Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3.

Chemical modifications of histones can mediate diverse DNA-templated processes, including gene transcription1-3. Here we provide evidence for a class of histone post-translational modification, serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in organisms that produce serotonin (also known as 5-hydroxytryptamine (5-HT)). We demonstrate that tissue transglutaminase 2 can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3)-marked nucleosomes, resulting in the presence of combinatorial H3K4me3Q5ser in vivo. H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of human serotonergic neurons, developing mouse brain and cultured serotonergic cells indicate that H3K4me3Q5ser nucleosomes are enriched in euchromatin, are sensitive to cellular differentiation and correlate with permissive gene expression, phenomena that are linked to the potentiation of TFIID4-6 interactions with H3K4me3. Cells that ectopically express a H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser-target loci, which leads to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signalling, in the mediation of permissive gene expression.

Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition.

BACKGROUND AND AIMS: The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. METHODS: The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. RESULTS: Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. CONCLUSIONS: ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.

Near-Field Probing of Microwave Oscillators with Josephson Microscopy.

Voltage-controlled oscillators, serving as fundamental components in semiconductor chips, find extensive applications in diverse modules such as phase-locked loops, clock generators, and frequency synthesizers within high-frequency integrated circuits. This study marks the first implementation of superconducting Josephson probe microscopy for near-field microwave detection on multiple voltage-controlled oscillators. Focusing on spectrum tracking, various phenomena, such as stray spectra and frequency drifts, were found under nonsteady operating states. Parasitic electromagnetic fields, originating from power supply lines and frequency divider circuits, were identified as sources of interference between units. The investigation further determined optimal working states by analyzing features of the microwave distributions. Our research not only provides insights into the optimization of circuit design and performance enhancement in oscillators but also emphasizes the significance of nondestructive near-field microwave microscopy as a pivotal tool in characterizing integrated millimeter-wave chips.

Unconventional Superconducting Diode Effects via Antisymmetry and Antisymmetry Breaking.

Symmetry breaking plays a pivotal role in unlocking intriguing properties and functionalities in material systems. For example, the breaking of spatial and temporal symmetries leads to a fascinating phenomenon: the superconducting diode effect. However, generating and precisely controlling the superconducting diode effect pose significant challenges. Here, we take a novel route with the deliberate manipulation of magnetic charge potentials to realize unconventional superconducting flux-quantum diode effects. We achieve this through suitably tailored nanoengineered arrays of nanobar magnets on top of a superconducting thin film. We demonstrate the vital roles of inversion antisymmetry and its breaking in evoking unconventional superconducting effects, namely a magnetically symmetric diode effect and an odd-parity magnetotransport effect. These effects are nonvolatilely controllable through in situ magnetization switching of the nanobar magnets. Our findings promote the use of antisymmetry (breaking) for initiating unconventional superconducting properties, paving the way for exciting prospects and innovative functionalities in superconducting electronics.

Tissue-specific distributions of organic ultraviolet absorbents in free-range chickens and domestic pigeons from Guangzhou, China.

The ecological risks of organic ultraviolet absorbents (UVAs) have been of increasing concern. Studies have found that these chemicals could be accumulated in terrestrial animals and pose toxicities. However, tissue distribution of UVAs in terrestrial species was far from well understood. In this study, free-range chickens and domestic pigeons were selected to investigate the occurrence and tissue distribution of UVAs. Total concentrations of eleven UVAs in muscles ranged from 778 to 2874 (mean 1413 ± 666) ng/g lipid weight, which were higher than those in aquatic species worldwide. Since low UVA concentrations in local environment were previously reported, the results implied the strong accumulation of UVAs in studied species. Brain, stomach and kidney were main target organs for studied UVAs, differentiating from the strong liver sequestration in aquatic species. The mean tissue-to-muscle ratios of 1.02-4.23 further indicated the preferential accumulation of target UVAs in these tissues. The tissue-to-blood ratios of benzophenone (BP), 2-ethylhexyl salicylate (EHS) and homosalate (HMS) in brain were 370, 1207 and 52.0, respectively, implying their preferential accumulation in brain. More research is needed to characterize the toxicokinetics and tissue distribution of UVAs in terrestrial wild species, in order to further understand their potential risks.

