Outcomes of pulmonary endarterectomy for patients with pulmonary artery sarcoma.

Objective: Pulmonary artery sarcoma (PAS) is an exceedingly rare and insufficiently investigated disease, leading to uncertain in its optimal management. This study aims to present our institutional experience and the outcomes of pulmonary endarterectomy for PAS. Methods: We gathered clinical characteristics, intraoperative data, postoperative outcomes, and prognosis information from PAS patients who underwent surgical treatment at our institution between December 2016 and September 2023. Results: A total of 20 patients with PAS underwent pulmonary endarterectomy. The median age of the patients was 52 (IQR 45, 57) years, with 12 patients (60%) being female. Intimal sarcoma was confirmed in 19 patients, while the remaining one was diagnosed with large cell neuroendocrine carcinoma. The perioperative mortality rate was three cases (15%). Follow-up was conducted for a median duration of 14 months (range: 1-61). During the follow-up period, 11 patients experienced recurrence or metastasis, and 5 patients succumbed to the disease. The estimated cumulative survival rates at 1 and 2 years for all 20 patients were 66.4% and 55.3%, respectively. Conclusion: Pulmonary endarterectomy emerges as a palliative but effective approach for managing PAS, particularly when complemented with postoperative therapies such as chemotherapy and targeted therapy, which collectively contribute to achieving favorable long-term survival outcomes.

Riociguat as bridging therapy to pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension: a retrospective cohort study.

Background: In operable chronic thromboembolic pulmonary hypertension (CTEPH) patients, the utilization of bridging therapy with targeted medications prior to pulmonary endarterectomy (PEA) remains a topic of controversy, despite being common in cases of severe hemodynamic impairment. This study aims to assess the impact of riociguat as a bridging therapy on postoperative hemodynamics and outcomes. Methods: We conducted a retrospective study involving patients undergoing PEA from December 2016 to November 2023. Patients were categorized into two groups based on the use of riociguat before PEA. Pulmonary vascular resistance (PVR) following riociguat administration was assessed pre-PEA. Postoperative outcomes, including mortality, complications, and hemodynamics, were compared, employing propensity score matching analysis. Results: Among the patients, 41.8% (n=56) received riociguat as bridging therapy. In patients with PVR ≥800 dynes·sec·cm-5, riociguat resulted in a reduction in PVR {1,207 [974-1,698] vs. 1,125 [928-1,486] dynes·sec·cm-5, P<0.01}, while no significant difference was observed in patients with PVR <800 dynes·sec·cm-5 {641 [474-740] vs. 600 [480-768] dynes·sec·cm-5, P=0.46}. After propensity score matching, each group included 26 patients. The overall perioperative mortality rate was 2.6%. Postoperative PVR {326 [254-398] vs. 361 [290-445] dynes·sec·cm-5, P=0.35} was similar in the riociguat group compared to the control group. The incidence of residual pulmonary hypertension (PH) and other postoperative outcomes were also comparable. Conclusions: The use of riociguat as bridging therapy demonstrated hemodynamic improvement before PEA in patients with high preoperative PVR. However, no additional benefits in postoperative mortality or hemodynamics were observed.

Targeting mitochondrial dysfunction in atopic dermatitis with trilinolein: A triacylglycerol from the medicinal plant Cannabis fructus.

