Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

FLT3+ DC inhibits immune rejection via interaction with Treg in liver transplantation.

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) primarily expressed in hematopoietic stem cells and dendritic cells (DCs). While FLT3 plays a critical role in the proliferation, development and maintenance of DCs, thus influencing immune responses under both normal and pathological conditions, there also exists some evidence that FLT3+DC may be involved with immune responses in liver transplantation (LT). In this study, results from single-cell sequencing data analysis revealed a clear relationship between FLT3+DCs and Regulatory T cells (Tregs) in liver tissue of LT recipients. In peripheral blood samples of LT patients, levels of FLT3+DCs were decreased post-LT-surgery, while Tregs were increased. In a LT mouse model, levels of FLT3+DCs in the liver and bone marrow exhibited an initial time-dependent decrease followed by an increase after LT surgery. Results as obtained with co-culture experiments using mature BMDCs and CD4+ T cells revealed fluctuations in Tregs in response to FLT3 inhibitors and the FLT3 ligand. These findings suggest that FLT3+DCs could emerge as a novel target for mitigating immune rejection in LT.

Refining the rheological characteristics of high drug loading ointment via SDS and machine learning.

This paper presents an optimized preparation process for external ointment using the Definitive Screening Design (DSD) method. The ointment is a Traditional Chinese Medicine (TCM) formula developed by Professor WYH, a renowned TCM practitioner in Jiangsu Province, China, known for its proven clinical efficacy. In this study, a stepwise regression model was employed to analyze the relationship between key process factors (such as mixing speed and time) and rheological parameters. Machine learning techniques, including Monte Carlo simulation, decision tree analysis, and Gaussian process, were used for parameter optimization. Through rigorous experimentation and verification, we have successfully identified the optimal preparation process for WYH ointment. The optimized parameters included drug ratio of 24.5%, mixing time of 8 min, mixing speed of 1175 rpm, petroleum dosage of 79 g, liquid paraffin dosage of 6.7 g. The final ointment formulation was prepared using method B. This research not only contributes to the optimization of the WYH ointment preparation process but also provides valuable insights and practical guidance for designing the preparation processes of other TCM ointments. This advanced DSD method enhances the screening approach for identifying the best preparation process, thereby improving the scientific rigor and quality of TCM ointment preparation processes.

Establishment of XRD fourier fingerprint identification method of realgar decoction pieces and its anti-tumor activity in tumor-in-situ transplanted mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Realgar, a traditional mineral Chinese medicine, has been used in China for more than 2000 years. It has been recorded in many ancient and modern works that it has anti-cancer and anti-tumor effects. Of course, colon cancer is also within the scope of its treatment. Realgar needs to be processed into realgar decoction pieces by water grinding before being used for medicine. To ensure the consistency of efficacy and quality of realgar decoction pieces, modern methods need to be used for further quality control. AIM OF THE STUDY: The research of traditional mineral Chinese medicine is relatively difficult, and the related research is less. The purpose of this study is to control the quality of realgar decoction pieces by modern analytical technology and analyze its components. On this basis, its anti-colon cancer activity was discussed. MATERIALS AND METHODS: Several batches of realgar decoction pieces were analyzed by XRD, and the components of realgar decoction pieces were obtained. The quality control fingerprints of realgar decoction pieces were established by processing XRD spectra and similarity evaluation. Then, the effects of realgar decoction pieces on apoptosis of CT26 and HTC-116 cells were observed in vitro by Hoechst 33258 staining, flow cytometry, measurement of mitochondrial membrane potential and Western blot; In vivo, the mouse model of tumor-in-situ transplantation of colon cancer was established, and the related indexes were observed. RESULT: The explorations showed that the XRD Fourier fingerprints of realgar decoction pieces samples that had the same phase revealed 10 common peaks, respectively. The similarity evaluation of the established XRD Fourier fingerprint was greater than 0.900. We also demonstrated that realgar decoction pieces can promote apoptosis and inhibit tumor growth in colon cancer cells, its activating effect on p53 protein, and its safety when used within reasonable limits. CONCLUSION: The quality control of realgar decoction pieces by XRD is scientific and has the inhibitory effect on colon cancer, which has the development potential.