Genomic characterization of dryland adaptation in endangered Anxi cattle in China.

Local species exhibit distinctive indigenous characteristics while showing unique productive and phenotypic traits. However, the advent of commercialization has posed a substantial threat to the survival of indigenous species. Anxi cattle, an endangered native breed in China, have evolved unique growth and reproductive characteristics in extreme desert and semidesert ecosystems. In this study, we conducted a genomic comparison of 10 Anxi cattle genomes with those of five other global populations/breeds to assess genetic diversity and identify candidate genomic regions in Anxi cattle. Population structure and genetic diversity analyses revealed that Anxi cattle are part of the East Asian cattle clade, exhibiting higher genetic diversity than commercial breeds. Through selective sweep analysis, we identified specific genetic variations linked to the environmental adaptability of Anxi cattle. Notably, we identified several candidate genes, including CERS3 involved in regulating skin permeability and antimicrobial functions, RBFOX2 associated with cardiac development, SLC16A7 participated in the regulation of pancreatic endocrine function, and SPATA3 related to reproduction. Our findings revealed the distinctive genomic features of Anxi cattle in dryland environments, provided invaluable insights for further research and breed preservation, and had important significance for enriching the domestic cattle breeding gene bank.

Neuronal Mechanisms that Drive Organismal Aging Through the Lens of Perception.

Sensory neurons provide organisms with data about the world in which they live, for the purpose of successfully exploiting their environment. The consequences of sensory perception are not simply limited to decision-making behaviors; evidence suggests that sensory perception directly influences physiology and aging, a phenomenon that has been observed in animals across taxa. Therefore, understanding the neural mechanisms by which sensory input influences aging may uncover novel therapeutic targets for aging-related physiologies. In this review, we examine different perceptive experiences that have been most clearly linked to aging or age-related disease: food perception, social perception, time perception, and threat perception. For each, the sensory cues, receptors, and/or pathways that influence aging as well as the individual or groups of neurons involved, if known, are discussed. We conclude with general thoughts about the potential impact of this line of research on human health and aging.

Mutations involving TGFB and MAPK may be associated with malignancy in granular cell tumors.

Granular cell tumors (GrCTs) are mesenchymal neoplasms of presumed schwannian differentiation that may present as solitary or multifocal lesions with excision usually being curative. A minority of cases, however, show histological features associated with an increased risk for metastasis and are highly aggressive leading to death in about a third of cases. While benign and malignant cases have been shown to harbor mutations in the H + ATPase genes, there is only limited data examining molecular aberrations associated with malignancy. The departmental archives were searched for cases of atypical/malignant GrCTs. Clinical and histopathological features were noted. Whole-exome sequencing was performed. Three cases of malignant GrCTs and one case of atypical GrCTs were included. All three malignant tumors metastasized to distant sites with a median disease-free survival of 16 months and an overall follow-up time of 35 months. Whole-exome sequencing showed mutations involving TGFß and MAPK pathways in all four tumors. Although the cohort size is small, our preliminary findings suggest that mutations involving the TGFß and MAPK pathways may be associated with tumor progression or malignant transformation in GrCT pathogenesis.

Highly Interfacial Active Gemini Surfactants as Simple and Versatile Emulsifiers for Stabilizing, Lubricating and Structuring Liquids.

To date, locking the shape of liquids into non-equilibrium states usually relies on jamming nanoparticle surfactants at an oil/water interface. Here we show that a synthetic water-soluble zwitterionic Gemini surfactant can serve as an alternative to nanoparticle surfactants for stabilizing, structuring and additionally lubricating liquids. By having a high binding energy comparable to amphiphilic nanoparticles at the paraffin oil/water interface, the surfactant can attain near-zero interfacial tensions and ultrahigh surface coverages after spontaneous adsorption. Owing to the strong association between neighboring surfactant molecules, closely packed monolayers with high mechanical elasticity can be generated at the oil/water interface, thus allowing the surfactant to produce not only ultra-stable emulsions but also structured liquids with various geometries by using extrusion printing and 3D printing techniques. By undergoing tribochemical reactions at its sulfonic terminus, the surfactant can endow the resultant emulsions with favorable lubricity even under high load-bearing conditions. Our study may provide new insights into creating complex liquid devices and new-generation lubricants capable of combining the characteristics of both liquid and solid lubricants.

