanies pollen germination, a critical role of ROPs in this process has not yet been demonstrated. Here, by genomic editing of all 4 Arabidopsis (Arabidopsis thaliana) ROPs that are preferentially expressed in pollen, we showed that ROPs are essential for polarity establishment during pollen germination. We further identified and characterized 2 ROP effectors in pollen germination (REGs) through genome-wide interactor screening, boundary of ROP domain (BDR) members BDR8 and BDR9, whose functional loss also resulted in no pollen germination. BDR8 and BDR9 were distributed in the cytosol and the vegetative nucleus of mature pollen grains but redistributed to the plasma membrane (PM) of the germination site and to the apical PM of growing pollen tubes. We demonstrated that the PM redistribution of BDR8 and BDR9 during pollen germination relies on ROPs but not vice versa. Furthermore, enhanced expression of BDR8 partially restored germination of rop1 pollen but had no effects on that of the quadruple rop pollen, supporting their genetic epistasis. Results presented here demonstrate an ROP signaling route essential for pollen germination, which supports evolutionarily conserved roles of Rho GTPases in polarity establishment.

LncRNA MALAT1 induces the dysfunction of ß cells via reducing the histone acetylation of the PDX-1 promoter in type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1DM) severely threatens human health, and the dysfunction of insulin-secreting ß cells in islets is related to the reduced PDX-1 expression. It has been reported that long non-coding RNA MALAT1 regulates ß cell function, while the potential mechanism is unclear. METHODS: Islets were isolated from non-obese diabetic (NOD) mice and wild type (WT) mice. Mouse islets and ß cell line (Min6) were stimulated by IL-1ß. The expression of MALAT1 was determined using real-time PCR, while the PDX-1 protein expression was determined using western blotting. ChIP-qPCR was carried out to determine the histone acetylation of the PDX-1 promoter. RESULTS: In NOD islets and IL-1ß-stimulated Min6 cells, the expression of MALAT1 was increased, while the mRNA and protein levels of PDX-1 were decreased at an age/time-dependent manner. Overexpressing MALAT1 suppressed the H3 histone acetylation of the PDX-1 promoter, inhibiting both mRNA and protein expressions of PDX-1. Knocking down MALAT1 restored the decrease of the histone acetylation of the PDX-1 promoter, as well as the PDX-1 expression, which was reduced by IL-1ß stimulation. Under high glucose stimulation, the overexpression of PDX-1 alone restored the insulin secretion which was inhibited by the simultaneous overexpression of MALAT1 and PDX-1. Under high glucose and IL-1ß stimulation, the simultaneous knockdown of MALAT1 and PDX-1 reduced the enhancement of the insulin secretion which was raised by knocking down MALAT1 alone. CONCLUSION: MALAT1 induces the dysfunction of ß cells via reducing the H3 histone acetylation of the PDX-1 promoter and subsequently inhibiting the expression of PDX-1, thus suppressing the insulin secretion.

Severe thyrotoxicosis induced by tislelizumab: a case report and literature review.

Immune checkpoint inhibitors (ICIs) have made significant breakthroughs in the treatment of a variety of malignancies. As its use increases, the unique immune-mediated toxicity profile of ICls are becoming apparent. We report a case of immune-related endocrine adverse events (irAE) in a patient with hepatocellular carcinoma treated with anti-programmed cell death protein 1 (PD-1) (tislelizumab). Although many irAEs have been reported, few cases of severe thyrotoxicosis have been described after immunotherapy in the literature. We present the case of a 49-year-old male who experienced a Grade 3 tislelizumab-related adverse reaction according to Common Terminology Criteria for Adverse Events (CTCAE5.0) and received methylprednisolone, thiamazole, and levothyroxine sodium tablets. Early identification of irAEs, risk factors, regular monitoring, use of steroids and/or immunoglobulins, and adjuvant supportive care are critical to the clinical prognosis of patients. It should be underlined that the tumor benefits of ICI therapy outweigh the risks associated with ICI-induced endocrine disorders, and ICI treatment should not be stopped or delayed except in rare cases (adrenal crisis, severe thyrotoxicosis). The familiarity of healthcare professionals with irAEs of the thyroid when thyrotoxicosis occurs is important to facilitate an effective diagnosis and appropriate treatment of this increasingly common thyroid disorder.

Polystyrene nanoplastics induce profound metabolic shift in human cells as revealed by integrated proteomic and metabolomic analysis.