An allocentric human odometer for perceiving distances on the ground plane.

We reliably judge locations of static objects when we walk despite the retinal images of these objects moving with every step we take. Here, we showed our brains solve this optical illusion by adopting an allocentric spatial reference frame. We measured perceived target location after the observer walked a short distance from the home base. Supporting the allocentric coding scheme, we found the intrinsic bias 1, 2 , which acts as a spatial reference frame for perceiving location of a dimly lit target in the dark, remained grounded at the home base rather than traveled along with the observer. The path-integration mechanism responsible for this can utilize both active and passive (vestibular) translational motion signals, but only along the horizontal direction. This anisotropic path-integration finding in human visual space perception is reminiscent of the anisotropic spatial memory finding in desert ants 3 , pointing to nature's wondrous and logically simple design for terrestrial creatures.

Single-cell RNA sequencing reveals recruitment of the M2-like CCL8high macrophages in Lewis lung carcinoma-bearing mice following hypofractionated radiotherapy.

BACKGROUND: Tumor-associated macrophages (TAMs) play a pivotal role in reshaping the tumor microenvironment following radiotherapy. The mechanisms underlying this reprogramming process remain to be elucidated. METHODS: Subcutaneous Lewis lung carcinoma (LLC) murine model was treated with hypofrationated radiotherapy (8 Gy × 3F). Single-cell RNA sequencing was utilized to identify subclusters and functions of TAMs. Multiplex assay and enzyme-linked immunosorbent assay (ELISA) were employed to measure serum chemokine levels. Bindarit was used to inhibit CCL8, CCL7, and CCL2. The infiltration of TAMs after combination treatment with hypofractionated radiotherapy and Bindarit was quantified with flow cytometry, while the influx of CD206 and CCL8 was assessed by immunostaining. RESULTS: Transcriptome analysis identified a distinct subset of M2-like macrophages characterized by elevated Ccl8 expression level following hypofractionated radiotherapy in LLC-bearing mice. Remarkbly, hypofractionated radiotherapy not only promoted CCL8high macrophages infiltration but also reprogrammed them by upregulating immunosuppressive genes, thereby fostering an immunosuppressive tumor microenvironment. Additioinally, hypofractionated radiotherapy enhanced the CCL signaling pathway, augmenting the pro-tumorigenic functions of CCL8high macrophages and boosting TAMs recruitment. The adjunctive treatment combining hypofractionated radiotherapy with Bindarit effectively reduced M2 macrophages infiltration and prolonged the duration of local tumor control. CONCLUSIONS: Hypofractionated radiotherapy enhances the infiltration of CCL8high macrophages and amplifies their roles in macrophage recruitment through the CCL signaling pathway, leading to an immunosuppressive tumor microenvironment. These findings highlight the potential of targeting TAMs and introduces a novel combination to improve the efficacy of hypofractionated radiotherapy.

Pediatric Pterygopalatine Fossa Schwannoma Presenting as Vision Loss: A Case Report and Literature Review.

Neurosynovial tumors, originating from Schwann cells within nerve sheaths, are benign entities, with 25% to 45% manifesting in the head and neck region. However, occurrences in the pterygopalatine fossa (PPF) are exceptionally rare, and only a handful of cases have been documented. In this report, we present the unique case of a 6-year-old child exhibiting a sizable soft tissue mass in the left PPF, extending into the inferior orbital fissure. The patient underwent successful intranasal endoscopic removal of PPF schwannoma utilizing the prelacrimal recess approach, with postoperative pathology confirming the diagnosis of schwannoma. Schwannomas within the PPF are particularly uncommon, and instances of such tumors in pediatric patients are even more exceptional. This case highlights the diagnostic and therapeutic challenges associated with PPF schwannomas in children, emphasizing the significance of a multidisciplinary approach for optimal management. In addition, a comprehensive literature review is presented to provide insights into the existing knowledge on this rare entity, further contributing to the understanding of pediatric PPF schwannomas.

STIC-HD live flow technology in the antenatal diagnosis of scimitar syndrome: A case report.