Sparstolonin B inhibits pancreatic adenocarcinoma through the NF-κB signaling pathway.

Pancreatic adenocarcinoma is a highly lethal malignant gastrointestinal tumor. Sparstolonin B is an isocoumarin whose anticancer activity has recently received increasing attention. This study aimed to investigate Sparstolonin B's potential antitumor effect on pancreatic adenocarcinoma. The effect of Sparstolonin B on pancreatic cancer target genes and molecular mechanism was predicted via network pharmacology; Sparstolonin B significantly decreased Panc-1 and SW1990 cell viability and effectively suppressed the proliferation, migration, and invasion of pancreatic cancer cells as shown by CCK-8, colony formation, and Transwell assays. Flow cytometry showed that it induced cell cycle arrest and apoptosis. Sparstolonin B also upregulated Bax levels but decreased those of MMP2 and Bcl-2, downregulated IκBα expression, and upregulated p65 and IκBα phosphorylation; however, it had no effect on total NF-κB p65 levels. The NF-κB pathway inhibitor QNZ reversed these effects. The treatment group (26 µmol/L) had reduced graft volume and weight and fewer Ki-67-positive cells than the control group. Therefore, Sparstolonin B can inhibit the growth and induce the apoptosis of pancreatic cancer cells via the NF-κB signaling pathway and may be a potential novel drug for pancreatic cancer treatment.

Occurrence of methylsiloxanes in indoor store dust in China and potential human exposure.

Methylsiloxanes are synthetic molecules with versatile and extensive applications. Because of their volatile properties, they are easily released from manufactured products and contaminate indoor environments, causing high human exposure. However, available information on their presence in specific microenvironments, and on the related potential risks for human health, is limited. We conducted a survey of sixteen methylsiloxanes species, including three cyclic (D4-D6) and thirteen linear (L4-L16) chemicals, in indoor dust samples from twenty-eight stores representative of six store categories in Beijing, China. Total methylsiloxane concentrations in store dust were 176-54,825 ng/g, depending on the store, with a median of 2196 ng/g. Linear chemicals represented a median proportion of 90.8% of total methylsiloxanes. The measured methylsiloxane concentrations in this study were marginally higher than those reported previously for standard living and working environments. The highest linear and total methylsiloxane concentrations were measured in electronic stores, while the highest cyclic methylsiloxane concentrations were measured in department stores. The presence of methylsiloxanes in the store dust samples was attributed mainly to their release from chemical additives in marketed products. Estimated median total exposure doses under normal and worst-case exposure scenarios were 0.237 and 0.888 ng/kg bw/d, respectively. Further investigation is needed to characterize methylsiloxane distribution in other microenvironments and to evaluate the associated health risks.

A whole genome scan reveals distinct features of selection in Zhaotong cattle of Yunnan province.

Over the years, indigenous cattle have not only played an essential role in securing primary food sources but have also been utilized for labor by humans, making them invaluable genetic resources. The Zhaotong cattle, a native Chinese breed from the Yunnan province, possess excellent meat quality and resistance to heat and humidity. Here we used whole genome sequencing data of 104 animals to delve into the population structure, genomic diversity and potential positive selection signals in Zhaotong cattle. The findings of this study demonstrate that the genetic composition of Zhaotong cattle was primarily derived from Chinese indicine cattle and East Asian cattle. The nucleotide diversity of Zhaotong cattle was only lower than that of Chinese indicine cattle, which was much higher than that of other taurine cattle. Genome-wide selection scans detected a series of positive candidate regions containing multiple key genes related to bone development and metabolism (CA10, GABRG3, GLDN and NOTUM), meat quality traits (ALG8, LINGO2, MYO5B, PRKG1 and GABRB1), immune response (ADA2, BMF, LEF1 and PAK6) and heat resistance (EIF2AK4 and LEF1). In summary, this study supplies essential genetic insights into the genome diversity within Zhaotong cattle and provides a foundational framework for comprehending the genetic basis of indigenous cattle breeds.