Nanoplastics (NPLs) are widespread in our environment. However, their impacts on human health and precise toxicity mechanisms remain poorly understood. Here we studied the internalization, release, and cytotoxicity of polystyrene nanoplastics (PSNPs) using the renal tubular epithelial cell line HKC and human derived liver cell line HL-7702. We also employed an integrated proteomic and metabolomic approach to investigate the potential biological effects of PSNPs on HKC cells. The abundances of 4770 proteins and 100 metabolites were quantified, with 785 proteins and 17 metabolites detected with altered levels in response to PSNPs. Most of the differential proteins and metabolites were enriched in a variety of metabolic pathways, for example, glycolysis, citrate cycle, oxidative phosphorylation, and amino acid metabolism, suggesting the potential effects of NPLs on global cellular metabolism shift in human cells. The altered energy metabolism induced by PSNPs was further confirmed by a Seahorse analysis. Moreover, lysosomal distribution study and western blotting showed that mTORC1 signaling, a central regulator of cellular metabolism, was inhibited upon nanoplastic exposure, likely serving as the link between lysosome dysfunction and metabolic defects. Taken together, our findings systematically mapped the key molecular changes induced by PSNPs in human cells and provide comprehensive biological insights for the risk estimation of NPLs contamination.

Edaravone Modulates Neuronal GPX4/ACSL4/5-LOX to Promote Recovery After Spinal Cord Injury.

The FDA-approved drug edaravone has a neuroprotective effect on spinal cord injury (SCI) and many other central nervous system diseases. However, its molecular mechanism remains unclear. Since edaravone is a lipid peroxidation scavenger, we hypothesize that edaravone exerts its neuroprotective effect by inhibiting ferroptosis in SCI. Edaravone treatment after SCI upregulates glutathione peroxidase 4 (GPX4) and system Xc-light chain (xCT), which are anti-ferroptosis proteins. It downregulates pro-ferroptosis proteins Acyl-CoA synthetase long-chain family member 4 (ACSL4) and 5-lipoxygenase (5-LOX). The most significant changes in edaravone treatment occur in the acute phase, two days post injury. Edaravone modulates neuronal GPX4/ACSL4/5-LOX in the spinal segment below the lesion, which is critical for maintaining locomotion. Moreover, the GPX4/ACSL4/5-LOX in motor neuron is also modulated by edaravone in the spinal cord. Therefore, secondary injury below the lesion site is reversed by edaravone via ferroptosis inhibition. The cytokine array revealed that edaravone upregulated some anti-inflammatory cytokines such as IL-10, IL-13, and adiponectin. Edaravone reduced microgliosis and astrogliosis, indicating reduced neuroinflammation. Edaravone has a long-term effect on neuronal survival, spinal cord tissue sparing, and motor function recovery. In summary, we revealed a novel mechanism of edaravone in inhibiting neuronal ferroptosis in SCI. This mechanism may be generalizable to other neurological diseases.

Coadministration of Compound Danshen dripping pills and bezafibrate has a protective effect against diabetic retinopathy.

Diabetic retinopathy (DR) is increasingly becoming a main complication of diabetes, and is difficult to cure. In our research, network pharmacology analysis suggested that both compound Danshen dripping pills (CDDP) and bezafibrate (BZF) have potential protective effects against DR and the two drugs may act synergistically. The pharmacological effects of the coadministration of CDDP and BZF were elucidated in db/db mice, which simulate DR. Fluorescein fundus angiography showed that coadministration attenuated vascular leakage. Optical coherence tomography and hematoxylin and eosin staining showed that coadministration improved retinal thickness better than CDDP monotherapy. In addition, cell fluorescence images of reactive oxygen species revealed that coadministration of CDDP and BZF had more potent effects against oxidative stress than CDDP monotherapy. Metabolomics analysis showed that coadministration reduced the ratio of oxidized glutathione to reduced glutathione further than CDDP monotherapy. Coadministration of CDDP and BZF may provide additional protective effects by resisting vascular leakage, increasing retinal thickness, and inhibiting inflammation and oxidative stress in DR.

LC-MS/MS-based arachidonic acid metabolomics in acute spinal cord injury reveals the upregulation of 5-LOX and COX-2 products.

Arachidonic acid (AA) plays a critical role in inflammatory regulation and secondary injury after spinal cord injury (SCI). However, the overall AA metabolism profile in the acute phase of SCI remains elusive. Here we quantified AA metabolomics by High Performance Liquid Chromatography-Tandem Mass Spectrometry-Based Method (LC-MS/MS) using spinal cord tissue collected at 4 h, 24 h and 48 h after contusive SCI in rats. Remarkably, Prostaglandin E2 (PGE2) and Leukotriene B4 (LTB4) were significantly increased throughout the acute SCI. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), the key enzymes involved in the production of PGE2 and LTB4, were elevated in the lesioned spinal cord tissue, validated by both western blot and immunofluorecnce. The spatial-temporal changes of COX-2 and 5-LOX mainly occurs in neurons both in epicenter and rostral and caudal spinal cord segments after SCI. Our study sheds light on the dynamic microenvironment changes in acute SCI by characterizing the profile of AA metabolism. The COX-2 and 5-LOX may be promising therapeutic target for SCI.

A positive feedback circuit for ROP-mediated polar growth.

