BACKGROUND AND HYPOTHESIS:Ketamine triggers cellular pyroptosis through an NOD-like receptor protein 3 (NLRP3)/caspase-1 pathway, leading to neurotoxicity and cognitive deficits. Dopamine receptor D1 (DRD1) activation, however, suppresses NLRP3 inflammasome activation, thereby curbing inflammation. We hypothesized that ketamine induces pyroptosis through the NLRP3/caspase-1 pathway, resulting in neurotoxicity and cognitive dysfunction, and that DRD1 activation could counteract these effects. STUDY DESIGN:To investigate the relationship between DRD1 and ketamine-induced pyroptosis and behavioral changes in mice, we conducted both in vivo and in vitro experiments. STUDY RESULTS:Our findings reveal that ketamine induces dose-dependent pyroptosis in HT22 cells, which is alleviated by NLRP3 and caspase-1 antagonists. Furthermore, a DRD1 agonist effectively reduces ketamine-induced pyroptosis in these cells. In vivo, DRD1 activation decreases ketamine-induced NLRP3/caspase-1-dependent neuronal pyroptosis and ameliorates cognitive impairment in mice by inhibiting NLRP3. Conversely, a DRD1 antagonist enhances NLRP3/caspase-1-mediated pyroptosis, replicating the behavioral deficits seen with ketamine exposure. Moreover, DRD1-specific knockdown in neuronal cells prevents ketamine-induced cognitive dysfunction and reduces pyroptosis. CONCLUSIONS:Dopamine receptor D1 activation mitigates ketamine-induced cognitive dysfunction in mice by inhibiting NLRP3/caspase-1-dependent pyroptosis. These findings offer new insights into the psychobehavioral disorders and cytotoxicity associated with ketamine.

ObjectiveThe study aimed to explore the inhibitory effect of stevioside on colorectal cancer and its molecular mechanism.MethodsColorectal cancer cells were selected for functional testing, including the following groups: 0 μM stevioside, 1 μM stevioside, 2.5 μM stevioside and 5 μM stevioside. CCK-8 kit and EdU staining were employed to assess the cell viability. Cell apoptosis was deterred by flow cytometry. Western blot assay was utilized to detect the protein expressions of cleaved-caspase-3, Bax, Bcl-2, E-cadherin and Vimentin. The polarization of macrophage was evaluated through flow cytometry, western blot and immunofluorescence staining. The effect of stevioside on the proliferation of tumor tissue was detected by tumor formation and immunohistochemical staining in nude mice.ResultsStevioside exhibited a significant concentration-dependent inhibitory effect on the proliferation, migration, and invasion of colorectal cancer cells, while promoting apoptosis in vitro. Following stevioside treatment, there was a notable reduction in tumor volume and weight observed. Flow cytometry and immunohistochemical staining results showed that compared with control group, CD86+ cell ratio was increased in stevioside treatment group, while the CD206+ cell ratio was decreased in stevioside treatment group. RT-qPCR analysis revealed that, compared to the control group, stevioside treatment significantly reduced the mRNA expressions of Arg-1 and IL-10, while concomitantly increasing the mRNA expressions of IL-12 and TNF-α in a concentration-dependent manner.ConclusionStevioside possesses the ability to significantly hinder the proliferation of colorectal cancer cells and induce apoptosis, the mechanism of which may be closely related to the regulation of macrophage M1 polarization.

Type 2 diabetes (T2D) is a chronic disease that seriously threatens human health. Puerarin, the primary bioactive component of Pueraria lobata , alleviates T2D through multiple mechanisms, including protection of pancreatic β-cells, enhancement of insulin sensitivity, and antioxidant effects. However, its specific mechanisms of action against T2D remain incompletely understood. This study aimed to investigate the curative effects of puerarin in ameliorating glucose and lipid metabolism disorders in T2D mice by preserving gut microbiota homeostasis and promoting adipose tissue thermogenesis. To achieve this, 16S rRNA gene sequencing and metabolomics were employed to assess its effects on gut microbiota and fecal metabolites, while qRT-PCR and western blot were conducted to evaluate its impact on the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway. The results demonstrated that puerarin promoted gut microbiota homeostasis and elevated butyrate levels. Specifically, it increased the abundance of beneficial bacteria (Lactobacillaceae, Muribaculaceae, and Akkermansiaceae) and reduced the abundance of harmful bacteria (Desulfovibrionaceae, Marinifilaceae, and Helicobacteraceae). Moreover, puerarin enhanced brown adipose tissue (BAT) activity via the PI3K/AKT pathway and induced a browning phenotype in white adipose tissue (WAT) through the PPARγ pathway. These effects promoted mitochondrial biosynthesis, lipolysis, glucose utilization, and energy expenditure. Puerarin also increased glucagon-like peptide-1 (GLP-1) secretion, thereby further improving insulin sensitivity. In conclusion, this study confirms that puerarin improves glucose and lipid metabolism disorders in T2D mice by regulating gut microbiota homeostasis and promoting adipose tissue thermogenesis, which holds considerable potential for the treatment of T2D.