Interventions and strategies to prevent medical device-related pressure injury in adult patients: A systematic review.

BACKGROUND: Current evidence shows that medical device-related pressure injury (MDRPI) has a high prevalence (10%) and incidence (12%), and much research has been done to prevent MDRPI in recent years. However, to our knowledge, there is limited systematic review available on interventions and strategies to prevent MDRPI. AIM: To synthesise research evidence on interventions and strategies used to prevent MDRPI. METHODS: This systematic review adhered to the PRISMA Guidelines. We searched six databases including Medline, CINAHL, EMBASE, Cochrane library, Web of Science and ProQuest with no restriction to year of publication. Data were extracted and checked by two authors independently. A narrative summary technique was used to describe the findings. Implementation strategies were grouped into six classifications: dissemination/implementation process/integration/capacity building/sustainability/scale-up strategies. RESULTS: Twenty-four peer-reviewed papers met the inclusion criteria, which comprised of 11 quality improvement projects and 13 original research. Types of devices included respiratory devices (non-invasive ventilation mask, CPAP/BiPAP mask, endotracheal tube), gastrointestinal/urinary devices and other devices. Interventions used included the use of dressing, hyperoxygenated fatty acids, full-face mask, training, and/or multidisciplinary education, use of special securement devices or tube holder, repositioning, application of stockinette, early removal and foam ring use. Common implementation strategies included ongoing staff education, audit and standardising documentation or guideline development. CONCLUSION: Much work on MDRPI prevention strategies has been undertaken. There were a variety of devices reported, however, it is evident that higher quality research is needed. RELEVANCE TO CLINICAL PRACTICE: Current evidence shows that interventions including use of dressing or special securement device, repositioning, and training/multidisciplinary education can be beneficial for MDRPI prevention. High-quality research, such as randomised controlled trials are needed to test the effectiveness of the interventions and their implementation strategies. No patient or public contribution.

Crystallizing Kagome Artificial Spin Ice.

Artificial spin ices are engineered arrays of dipolarly coupled nanobar magnets. They enable direct investigations of fascinating collective phenomena from their diverse microstates. However, experimental access to ground states in the geometrically frustrated systems has proven difficult, limiting studies and applications of novel properties and functionalities from the low energy states. Here, we introduce a convenient approach to control the competing diploar interactions between the neighboring nanomagnets, allowing us to tailor the vertex degeneracy of the ground states. We achieve this by tuning the length of selected nanobar magnets in the spin ice lattice. We demonstrate the effectiveness of our method by realizing multiple low energy microstates in a kagome artificial spin ice, particularly the hardly accessible long range ordered ground state-the spin crystal state. Our strategy can be directly applied to other artificial spin systems to achieve exotic phases and explore new emergent collective behaviors.

Puerarin-V prevents the progression of hypoxia- and monocrotaline-induced pulmonary hypertension in rodent models.