Scimitar syndrome (SS) is a rare entity with an incidence of approximately 1-3 in 200 000 people. It is typically characterized by complete or partial anomalous pulmonary venous drainage from the right lung into the systemic venous circulation, most commonly the inferior vena cava (IVC). For the first time, we report the diagnosis of SS in a fetus in utero using four-dimensional (4D) spatiotemporal image correlation combined with high-definition live flow rendering mode (STIC-HD live flow).

SIRT3-dependent mitochondrial redox homeostasis mitigates CHK1 inhibition combined with gemcitabine treatment induced cardiotoxicity in hiPSC-CMs and mice.

Administration of CHK1-targeted anticancer therapies is associated with an increased cumulative risk of cardiac complications, which is further amplified when combined with gemcitabine. However, the underlying mechanisms remain elusive. In this study, we generated hiPSC-CMs and murine models to elucidate the mechanisms underlying CHK1 inhibition combined with gemcitabine-induced cardiotoxicity and identify potential targets for cardioprotection. Mice were intraperitoneally injected with 25 mg/kg CHK1 inhibitor AZD7762 and 20 mg/kg gemcitabine for 3 weeks. hiPSC-CMs and NMCMs were incubated with 0.5 uM AZD7762 and 0.1 uM gemcitabine for 24 h. Both pharmacological inhibition or genetic deletion of CHK1 and administration of gemcitabine induced mtROS overproduction and pyroptosis in cardiomyocytes by disrupting mitochondrial respiration, ultimately causing heart atrophy and cardiac dysfunction in mice. These toxic effects were further exacerbated with combination administration. Using mitochondria-targeting sequence-directed vectors to overexpress CHK1 in cardiomyocyte (CM) mitochondria, we identified the localization of CHK1 in CM mitochondria and its crucial role in maintaining mitochondrial redox homeostasis for the first time. Mitochondrial CHK1 function loss mediated the cardiotoxicity induced by AZD7762 and CHK1-knockout. Mechanistically, mitochondrial CHK1 directly phosphorylates SIRT3 and promotes its expression within mitochondria. On the contrary, both AZD7762 or CHK1-knockout and gemcitabine decreased mitochondrial SIRT3 abundance, thus resulting in respiration dysfunction. Further hiPSC-CMs and mice experiments demonstrated that SIRT3 overexpression maintained mitochondrial function while alleviating CM pyroptosis, and thereby improving mice cardiac function. In summary, our results suggest that targeting SIRT3 could represent a novel therapeutic approach for clinical prevention and treatment of cardiotoxicity induced by CHK1 inhibition and gemcitabine.

A Rare Case of Sinonasal Pleomorphic Adenoma.

Pleomorphic adenoma (PA) is the most prevalent benign tumor of the salivary glands, characterized by both epithelial and mesenchymal differentiation. It primarily originates within the parotid and submandibular glands, with only rare occurrences in the minor salivary glands. PA in the sinonasal area is extremely rare. Herein, we present a case of a 61-year-old female with a large soft tissue mass in the paranasal sinus and nasal cavity, as evidenced by computed tomography imaging. The patient suffered from repeated nasal congestion for more than 6 months. Eventually, the mass was completely resected using an endoscopic endonasal prelacrimal approach under general anesthesia. Postoperative pathological examination revealed the presence of PA in the nasal sinus.

Expression and Significance of Galectin-1 and Galectin-3 in the Serum and Placental Tissues of Patients with Intrahepatic Cholestasis of Pregnancy.

Background: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease, usually occurring in the third trimester of pregnancy. Its typical clinical manifestations are itching and elevated serum total bile acid levels, which are more harmful to the fetus, and can lead to a variety of adverse pregnancy outcomes. This paper discusses the expressions of galectin -1 and 3 in the serum and placenta of ICP patients and their relationship with the effect of the incidence of ICP. Methods: Galectin-1 and 3 in serum and placenta were detected in 22 pregnant women with ICP and 20 healthy pregnant women admitted to the obstetrics Department of Northern Jiangsu People's Hospital from May 2021 to February 2022. Results: Serum levels of galectin-1 and galectin-3 in ICP pregnant women were significantly higher than those in controls, with significant differences (P<0.05). Placental galectin-1 and 3 were higher in normal pregnant women, and there were statistical differences between groups (P<0.05). Conclusion: In ICP, the maternal serum and placental galectin-1 and 3 levels were significantly increased, both of which may play an important role in the development of ICP, which may be the initiation factor of ICP pathophysiology, a marker of ICP prediction, and a target of ICP prevention strategies.