BACKGROUND: Atopic dermatitis (AD) is a common skin condition that causes chronic and recurring eczema lesions. Prior research has indicated that Cannabis fructus, the mature fruit of Cannabis sativa, has an antioxidant effect. Historically, Cannabis fructus has been used in cosmetics and medicine. However, there is limited knowledge regarding its biological components and the mechanisms by which it prevents and treats AD. OBJECTIVES: HPLC-ESI-MS/MS analysis was utilized to identify the main compounds of Cannabis fructus, and trilinolein was extracted using chromatographic techniques. The potential of trilinolein in the prevention of AD was assessed, and its underlying mechanisms of action were elucidated. METHODS: The distribution of distinct cellular subpopulations and the principal biological processes implicated in the pathogenesis of AD were assessed through a comparative study involving chronic AD patients and healthy controls (HCs). Differential gene expression was validated in clinical samples from the lesions of AD patients and the healthy skin of controls. The pharmacodynamic activity of trilinolein was validated in dinitrochlorobenzene (DNCB)-induced BALB/c mice and in IL-4- and TNF-α-induced HaCaT cells. Proteomics analyse was employed to investigate its mechanisms. RESULTS: Single-cell transcriptome analysis revealed that chronic AD is characterized by abnormal keratinocyte differentiation and oxidative stress damage. When topically applied, trilinolein can effectively improve AD-like skin lesions induced by DNCB. It increases the expression of terminal differentiation proteins and decreases the expression of NADPH oxidase 2 (NOX2), with a therapeutic effect comparable to that of the positive control drug crisaborole. Additionally, trilinolein reduced ROS fluorescence intensity, restored mitochondrial morphology and membrane potential, and decreased mitochondrial DNA (mtDNA) release in keratinocytes stimulated with IL-4 and TNF-α. Moreover, trilinolein increased the protein expression of AhR, CYP1A1, and Nrf2 in a dose-dependent manner. The effect of trilinolein on keratinocyte terminal differentiation proteins and ROS levels was blocked by the addition of an AhR inhibitor. CONCLUSION: The study suggests that trilinolein from Cannabis fructus alleviates NOX2-dependent mitochondrial dysfunction and repair the skin barrier via AhR-Nrf2 pathway, making it a promising agent for the prevention and treatment of AD.

Integrated transcriptomic and immunological profiling reveals new diagnostic and prognostic models for cutaneous melanoma.

The mortality rate associated with cutaneous melanoma (SKCM) remains alarmingly high, highlighting the urgent need for a deeper understanding of its molecular underpinnings. In our study, we leveraged bulk transcriptome sequencing data from the SKCM cohort available in public databases such as TCGA and GEO. We utilized distinct datasets for training and validation purposes and also incorporated mutation and clinical data from TCGA, along with single-cell sequencing data from GEO. Through dimensionality reduction, we annotated cell subtypes within the single-cell data and analyzed the expression of tumor-related pathways across these subtypes. We identified differentially expressed genes (DEGs) in the training set, which were further refined using the Least Absolute Shrinkage and Selection Operator (LASSO) machine learning algorithm, employing tenfold cross-validation. This enabled the construction of a prognostic model, whose diagnostic efficacy we subsequently validated. We conducted Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses on the DEGs, and performed immunological profiling on two risk groups to elucidate the relationship between model genes and the immune responses relevant to SKCM diagnosis, treatment, and prognosis. We also knocked down the GMR6 expression level in the melanoma cells and verified its effect on cancer through multiple experiments. The results indicate that the GMR6 gene plays a role in promoting the proliferation, invasion, and migration of cancer cells in human melanoma. Our findings offer novel insights and a theoretical framework that could enhance prognosis, treatment, and drug development strategies for SKCM, potentially leading to more precise therapeutic interventions.

High-Valence Cu Induced by Photoelectric Reconstruction for Dynamically Stable Oxygen Evolution Sites.

Oxygen vacancies are generally considered to play a crucial role in the oxygen evolution reaction (OER). However, the generation of active sites created by oxygen vacancies is inevitably restricted by their condensation and elimination reactions. To overcome this limitation, here, we demonstrate a novel photoelectric reconstruction strategy to incorporate atomically dispersed Cu into ultrathin (about 2-3 molecular) amorphous oxyhydroxide (a-CuM, M = Co, Ni, Fe, or Zn), facilitating deprotonation of the reconstructed oxyhydroxide to generate high-valence Cu. The in situ XAFS results and first-principles calculations reveal that Cu atoms are stabilized at high valence during the OER process due to Jahn-Teller distortion, resulting in para-type double oxygen vacancies as dynamically stable catalytic sites. The optimal a-CuCo catalyst exhibits a record-high mass activity of 3404.7 A g-1 at an overpotential of 300 mV, superior to the benchmarking hydroxide and oxide catalysts. The developed photoelectric reconstruction strategy opens up a new pathway to construct in situ stable oxygen vacancies by high-valence Cu single sites, which extends the design rules for creating dynamically stable active sites.

Disulfidptosis, A Novel Cell Death Pathway: Molecular Landscape and Therapeutic Implications.