Tip growth is a special type of polarized growth in which a single and unique polarization site is established and maintained. Rho of Plants (ROP) proteins, which represent the only class of Rho GTPases in plants, regulate tip growth. The dynamic and asymmetric distribution of ROPs is critical for the establishment and maintenance of tip growth, and requires at least one positive feedback loop, which is still elusive. Here, we report a positive feedback circuit essential for tip growth of root hairs, in which ROPs, ROP activators and effectors, and AGC1.5 subfamily kinases are interconnected by sequential oligomerization and phosphorylation. AGC1.5 subfamily kinases interact with and phosphorylate two guanine nucleotide exchange factors (GEFs) of ROPs, RopGEF4 and RopGEF10. They also interact with two ROP effectors, ICR2/RIP3 and MIDD1/RIP4, which bridge active ROPs with AGC1.5. Functional loss of the AGC1.5 subfamily kinases or ICR2 and MIDD1 compromised root hair growth due to reduced ROP signaling. We found that asymmetric targeting of RopGEF4 and RopGEF10 is controlled by AGC1.5-dependent phosphorylation. Interestingly, we discovered that the ROP effectors recruit AGC1.5 to active ROP domains at the plasma membrane during root hair growth and are critical for AGC1.5-dependent phosphorylation of RopGEFs. Given the large number of AGC kinases in plants, this positive feedback circuit may be a universal theme for plant cell polar growth.

Inhibition of Soluble Epoxide Hydrolase Attenuates Bosutinib-Induced Blood Pressure Elevation.

[Figure: see text].

Redox environment metabolomic evaluation (REME) of the heart after myocardial ischemia/reperfusion injury.

Myocardial ischemia/reperfusion injury (MIRI) is closely related to oxidative stress. However, the redox environment of the heart has not been evaluated thoroughly after MIRI, which limits precise redox intervention. In this study, we developed the redox environment metabolomic evaluation (REME) method to analyze the redox metabolites of the heart after MIRI. Based on the targeted metabolomics strategy, we established a detection panel for 22 redox-related molecules, including the major redox couples nicotinamide adenine dinucleotide (NADH/NAD+), nicotinamide adenine dinucleotide phosphate (NADPH/NADP+), and glutathione/glutathione disulfide (GSH/GSSG), reactive oxygen and nitrogen species-related molecules, and some lipid peroxidation products. The high sensitivity and specificity of the method make it suitable for evaluating the endogenous redox environment. The REME method showed that the heart tissue in a MIRI mouse model had a different redox profile from that in the control group. Different redox species changed in different ways. The ratios of GSSG/GSH and NADP+/NADPH increased, but the levels of both NAD+ and NADH decreased in the risk area of the infarcted heart after reperfusion. In addition, some reactive nitrogen species-related metabolites (tetrahydrobiopterin, arginine, and S-nitrosoglutathione) decreased and some lipid peroxides (4-hydroxy-2-nonenal, 4-hydroxy-2-hexenal, and benzaldehyde) increased. The redox metabolites GSH, GSSG, NADPH, NAD+, S-nitrosoglutathione, arginine, and tetrahydrobiopterin had a positive correlation with the ejection fraction and a negative correlation with the level of lactate dehydrogenase in plasma. In summary, we achieved a comprehensive, systemic understanding of the changes in the redox environment after MIRI. Our REME method could be used to evaluate the redox environment in other processes.

Impacts of Building Features on the Cooling Effect of Vegetation in Community-Based MicroClimate: Recognition, Measurement and Simulation from a Case Study of Beijing.

Due to the accumulation of heat, the urban environment and human health are threatened. Land surface cover has effects on the thermal environment; nevertheless, the effects of land surface features and spatial patterns remain poorly known in a community-based microclimate. This study quantified and verified the impacts of normalized difference vegetation index (NDVI) on land surface temperature (LST) (K, the slope of the trend line of a linear regression between NDVI and LST) in different building density by using building outline and Landsat 8 satellite imagery. Comparing the cooling effect and distribution of vegetation showed that the vegetative cover had a cooling effect on LST, characterized by synchronous change, and building density had a significant impact on the cooling effect of vegetation. Through identification and simulation, it was found that the key factor is the wind speed between the buildings because, in different building densities, the wind speed was different, and studies had shown that when the building density was between 0.35 and 0.50, the wind speed between buildings was higher, resulting in a better cooling effect of vegetation. This conclusion has important reference significance for urban planning and mitigating the impact of the thermal environment on human health.

Synthesized different derivatives of low molecular fucoidan extracted from Laminaria japonica and their potential antioxidant activity in vitro.

Six low molecular fucoidan (DFPS) derivatives were synthesized successfully, and their potential antioxidant activities were investigated employing various established in vitro systems. All DFPS derivatives possessed considerable antioxidant activity, and had stronger antioxidant ability than DFPS in certain tests. The benzoylated DFPS (PHDF) showed strongest scavenging activity on superoxide, hydroxyl and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, however, DFPS exhibited greatest reducing power. Available data suggested that substituted groups of DFPS played an important role on antioxidant activity, and the mechanism on influence the antioxidant activity of samples of substituted group was indicated.