Short-chain fatty acids (SCFAs) as potential resuscitation factors that promote the isolation and culture of uncultured bacteria in marine sediments.

Many marine bacteria are difficult to culture because they are dormant, rare or found in low-abundances. Enrichment culturing has been widely tested as an important strategy to isolate rare or dormant microbes. However, many more mechanisms remain uncertain. Here, based on 16S rRNA gene high-throughput sequencing and metabolomics technology, it was found that the short-chain fatty acids (SCFAs) in metabolites were significantly correlated with uncultured bacterial groups during enrichment cultures. A pure culture analysis showed that the addition of SCFAs to media also resulted in high efficiency for the isolation of uncultured strains from marine sediments. As a result, 238 strains belonging to 10 phyla, 26 families and 82 species were successfully isolated. Some uncultured rare taxa within Chlorobi and Kiritimatiellaeota were successfully cultured. Amongst the newly isolated uncultured microbes, most genomes, e.g. bacteria, possess SCFA oxidative degradation genes, and these features might aid these microbes in better adapting to the culture media. A further resuscitation analysis of a viable but non-culturable (VBNC) Marinilabiliales strain verified that the addition of SCFAs could break the dormancy of Marinilabiliales in 5 days, and the growth curve test showed that the SCFAs could shorten the lag phase and increase the growth rate. Overall, this study provides new insights into SCFAs, which were first studied as resuscitation factors in uncultured marine bacteria. Thus, this study can help improve the utilisation and excavation of marine microbial resources, especially for the most-wanted or key players. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00187-w.

Glycyrrhizic acid glycosides reduces extensive tripterygium glycosides-induced lipid deposition in hepatocytes.

Aim: Tripterygium glycosides (TG) extracted from the plant Tripterygium wilfordii Hook F has been used to treat chronic kidney diseases for many years. However, hepatotoxicity limits its clinical application. Glycyrrhizic acid glycosides (GA) can reduce TG hepatotoxicity, however, further investigation into the underlying molecular mechanisms by which GA attenuates TG-induced hepatotoxicity is required. Methods: Sprague‒Dawley rats were randomly divided into the control group, the TG groups (TG189 mg/kg group, TG472.5 mg/kg group), and the TG + GA groups (TG189 mg/kg + GA20.25 mg/kg group, TG472.5 mg/kg + GA20.25 mg/kg group). After 21 consecutive days of intragastric administration, structural and molecular changes in hepatocytes were detected. Results: After 21 days of TG treatment, the serum level of the total bilirubin, triglyceride, total cholesterol, and low-density lipoprotein cholesterol increased in the TG189 mg/kg and TG472.5 mg/kg groups when compared to the control group. High-density lipoprotein cholesterol levels were reduced in both TG groups. The ultrastructure of hepatocytes and the structural integrity of the liver were compromised. In addition, the relevant molecular level of the peroxisome proliferators-activated receptor α (PPARα) and acyl-CoA synthetase long-chain family members (ACSLs) pathway was modulated. With the addition of 20.25 mg/kg GA, the serum biochemical indexes and liver tissue structure ultrastructure of hepatocytes were improved, and the PPARα-ACSLs pathway was corrected. Conclusion: The combined application of GA and TG improved abnormal lipid metabolism, repaired liver structure, reduced lipid deposition in hepatocytes, and reduced TG-induced hepatotoxicity.