Programmed cell death is pivotal for several physiological processes, including immune defense. Further, it has been implicated in the pathogenesis of developmental disorders and the onset of numerous diseases. Multiple modes of programmed cell death, including apoptosis, pyroptosis, necroptosis, and ferroptosis, have been identified, each with their own unique characteristics and biological implications. In February 2023, Liu Xiaoguang and his team discovered "disulfidptosis," a novel pathway of programmed cell death. Their findings demonstrated that disulfidptosis is triggered in glucose-starved cells exhibiting high expression of a protein called SLC7A11. Furthermore, disulfidptosis is marked by a drastic imbalance in the NADPH/NADP+ ratio and the abnormal accumulation of disulfides like cystine. These changes ultimately lead to the destabilization of the F-actin network, causing cell death. Given that high SLC7A11 expression is a key feature of certain cancers, these findings indicate that disulfidptosis could serve as the basis of innovative anti-cancer therapies. Hence, this review delves into the discovery of disulfidptosis, its underlying molecular mechanisms and metabolic regulation, and its prospective applications in disease treatment.

Endoplasmic Reticulum Dysfunction: An Emerging Mechanism of Vitiligo Pathogenesis.

The endoplasmic reticulum (ER) is the main site of protein synthesis, transport, and modification. Its abnormal status has now emerged as an established cause of many pathological processes, such as tumors and autoimmune diseases. Recent studies also demonstrated that the defective functions of ER may lead to pigmentary diseases. Vitiligo is a depigmenting ailment skin disorder whose pathogenesis is now found to be associated with ER. However, the detailed mechanism is still unclear. In this review, we try to link the association between ER with its inter- and intra-organellar interactions in vitiligo pathogenesis and focus on the function, mechanism, and clinical potential of ER with vitiligo. Expand ER is found in melanocytes of vitiligo and ER stress (ERS) might be a bridge between oxidative stress and innate and adaptive immunity. Meanwhile, the tight association between ER and mitochondria or melanosomes in organelles levels, as well as genes and cytokines, is the new paradigm in the pathogenesis of vitiligo. This undoubtedly adds a new aspect to the understanding of vitiligo, facilitating the design of targeted therapies for vitiligo.

Melatonin suppresses atherosclerosis by ferroptosis inhibition via activating NRF2 pathway.

Melatonin (MLT), a conserved small indole compound, exhibits anti-inflammatory and antioxidant properties, contributing to its cardioprotective effects. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is associated with atherosclerosis disease risk, and is known as an atherosclerosis risk biomarker. This study aimed to investigate the impact of MLT on Lp-PLA2 expression in the atherosclerotic process and explore the underlying mechanisms involved. In vivo, ApoE-/- mice were fed a high-fat diet, with or without MLT administration, after which the plaque area and collagen content were assessed. Macrophages were pretreated with MLT combined with ox-LDL, and the levels of ferroptosis-related proteins, NRF2 activation, mitochondrial function, and oxidative stress were measured. MLT administration significantly attenuated atherosclerotic plaque progression, as evidenced by decreased plaque area and increased collagen. Compared with those in the high-fat diet (HD) group, the levels of glutathione peroxidase 4 (GPX4) and SLC7A11 (xCT, a cystine/glutamate transporter) in atherosclerotic root macrophages were significantly increased in the MLT group. In vitro, MLT activated the nuclear factor-E2-related Factor 2 (NRF2)/SLC7A11/GPX4 signaling pathway, enhancing antioxidant capacity while reducing lipid peroxidation and suppressing Lp-PLA2 expression in macrophages. Moreover, MLT reversed ox-LDL-induced ferroptosis, through the use of ferrostatin-1 (a ferroptosis inhibitor) and/or erastin (a ferroptosis activator). Furthermore, the protective effects of MLT on Lp-PLA2 expression, antioxidant capacity, lipid peroxidation, and ferroptosis were decreased in ML385 (a specific NRF2 inhibitor)-treated macrophages and in AAV-sh-NRF2 treated ApoE-/- mice. MLT suppresses Lp-PLA2 expression and atherosclerosis processes by inhibiting macrophage ferroptosis and partially activating the NRF2 pathway.

A mutation in CCDC91, Homo sapiens coiled-coil domain containing 91 protein, cause autosomal-dominant acrokeratoelastoidosis.