Pulmonary hypertension (PH) is a cardiopulmonary disease characterized by a progressive increase in pulmonary vascular resistance. One of the initial pathogenic factors of PH is pulmonary arterial remodeling under various stimuli. Current marketed drugs against PH mainly relieve symptoms without significant improvement in overall prognosis. Discovering and developing new therapeutic drugs that interfere with vascular remodeling is in urgent need. Puerarin is an isoflavone compound extracted from the root of Kudzu vine, which is widely used in the treatment of cardiovascular diseases. In the present study, we evaluated the efficacy of puerarin in the treatment of experimental PH. PH was induced in rats by a single injection of MCT (50 mg/kg, sc), and in mice by exposure to hypoxia (10% O2) for 14 days. After MCT injection the rats were administered puerarin (10, 30, 100 mg · kg-1 · d-1, i.g.) for 28 days, whereas hypoxia-treated mice were pre-administered puerarin (60 mg · kg-1 · d-1, i.g.) for 7 days. We showed that puerarin administration exerted significant protective effects in both experimental PH rodent models, evidenced by significantly reduced right ventricular systolic pressure (RVSP) and lung injury, improved pulmonary artery blood flow as well as pulmonary vasodilation and contraction function, inhibited inflammatory responses in lung tissues, improved resistance to apoptosis and abnormal proliferation in lung tissues, attenuated right ventricular injury and remodeling, and maintained normal function of the right ventricle. We revealed that MCT and hypoxia treatment significantly downregulated BMPR2/Smad signaling in the lung tissues and PPARγ/PI3K/Akt signaling in the lung tissues and right ventricles, which were restored by puerarin administration. In addition, we showed that a novel crystal type V (Puer-V) exerted better therapeutic effects than the crude form of puerarin (Puer). Furthermore, Puer-V was more efficient than bosentan (a positive control drug) in alleviating the abnormal structural changes and dysfunction of lung tissues and right ventricles. In conclusion, this study provides experimental evidence for developing Puer-V as a novel therapeutic drug to treat PH.

Routine replacement versus replacement as clinical indicated of peripheral intravenous catheters: A multisite randomised controlled trial.

AIMS AND OBJECTIVES: To compare the safety of replacing peripheral intravenous catheter as clinically indicated versus routine replacement on patient outcomes in the Chinese context. BACKGROUND: Some evidence from developed countries recommend replacing peripheral intravenous catheter as clinically indicated; however, there is limited evidence from developing countries. DESIGN: A multisite randomised controlled trial. METHODS: The 3050 participants from three hospitals in China were randomly assigned to clinically indicated or routine replacement groups. Patients in the clinically indicated group had the catheters kept in situ until any of the following clinical signs appeared: phlebitis, infiltration, occlusion, displacement, local infection and diagnosed catheter-related bloodstream infection. Patients in the routine replacement group had their peripheral intravenous catheters replaced every 96 hours. The outcomes of phlebitis, infiltration, occlusion, displacement; catheter-related bloodstream infection, all-cause bloodstream infection, and local infection were compared. CONSORT checklist was used to guide the reporting of this RCT. RESULTS: The risk of phlebitis, phlebitis per 1000 catheter days, occlusion, dislodgement, all bloodstream infections, local infection and mortality between the two groups were not significantly different. The risk of infiltration was increased in the clinically indicated group (HR 1.29). There was no catheter-related bloodstream infection reported in either group. Patients' first peripheral intravenous catheter dwelling time and cumulative indwelling time of all peripheral intravenous catheters in the clinically indicated group were significantly longer than the routine replacement group. There was no statistical significant difference in survival times from phlebitis between the two groups. CONCLUSIONS: In the Chinese context, removing peripheral catheters as clinical indicated did not increase the risk of phlebitis, occlusion, catheter displacement and catheter infection; however, there was an increased infiltration incidence. RELEVANCE TO CLINICAL PRACTICE: In developing countries, removing peripheral catheters as clinical indicated is feasible, but more frequent observations of infiltration are highly recommended.

Occurrence of methylsiloxanes in sediments from a subtropical river-lake system in eastern China and its implication for ecological risks.

Distribution of methylsiloxanes in environment is still far from being well studied. Little is known about the concentrations and associated risks of these chemicals in river-lake systems. This study investigated the occurrence of twelve methylsiloxanes (D4-D6, L5-L13) in the sediments from Lake Chaohu and its inflowing rivers, China, and found the total concentrations (ng/g dry weight) were in the range of 47.1-496 and 239-3593, respectively. Linear congeners were dominant, representing a median of 62.8% and 58.7% of the total concentrations found in the lake and its inflowing rivers, respectively. In general, the concentrations of sediment methylsiloxanes in the investigated river-lake system were low to moderate, compared with the results reported previously in other waters. Source assessment indicated that the emissions from industrial activities and the use of silicone-containing products were the main contributors of sediment methylsiloxanes in the investigated waters. D4 and D5 in 18.5% and 11.1% of river sediment samples might pose ecological risks to fish. The risks from the linear congeners in sediments in the area were not estimated due to no related benchmarks available. More studies are needed to investigate the occurrence of these chemicals and associated risks in aquatic environment.