Observation on the curative effect of neck acupuncture and scalp acupuncture in improving cognitive impairment and quality of life after stroke

Objective: To explore the intervention value of needle acupuncture and scalp acupuncture in improving cognitive impairment and life in stroke patients; Methods: A total of 62 stroke patients who were healed in our hospital from August 2019 to October 2021 were retrospectively selected as the research objects, and were divided into a combined healing cluster (Combined healing cluster, CTG, n=31, The patients received conventional healing combined with acupuncture and acupuncture) and the general healing cluster (GTG, n=31). The healing effects of the two clusters were contrast, and the National Institutes of Health Stroke Scale (NIHSS), neurological deficit score before and after healing Table (NDS) and Barthel Index (BI) score changes, the follow-up outcomes of the two clusters of patients were calculated and contrast between the two clusters; Results: (1) The total effective rate of patients in CTG cluster was 96.77%, and the total effective rate of patients in GTG cluster was 80.65%, and the variation in effective rate between the two clusters was notable (P<0.05). The NIHSS and NDS marks of the CTG cluster were notably bottom than those of the GTG cluster, and the variation between the clusters was notable (P<0.05). (3) On the 7th, 15th and 30th days of healing, the BI marks of the CTG cluster were notably upper than those in the GTG cluster, and the variation between the clusters was notable (P<0.05). (4) There were a total of 3 recurrences in the CTG cluster after 6 months of follow-up, with a recurrence rate of 10.00%, and a total of 9 recurrences in the GTG cluster. The recurrence rate of patients in the CTG cluster was notably bottom than that in the GTG cluster (P<0.05) (AU)

Feasibility analysis of combined traditional Chinese medicine fumigation and electromyography biofeedback in injured players with shoulder-hand syndrome after stroke

Objective: Exploring the feasibility of combining herbal fumigation and myoelectric biofeedback therapy in injured players with post-stroke shoulder-hand syndrome. Methods: A total of 80 players with shoulder-hand syndrome after stroke who were healed in our hospital from July 2019 to June 2021 were retrospectively opted as the research subjects, and were divided into a joint intervention cluster (JIG) according to the variations in their healing methods. cluster, n=40, receiving traditional Chinese medicine fumigation and EMG biofeedback healing) and EMG healing cluster (Electromyobiological feedback cluster, EFG cluster, n=40), the healing effect, changes in simplified FMA mark of upper limbs before and after healing, and healing effects were contrasted between the two clusters. The changes of the front and rear shoulder pain and the pain part of the High Coast Shoulder Joint Function Rating Scale were recorded, and the occurrence of adverse reactions in the two clusters of injured players was recorded; Results: The total effective rate of injured players in the JIG cluster was 97.50% (39/40), which was notably upper than 85.00% (34/40) in the EFG cluster, and the variation between the clusters was notable (P<0.05). None notable variation in the simplified FMA mark between the clusters (P>0.05). On the 7th, 14th, and 28th days of healing, the simplified FMA mark of the upper limbs of the JIG cluster was notably upper than that of the EFG cluster, and the variation was notable (P>0.05). P<0.05); before healing, None notable variation between the two clusters in the degree of shoulder pain and the pain part of the Gaoshore Shoulder Joint Function Assessment Scale (P>0.05). After 28 days of healing, the degree of shoulder pain in the JIG cluster was notably bottom In the EFG cluster, the pain mark of the Gaoan Shoulder Joint Function Assessment Scale was notably upper than that in the EFG cluster, and the variation between the two clusters was notable (P<0.05) (AU)

Inhibition of ACSL4 Alleviates Parkinsonism Phenotypes by Reduction of Lipid Reactive Oxygen Species.

Ferroptosis is a programmed cell death pathway that is recently linked to Parkinson's disease (PD), where the key genes and molecules involved are still yet to be defined. Acyl-CoA synthetase long-chain family member 4 (ACSL4) esterifies polyunsaturated fatty acids (PUFAs) which is essential to trigger ferroptosis, and is suggested as a key gene in the pathogenesis of several neurological diseases including ischemic stroke and multiple sclerosis. Here, we report that ACSL4 expression in the substantia nigra (SN) was increased in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated model of PD and in dopaminergic neurons in PD patients. Knockdown of ACSL4 in the SN protected against dopaminergic neuronal death and motor deficits in the MPTP mice, while inhibition of ACSL4 activity with Triacsin C similarly ameliorated the parkinsonism phenotypes. Similar effects of ACSL4 reduction were observed in cells treated with 1-methyl-4-phenylpyridinium (MPP+) and it specifically prevented the lipid ROS elevation without affecting the mitochondrial ROS changes. These data support ACSL4 as a therapeutic target associated with lipid peroxidation in PD.