Acrokeratoelastoidosis (AKE) is a rare autosomal dominant hereditary skin disease characterized by small, round-oval, flat-topped keratotic papules on the palms, soles and dorsal aspect of hands or feet. The causative gene for AKE remains unidentified. This study aims to identify the causative gene of AKE and explore the underlying biological mechanisms. A large, three-generation Chinese family exhibiting classic AKE symptoms was identified. A genome-wide linkage analysis and whole-exome sequencing were employed to determine the causative gene. shRNA knockdown in human skin fibroblasts and CRISPR/Cas9 knockout in HEK293T cells were utilized to assess gene functions in the progression of elastic fiber biosynthesis. The linkage analysis identified a susceptibility region between rs7296765 to rs10784618 on chromosome 12. Whole-exome sequencing confirmed a splicing mutation of 1101 + 1 G > A in the CCDC91 gene, resulting in exon 11 skipping and a subsequent 59-amino-acid-residue loss (residues L309-Q367del). Further functional analysis revealed distended Golgi cisternae, cytoplasmic vesicle accumulation, and lysosome presence. Immnunostaining of si-CCDC91-HSF cells demonstrated tropoelastin accumulation in the Golgi and abnormal extracellular aggregates. There are no significant changes in Fibrillin-1 microfibril assembly and lysyl oxidase activity. The findings strongly suggest that the protein product of the CCDC91 gene plays a crucial role in elastin transport. This discovery enhances our understanding of CCDC91's function and broadens the known pathogenic mechanisms of AKE.

Clinicopathologic assessment of secondary syphilis avoids misdiagnosis: results of comprehensive evaluation of 114 cases.

Introduction: Secondary syphilis is well-known for its protean cutaneous manifestations and therefore very easy to be misdiagnosed. Aim: The current study was to observe the frequency of histopathological features characterizing secondary syphilis, and summarize the diseases most likely to be misdiagnosed. Material and methods: In this study a total of 129 pathological specimens from 114 patients with biopsy-proven secondary syphilis were retrospectively analysed and categorized according to clinicopathologic characteristics. The frequency of histopathological features characterizing secondary syphilis were analysed by comparison with clinical features. Results: We found that in a single sample there is at least one feature or at most 13 features exist concurrently, and most demonstrated between 5 and 9 diagnostic features. Plasma cells (97.6% overall vs. 94.0% ≤ 6 features), endothelial swelling (86.8% vs. 74.0%), epidermis hyperplasia (73.6% vs. 62.0%) especially irregular acanthosis, lymphocytes infiltration (71.3% vs. 52.0%) and interstitial patterns (69% vs. 72.0%) were the most common findings in all cases as well as in cases with ≤ 6 features. Granulomatous inflammation is an uncommon histopathologic pattern in secondary syphilis (12.4%). The rash morphologies of our biopsies mainly manifesting as macules and maculopapules were more likely to have 6 or fewer features, which were not only easily misdiagnosed for pityriasis rosea, tinea and erythema multiforme, but also mostly taken from the trunk and genitalia. Atypical morphologies can be combined with plasma cell infiltration and T. pallidum immunohistochemical stain to confirm the diagnosis. Conclusions: In this study plasma cells from superficial and deep perivascular distribution to nodular infiltration were a crucial clue for diagnosis of secondary syphilis.

Risk factor and correlation between postoperative serum myoglobin and acute kidney injury after pulmonary endarterectomy.

Background: Acute kidney injury (AKI) is a common and life-threatening complication following pulmonary endarterectomy (PEA). Our study aimed to investigate the risk factors associated with AKI and evaluate the correlation between serum myoglobin (sMb) levels and postoperative AKI. Methods: We conducted a retrospective study involving 134 patients who underwent PEA at China-Japan Friendship Hospital. AKI was defined and staged according to the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Results: During the study period, the incidence of postoperative AKI was 57.5%, and the associated mortality rate was 6.0%. Severe AKI was found to be significantly associated with worse short-term outcomes (P<0.05). Logarithmically transformed postoperative day (POD) 0 sMb levels were significantly associated with AKI [odds ratio (OR) =5.174; 95% confidence interval (CI), 2.307-11.603; P<0.001] and severe AKI (OR =4.605; 95% CI, 1.510-14.048; P=0.007), also had independent predictive value [area under the curve (AUC) =0.776 in AKI and AUC =0.737 in severe AKI]. The optimal cut-off values were 370.544 ng/mL for AKI and 419.473 ng/mL for severe AKI. Furthermore, albumin concentration was found to play a protective role in the development of severe AKI (OR =0.838; 95% CI, 0.716-0.980; P=0.027) when higher than 40.350 g/L. Conclusions: Our findings suggest that a high concentration of POD0 sMb may increase the risk of developing AKI following PEA surgery. Increasing albumin concentration could serve as an effective preventive measure against AKI.