Occurrence and trophic transfer of synthetic musks in the freshwater food web of a large subtropical lake.

Synthetic musks (SMs) have drawn worldwide attention, as they are persistent, bioaccumulative, and toxic to many organisms. There is not enough information on the bioaccumulation and trophodynamic behavior of SMs in freshwater food webs to reliably understand the associated ecological risks. In this study, the concentrations of six SM congeners in fifteen aquatic species from Lake Chaohu, China, was investigated. The total concentrations of the six SMs ranged from 0.29 to 59.7 ng/g dry weight (median, 4.41) in fish muscle tissue and in the whole body tissues of small fish species and shrimps. Galaxolide (HHCB) and tonalide (AHTN) were the predominant congeners, accounting for 65.0% and 28.5% of the total SM concentration, respectively. On the whole, the total concentrations of SMs in livers and gills were 0.18-32.8 and 0.84-254 times higher than those in muscle tissues in fish species, respectively. In the food web of Lake Chaohu, cashmeran (DPMI) and HHCB showed a trend towards trophic magnification, and AHTN tended to show trophic dilution, but these trends were not statistically significant. This suggested that the trophic transfer of these chemicals through the food web was strongly influenced by many factors, including tissue-specific distribution within individuals at higher trophic levels. More investigation into the trophic transfer of SMs in aquatic ecosystems and the factors influencing uptake is needed.

Reconfigurable Pinwheel Artificial-Spin-Ice and Superconductor Hybrid Device.

The ability to control the potential landscape in a medium of interacting particles could lead to intriguing collective behavior and innovative functionalities. Here, we utilize spatially reconfigurable magnetic potentials of a pinwheel artificial-spin-ice (ASI) structure to tailor the motion of superconducting vortices. The reconstituted chain structures of the magnetic charges in the pinwheel ASI and the strong interaction between magnetic charges and superconducting vortices allow significant modification of the transport properties of the underlying superconducting thin film, resulting in a reprogrammable resistance state that enables a reversible and switchable vortex Hall effect. Our results highlight an effective and simple method of using ASI as an in situ reconfigurable nanoscale energy landscape to design reprogrammable superconducting electronics, which could also be applied to the in situ control of properties and functionalities in other magnetic particle systems, such as magnetic skyrmions.

Formononetin ameliorates myocardial ischemia/reperfusion injury in rats by suppressing the ROS-TXNIP-NLRP3 pathway.

Formononetin (FN), a methoxy isoflavone abundant in many plants and herbs, has been evidently proven to possess multiple medicinal properties. Our study aimed to clarify the impact of FN on myocardial ischemia/reperfusion (I/R) injury (MIRI) and the involved mechanism. A rat model of MIRI was produced by ligation and loosening of the left anterior descending (LAD) branch of the coronary artery. Rats received 10 and 30 mg/kg of FN when the reperfusion started. At 24 h after surgery, cardiac function, infarct size, and sera levels of the cardiac markers and inflammatory mediators were measured. To mimic the inflammasome activation in cardiomyocytes, neonatal rat cardiomyocytes (NRCMs) were cultured and treated with lipopolysaccharide (LPS) plus nigericin. Cell death and reactive oxygen species (ROS) were determined. Myocardial expression and activation of the nucleotide-binding domain and leucine-rich repeat-containing protein 3 (NLRP3) inflammasome in rats were examined by western blotting. The level of thioredoxin interacting protein (TXNIP)-NLRP3 interaction was assessed. FN notably attenuated cardiac dysfunction, infarct size, release of cardiac markers, and elevation of TNF-α, IL-1ß, and IL-6. FN alleviated LPS plus nigericin-induced injury and ROS increase in NRCMs. Western blotting revealed that FN suppressed the activation of NLRP3 inflammasome and TXNIP-NLRP3 interaction in rats. These findings indicate that FN ameliorated MIRI in rats and inhibited the activation of the NLRP3 inflammasome, at least partially, attributable to suppression of the ROS-TXNIP-NLRP3 pathway.