Construction and analysis of a conjunctive diagnostic model of HNSCC with random forest and artificial neural network.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous tumor that is highly aggressive and ranks fifth among the most common cancers worldwide. Although, the researches that attempted to construct a diagnostic model were deficient in HNSCC. Currently, the gold standard for diagnosing head and neck tumors is pathology, but this requires a traumatic biopsy. There is still a lack of a noninvasive test for such a high-incidence tumor. In order to screen genetic markers and construct diagnostic model, the methods of random forest (RF) and artificial neural network (ANN) were utilized. The data of HNSCC gene expression was accessed from Gene Expression Omnibus (GEO) database; we selected three datasets totally, and we combined 2 datasets (GSE6631 and GSE55547) for screening differentially expressed genes (DEGs) and chose another dataset (GSE13399) for validation. Firstly, the 6 DEGs (CRISP3, SPINK5, KRT4, MMP1, MAL, SPP1) were screened by RF. Subsequently, ANN was applied to calculate the weights of 6 genes. Besides, we created a diagnostic model and nominated it as neuralHNSCC, and the performance of neuralHNSCC by area under curve (AUC) was verified using another dataset. Our model achieved an AUC of 0.998 in the training cohort, and 0.734 in the validation cohort. Furthermore, we used the Cell-type Identification using Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm to investigate the difference in immune cell infiltration between HNSCC and normal tissues initially. The selected 6 DEGs and the constructed novel diagnostic model of HNSCC would make contributions to the diagnosis.

Salivary Duct Carcinoma Originated from the Inferior Turbinate: A Rare Case Report.

Salivary duct carcinoma (SDC) is an uncommon but highly aggressive tumor with a poor prognosis. SDC mainly arises from the major salivary glands, typically the parotid gland. Here, we report a rare case of sinonasal SDC in a 54-year-old male patient that might have originated from the inferior turbinate. The patient presented with left nasal congestion and rhinorrhea. Following an endoscopic intervention, the histopathological examination revealed a diagnosis of SDC, characterized by the formation of solid cancer nests and central comedo-type necrosis. Given the highly aggressive nature and unfavorable prognosis of SDC, it is essential to consider it as a differential diagnosis for unilateral nasal tumors.

Insulin reduces pyroptosis-induced inflammation by PDHA1 dephosphorylation-mediated NLRP3 activation during myocardial ischemia-reperfusion injury.

BACKGROUND: Previous studies proved that pyrin domain-containing protein 3 (NLRP3)-induced pyroptosis plays an important role in Myocardial ischemia-reperfusion injury (MIRI). Insulin can inhibit the activation of NLRP3 inflammasome, although the exact mechanism remains unclear. The aim of this study was to determine whether insulin reduces NLRP3-induced pyroptosis by regulating pyruvate dehydrogenase E1alpha subunit (PDHA1) dephosphorylation during MIRI. METHODS: Rat hearts were subject to 30 min global ischemia followed by 60 min reperfusion, with or without 0.5 IU/L insulin. Myocardial ischemia-reperfusion injury was evaluated by measuring myocardial enzymes release, Cardiac hemodynamics, pathological changes, infarct size, and apoptosis rate. Cardiac aerobic glycolysis was evaluated by measuring ATP, lactic acid content, and pyruvate dehydrogenase complex (PDHc) activity in myocardial tissue. Recombinant adenoviral vectors for PDHA1 knockdown were constructed. Pyroptosis-related proteins were measured by Western blotting analysis, immunohistochemistry staining, and ELISA assay, respectively. RESULTS: It was found that insulin significantly reduced the area of myocardial infarction, apoptosis rate, and improved cardiac hemodynamics, pathological changes, energy metabolism. Insulin inhibits pyroptosis-induced inflammation during MIRI. Subsequently, Adeno-associated virus was used to knock down cardiac PDHA1 expression. Knockdown PDHA1 not only promoted the expression of NLRP3 but also blocked the inhibitory effect of insulin on NLRP3-mediated pyroptosis in MIRI. CONCLUSIONS: Results suggest that insulin protects against MIRI by regulating PDHA1 dephosphorylation, its mechanism is not only to improve myocardial energy metabolism but also to reduce the NLRP3-induced pyroptosis.