Hypoxia macrophage-derived exosomal miR-26b-5p targeting PTEN promotes the development of keloids.

Background: Hypoxia is the typical characteristic of keloids. The development of keloids is closely related to the abnormal phenotypic transition of macrophages. However, the role of exosomal microRNAs (miRNAs) derived from hypoxic macrophages in keloids remains unclear. This study aimed to explore the role of hypoxic macrophage-derived exosomes (HMDE) in the occurrence and development of keloids and identify the critical miRNA. Methods: The expression of CD206+ M2 macrophage in keloids and normal skin tissues was examined through immunofluorescence. The polarization of macrophages under a hypoxia environment was detected through flow cytometry. The internalization of macrophage-derived exosomes in human keloid fibroblasts (HKFs) was detected using a confocal microscope. miRNA sequencing was used to explore the differentially expressed miRNAs in exosomes derived from the normoxic and hypoxic macrophage. Subsequently, the dual-luciferase reporter assay verified that phosphatase and tension homolog (PTEN) was miR-26b-5p's target. The biological function of macrophage-derived exosomes, miR-26b-5p and PTEN were detected using the CCK-8, wound-healing and Transwell assays. Western blot assay was used to confirm the miR-26b-5p's underlying mechanisms and PTEN-PI3K/AKT pathway. Results: We demonstrated that M2-type macrophages were enriched in keloids and that hypoxia treatment could polarize macrophages toward M2-type. Compared with normoxic macrophages-derived exosomes (NMDE), HMDE promote the proliferation, migration and invasion of HKFs. A total of 38 differential miRNAs (18 upregulated and 20 downregulated) were found between the NMDE and HMDE. miR-26b-5p was enriched in HMDE, which could be transmitted to HKFs. According to the results of the functional assay, exosomal miR-26b-5p produced by macrophages facilitated HKFs' migration, invasion and proliferation via the PTEN-PI3K/AKT pathway. Conclusions: The highly expressed miR-26b-5p in HMDE promotes the development of keloids via the PTEN-PI3K/AKT pathway.

Association of coagulation markers with the severity of white matter hyperintensities in cerebral small vessel disease.

Background and purpose: This study aimed to explore the correlation and causal relationship between fibrinogen, D-dimer, and the severity of cerebral white matter hyperintensity (MMH). Methods: A retrospective analysis of 120 patients with cerebral small vessel disease (CSVD) confirmed by head MRI attending the Third Affiliated Hospital of Beijing University of Traditional Chinese Medicine from August 2021 to February 2023 was performed. According to the Fazekas scale score, the patients were divided into 42 cases in the mild group, 44 cases in the moderate group, and 34 cases in the severe group. The levels of fibrinogen and D-dimer were compared among the three groups; the correlations between fibrinogen, D-dimer, and WMH severity were further analyzed; and independent risk factors for WMH severity were explored using the multivariate ordered logistic regression analysis. Furthermore, a two-sample Mendelian randomization (MR) analysis was performed to investigate the genetically predicted effect of fibrinogen and D-dimer on WMH. Results: As the severity of WMH increased, the levels of D-dimer and fibrinogen also gradually increased, and the results showed a positive correlational association, with significant differences within the groups (all p < 0.05); the multivariate ordered logistic regression model showed that after adjusting for the relevant covariates, D-dimer (OR = 5.998, 95% CI 2.213-16.252, p < 0.001) and fibrinogen (OR = 9.074, 95% CI 4.054-20.311, p < 0.001) remained independent risk factors for the severity of WMH. In the MR study, the random-effect inverse variance weighted (IVW) model showed that increased levels of genetically predicted D-dimer (OR, 1.01; 95% confidence interval 0.95-1.06; p = 0.81) and fibrinogen (OR, 1.91; 95% confidence interval 0.97-3.78; p = 0.06) were not associated with increased risk of WMH. The authors did not obtain strong evidence of a direct causal relationship between D-dimer, fibrinogen, and WMH. Conclusion: In this retrospective-based study, the authors found possible associations between D-dimer, fibrinogen, and WMH, but there was no obvious causal evidence. Further efforts are still needed to investigate the pathophysiology between D-dimer, fibrinogen, and WMH.

Generation of streptocarbazoles with cytotoxicities by pathway engineering and insights into their biosynthesis.