Intestinal obstruction is a common surgical emergency characterised by rapid progression and high mortality. However, the underlying mechanisms remain incompletely elucidated. Here, we show, by combining single-cell RNA sequencing with in vivo pharmacological modulation in male rats, the temporal dynamics of neutrophil extracellular traps (NETs) formation and their contribution to barrier dysfunction in incarcerated small-bowel obstruction. Profiling of 23,320 intestinal cells reveals pronounced neutrophil infiltration in late-stage obstruction (24.59% of total cells) and enables identification of a discrete "NETs-associated neutrophil subset (Neu_NETs)". These Neu_NETs exhibit marked transcriptional enrichment of IL-17, NF-κB and TNF signalling pathways. Functional analyses demonstrate a time-dependent accumulation of NETs within obstructed segments that inversely correlates with the expression of intestinal tight junction proteins. In vivo administration of the PAD4 inhibitor Cl-amidine significantly attenuates NETs formation, ameliorates histopathological injury, and decreases local levels of IL-1β and TNF-α. Therefore, targeting NETs may represent a strategy for treating intestinal obstruction.

Toll-like receptor 4 (TLR4), a pattern-recognition receptor located on the plasma membrane, senses extracellular danger signals to initiate inflammatory immune responses. It is initially synthesized in the endoplasmic reticulum (ER), undergoes N-linked glycosylation, and is subsequently transported to the Golgi before ultimately reaching the plasma membrane. However, the mechanisms underlying the processing and maturation of TLR4 in the ER remain elusive. Through whole genome-wide CRISPR screening, CCDC134 was identified as a critical and essential factor for TLR4-dependent inflammatory response. Localization of CCDC134 in the ER lumen rather than its exosome-mediated secretion is required for its role in TLR4 signaling. Loss of CCDC134 results in the retention of TLR4 in the ER for subsequent ER-associated degradation, and thus blockade of TLR4 maturation and plasma membrane trafficking. Defects in TLR4 processing and maturation in the ER in CCDC134-depleted cells are caused by aberrant hyperglycosylation and destabilization of glycoprotein 96 (gp96), a key chaperone of TLR4. These results suggest that CCDC134 controls gp96 glycosylation to facilitate TLR4 maturation in the ER.

BACKGROUND:Sepsis-associated acute lung injury (ALI) remains a critical clinical challenge with limited therapeutic options. The NLRP3 inflammasome drives pathological inflammation in ALI, yet clinical translation of existing inhibitors is hindered by toxicity. Natural products offer safer alternatives, but their mechanisms in targeting NLRP3 assembly are poorly defined. METHODS:We screened a natural compound library for NLRP3 inhibitors using LPS/nigericin-stimulated murine peritoneal macrophages, measuring IL-1β release by ELISA. Mechanistic studies included immunoprecipitation (NEK7-NLRP3/ASC-NLRP3 interactions), ASC oligomerization/speck formation assays, DARTS, CETSA, and molecular docking. In vivo efficacy was evaluated in LPS-induced ALI and endotoxemia mouse models (histopathology, cytokine analysis, immunoblotting). RESULTS:Nimbolide was identified as a potent NLRP3 inhibitor. It dose-dependently suppressed IL-1β secretion and caspase-1/GSDMD cleavage in murine/human (THP-1) macrophages, without affecting AIM2/NLRC4 inflammasomes or TNF-α production. Mechanistically, Nimbolide disrupted NEK7-NLRP3 binding and ASC oligomerization, thereby blocking NLRP3 inflammasome assembly. Further investigations revealed that Nimbolide enhanced the thermal stability of NLRP3 as demonstrated by the cell thermal shift assay (CETSA), conferred protease resistance as evidenced by the drug affinity responsive target stability (DARTS) assay, and exhibited high-affinity binding to NLRP3 with a binding energy of -7.62 kcal/mol through molecular docking studies. These results collectively suggest that Nimbolide can directly bind to NLRP3. In vivo, Nimbolide reduced pulmonary IL-1β levels, suppressed GSDMD cleavage, and attenuated lung injury pathology. CONCLUSION:Nimbolide is a new natural inhibitor that selectively targets the NLRP3 interface and block NLRP3 inflammasome activation, offering a promising therapeutic strategy for NLRP3-driven inflammatory disorders like sepsis-associated ALI.

Pulmonary arterial hypertension (PAH) is a rare and life-threatening pulmonary vascular disease distinguished by vasoconstriction and remodeling of the pulmonary artery, leading to sustained elevated pulmonary artery pressure, right ventricular failure, and even death. Receptor tyrosine kinases (RTKs) are critical in PAH pathogenesis, and targeted therapies against RTKs are becoming a research hotspot due to their potential to inhibit cell proliferation and right ventricular hypertrophy. Abnormal activation of RTKs induces downstream signaling cascades, including metabolic reprogramming through multiple regulatory crosstalk, to meet high energy requirements during cell proliferation. However, the crucial connection between metabolic reprogramming and RTKs in PAH remains largely unexplored. In this review, we focus on four key RTKs: Platelet-Derived Growth Factor Receptor (PDGFR), Epidermal Growth Factor Receptor (EGFR), Fibroblast Growth Factor Receptor (FGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR) in the metabolic reprogramming of PAH and explore hypotheses that require further validation. The aim is to highlight how these mechanisms can be applied to develop better therapeutic strategies.

FOSB, a member of the FOS gene family, forms heterodimers with JUN family proteins to engage in diverse cellular processes. Its biological impacts vary among different types of tumors, yet its specific function in colon cancer (CC) remains ambiguous. In this study, quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC) are applied to measure FOSB expression levels, followed by an analysis of the association between FOSB expression and patients' clinical parameters. In vitro experiments are performed to assess cell proliferation, including growth rate, cell cycle distribution, and apoptosis. A subcutaneous xenograft model in nude mice is utilized to monitor tumor growth in vivo. Additionally, chromatin immunoprecipitation (ChIP) and luciferase reporter assays are conducted to dissect the interactions among FOSB, miR-133b, and POU2F1. The results indicate that FOSB expression is downregulated in CC tissues relative to normal controls. Overexpression of FOSB suppresses proliferation and promotes apoptosis in CC cells. Mechanistically, FOSB binds to the promoter region of miR-133b, enhancing its transcription and subsequently repressing POU2F1 expression. Notably, decreased POU2F1 expression also alleviates the transcriptional repression of the FOSB promoter region, establishing a FOSB-miR-133b-POU2F1 feedback loop that inhibits CC proliferation. In summary, our findings suggest that FOSB acts as a tumor suppressor gene in CC and may exert its inhibitory effects on CC growth via the FOSB-miR-133b-POU2F1 feedback loop.

The mechanism underlying vascular remodeling in pulmonary arterial hypertension (PAH) involves complex interactions among various cell types, with dysregulation of endothelial cells (ECs) homeostasis considered a crucial pathological factor. However, their local cellular changes still need to be fully identified during PAH. This study utilized single-cell RNA sequencing data from the GEO database to analyze lung tissue samples from PAH patients and normal controls, revealing significant heterogeneity in lung ECs and dysregulated metabolic pathways. We identified a significant expansion of capillary ECs in PAH patients, linked to dysregulated angiogenesis and glycolysis-tricarboxylic acid cycle metabolic pathways. Through integrative high-dimensional weighted gene co-expression network analysis (hdWGCNA) and machine learning, we identified SPRY1 as a novel key biomarker in PAH pathogenesis and validated its significant downregulation in a monocrotaline-induced PAH rat model. These findings establish capillary ECs expansion and SPRY1 deficiency as pivotal drivers in PAH pathogenesis, providing a foundation for precise therapeutic targeting.

Pyroptosis is a type of programmed inflammatory cell death characterized by balloon-like swelling, membrane rupture, and the release of inflammatory cytokines and danger signals. Pyroptosis is directly triggered by activated gasdermins (GSDMs) which bind to membrane phospholipids, oligomerize, and form pores in cell membranes. GSDM activation is mediated by various effector proteases via cleavage of the linker region or post-translational modification to release the active N-terminal fragment in response to a variety of pathogenic or intrinsic danger signals. GSDM-mediated pyroptosis is involved in the pathogenesis of an array of infectious and inflammatory diseases and cancers. This review discusses recent advances related to the physiological and pathological functions of GSDM-mediated pyroptosis, as well as therapeutic strategies targeting pyroptosis.