Streptocarbazoles are a class of indolocarbazole (ICZ) compounds produced by Streptomyces strains that feature unique cyclic N-glycosidic linkages between the 1,3-carbon atoms of the glycosyl moiety and the two indole nitrogen atoms. Although several streptocarbazole compounds display effective cytotoxic activity, their biosynthesis remains unclear. Herein, through the inactivation of the aminotransferase gene spcI in the staurosporine biosynthetic gene cluster spc followed by heterologous expression, two new streptocarbazole derivatives (1 and 3) and three known ICZs (2, 4, and 5) were generated. Their structures were determined by a combination of spectroscopic methods, circular dichroism measurements, and single-crystal X-ray diffraction. Compounds 1-4 displayed moderate cytotoxicity against HCT-116 cell line, and compounds 3 and 4 were effective against Huh 7 cell line. Double-gene knockout experiments allowed us to propose a biosynthetic pathway for streptocarbazole productions. Furthermore, by overexpression of the involving key enzymes, the production of streptocarbazoles 1 and 3 were improved by approximately 1.5-2.5 fold. IMPORTANCE: Indolocarbazoles (ICZs) are a group of antitumor agents, with several analogs used in clinical trials. Therefore, the identification of novel ICZ compounds is important for drug discovery. Streptocarbazoles harbor unique N-glycosidic linkages (N13-C1' and N12-C3'), distinguishing them from the representative ICZ compound staurosporine; however, their biosynthesis remains unclear. In this study, two new streptocarbazoles (1 and 3) with cytotoxic activities were obtained by manipulating the staurosporine biosynthetic gene cluster spc followed by heterologous expression. The biosynthetic pathway of streptocarbazoles was proposed, and their productions were improved through the overexpression of the key enzymes involved. This study enriches the structural diversity of ICZ compounds and would facilitate the discovery of new streptocarbazoles via synthetic biological strategies.

GRELinker: A Graph-Based Generative Model for Molecular Linker Design with Reinforcement and Curriculum Learning.

Fragment-based drug discovery (FBDD) is widely used in drug design. One useful strategy in FBDD is designing linkers for linking fragments to optimize their molecular properties. In the current study, we present a novel generative fragment linking model, GRELinker, which utilizes a gated-graph neural network combined with reinforcement and curriculum learning to generate molecules with desirable attributes. The model has been shown to be efficient in multiple tasks, including controlling log P, optimizing synthesizability or predicted bioactivity of compounds, and generating molecules with high 3D similarity but low 2D similarity to the lead compound. Specifically, our model outperforms the previously reported reinforcement learning (RL) built-in method DRlinker on these benchmark tasks. Moreover, GRELinker has been successfully used in an actual FBDD case to generate optimized molecules with enhanced affinities by employing the docking score as the scoring function in RL. Besides, the implementation of curriculum learning in our framework enables the generation of structurally complex linkers more efficiently. These results demonstrate the benefits and feasibility of GRELinker in linker design for molecular optimization and drug discovery.

Identification of key pyroptosis-related genes and microimmune environment among peripheral arterial beds in atherosclerotic arteries.

Atherosclerosis is a chronic inflammatory disease characterized with innate and adaptive immunity but also involves pyroptosis. Few studies have explored the role of pyroptosis in advanced atherosclerotic plaques from different vascular beds. Here we try to identify the different underlying function of pyroptosis in the progression of atherosclerosis between carotid arteries and femoral. arteries. We extracted gene expression levels from 55 advanced carotid or femoral atherosclerotic plaques. The pyroptosis score of each sample was calculated by single-sample-gene-set enrichment analysis (ssGSEA). We then divided the samples into two clusters: high pyroptosis scores cluster (PyroptosisScoreH cluster) and low pyroptosis scores cluster (PyroptosisScoreL cluster), and assessed functional enrichment and immune cell infiltration in the two clusters. Key pyroptosis related genes were identified by the intersection between results of Cytoscape and LASSO (Least Absolute Shrinkage and Selection Operator) regression analysis. Finally, all key pyroptosis related genes were validated in vitro. We found all but one of the 29 carotid plaque samples belonged to the PyroptosisScoreH cluster and the majority (19 out of 26) of femoral plaques were part of the PyroptosisScoreL cluster. Atheromatous plaque samples in the PyroptosisScoreL cluster had higher proportions of gamma delta T cells, M2 macrophages, myeloid dendritic cells (DCs), and cytotoxic lymphocytes (CTLs), but lower proportions of endothelial cells (ECs). Immune full-activation pathways (e.g., NOD-like receptor signaling pathway and NF-kappa B signaling pathway) were highly enriched in the PyroptosisScoreH cluster. The key pyroptosis related genes GSDMD, CASP1, NLRC4, AIM2, and IL18 were upregulated in advanced carotid atherosclerotic plaques. We concluded that compared to advanced femoral atheromatous plaques, advanced carotid atheromatous plaques were of higher grade of pyroptosis. GSDMD, CASP1, NLRC4, AIM2, and IL18 were the key pyroptosis related genes, which might provide a new sight in the prevention of fatal strokes in advanced carotid atherosclerosis.

Chlorogenic acid attenuates deoxynivalenol-induced apoptosis and pyroptosis in human keratinocytes via activating Nrf2/HO-1 and inhibiting MAPK/NF-κB/NLRP3 pathways.

Deoxynivalenol (DON) is a common mycotoxic contaminant, frequently found in food and feed, causing a severe threat to human and animal health. Because of the widespread contamination of DON, humans involved in agricultural practices may be directly exposed to DON through the skin route. Chlorogenic acid (CGA) is a phenolic acid, which has anti-inflammatory and antioxidant properties. However, it is still unclear whether CGA can protect against DON-induced skin damage. Here, the effect of CGA on mitigating damage to human keratinocytes (HaCaT) triggered by DON, as well as its underlying mechanisms were investigated. Results demonstrated that DON exposure significantly decreased cell viability, and induced excessive mitochondrial reactive oxygen species (mtROS) generation, mitochondrial damage, oxidative stress, cell apoptosis and pyroptosis. However, CGA pretreatment for 2 h significantly increased cell viability and reversed DON-induced oxidative stress by improving antioxidant enzyme activities such as superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), reducing mtROS generation and enhancing mitochondrial function through activating Nrf2/HO-1 pathway. Moreover, CGA significantly increased the Bcl-2 protein expression, decreased the protein expressions of Bax and cleaved Caspase-3, and suppressed the phosphorylated of ERK, JNK, NF-κB. Further experiments revealed that CGA could also inhibit the pyroptosis-related protein expressions including NLRP3, cleaved Caspase-1, GSDMD-N, cleaved IL-1ß and IL-18. In conclusion, our results suggest that CGA could attenuate DON-induced oxidative stress, inflammation, and apoptosis by activating the Nrf2/HO-1 pathway and inhibiting MAPK/NF-κB/NLRP3 pathway. CGA might be a novel promising therapeutic agent for alleviating the dermal damage triggered by DON.

The role of snapin in regulation of brain homeostasis.

Brain homeostasis refers to the normal working state of the brain in a certain period, which is important for overall health and normal life activities. Currently, there is a lack of effective treatment methods for the adverse consequences caused by brain homeostasis imbalance. Snapin is a protein that assists in the formation of neuronal synapses and plays a crucial role in the normal growth and development of synapses. Recently, many researchers have reported the association between snapin and neurologic and psychiatric disorders, demonstrating that snapin can improve brain homeostasis. Clinical manifestations of brain disease often involve imbalances in brain homeostasis and may lead to neurological and behavioral sequelae. This article aims to explore the role of snapin in restoring brain homeostasis after injury or diseases, highlighting its significance in maintaining brain homeostasis and treating brain diseases. Additionally, it comprehensively discusses the implications of snapin in other extracerebral diseases such as diabetes and viral infections, with the objective of determining the clinical potential of snapin in maintaining brain homeostasis.

Tree-Invent: A Novel Multipurpose Molecular Generative Model Constrained with a Topological Tree.

De novo molecular design plays an important role in drug discovery. Here, a novel generative model, Tree-Invent, was proposed to integrate topological constraints in the generation of a molecular graph. In this model, a molecular graph is represented as a topological tree in which a ring system, a nonring atom, and a chemical bond are regarded as the ring node, single node, and edge, respectively. The molecule generation is driven by three independent submodels for carrying out operations of node addition, ring generation, and node connection. One unique feature of the generative model is that the topological tree structure can be specified as a constraint for structure generation, which provides more precise control of structure generation. Combined with reinforcement learning, the Tree-Invent model could efficiently explore targeted chemical space. Moreover, the Tree-Invent model is flexible enough to be used in versatile molecule design settings such as scaffold decoration, scaffold hopping, and linker generation.