BACKGROUND:Sepsis and its related complication acute kidney injury (septic-AKI) are associated with high mortality and morbidity, and have become a global health challenge. Xuebijing (XBJ) injection prepared from five traditional Chinese medicines (TCM) is commonly used for clinical treatment of sepsis and septic-AKI. Yet, the underlying therapeutic mechanism of XBJ is remain elusive. This study aims to unveil the underlying mechanisms of XBJ in treating sepsis and septic-AKI. METHODS:In this study, we used network pharmacology and molecular docking to screen the core drug-disease targets and predict the potential mechanism involving in XBJ against sepsis and septic AKI. Furthermore, in vitro experiments were performed to verify the predicted results and clarify the underlying mechanism. RESULTS:Five hub targets including MMP9, TNF, IL-6, STAT3 and TP53 were identified by constructing and analyzing protein-protein interaction network. Eight key active components linking to five hub targets were also reversely screened. The results of gene ontology (GO) and pathway enrichment analysis showed that on the list of top 10 significant GO terms and pathways, most were inflammatory signaling pathways. The molecular docking results suggested that eight active components more preferentially bound to MMP9 and TNFα with the highest affinity. In vitro, XBJ significantly decreased the mRNA and protein levels of IL-1β, IL-6, TNFα and MMP9 in HEK-293 cells exposed to lipopolysaccharides (LPS). CONCLUSIONS:XBJ exerted therapeutic effects on sepsis and septic-AKI through suppression IL-1β/MMP9, IL-6/MMP9 and TNFα/MMP9 at both mRNA and protein level. This study provides a pharmacological basis for further validating the therapeutic mechanism of XBJ in treating sepsis and septic-AKI by in vitro and in vivo experiments.

Pyroptosis, a novel mode of inflammatory cell death, is executed by membrane pore-forming gasdermin (GSDM) family members in response to extracellular or intracellular injury cues and is characterized by a ballooning cell morphology, plasma membrane rupture and the release of inflammatory mediators such as interleukin-1β (IL-1β), IL-18 and high mobility group protein B1 (HMGB1). It is a key effector mechanism for host immune defence and surveillance against invading pathogens and aberrant cancerous cells, and contributes to the onset and pathogenesis of inflammatory and autoimmune diseases. Manipulating the pore-forming activity of GSDMs and pyroptosis could lead to novel therapeutic strategies. In this Review, we discuss the current knowledge regarding how GSDM-mediated pyroptosis is initiated, executed and regulated, its roles in physiological and pathological processes, and the crosstalk between different modes of programmed cell death. We also highlight the development of drugs that target pyroptotic pathways for disease treatment. Activation of gasdermins (GSDMs) in response to infection or cell damage triggers membrane pore formation, leading to pyroptotic cell death. This Review discusses recent molecular and structural insights into the regulation of GSDMs and explores their physiological roles and involvement in inflammatory diseases.

Abdominal Aortic Aneurysm (AAA) is a disease characterized by localized dilation of the abdominal aorta, involving multiple factors in its occurrence and development, ultimately leading to vessel rupture and severe bleeding. AAA has a high mortality rate, and there is a lack of targeted therapeutic drugs. Epigenetic regulation plays a crucial role in AAA, and the treatment of AAA in the epigenetic field may involve a series of related genes and pathways. Abnormal expression of these genes may be a key factor in the occurrence of the disease and could potentially serve as promising therapeutic targets. Understanding the epigenetic regulation of AAA is of significant importance in revealing the mechanisms underlying the disease and identifying new therapeutic targets. This knowledge can contribute to offering AAA patients better clinical treatment options beyond surgery. This review systematically explores various aspects of epigenetic regulation in AAA, including DNA methylation, histone modification, non-coding RNA, and RNA modification. The analysis of the roles of these regulatory mechanisms, along with the identification of relevant genes and pathways associated with AAA, is discussed comprehensively. Additionally, a comprehensive discussion is provided on existing treatment strategies and prospects for epigenetics-based treatments, offering insights for future clinical interventions.

BACKGROUND:Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear.METHODS:We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples.RESULTS:Plasma proteomics identified high protein abundance levels of B2M (beta 2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF.CONCLUSIONS:Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.

BACKGROUND:Pulmonary hypertension (PH) is a major complication linked to adverse outcomes in heart failure with preserved ejection fraction (HFpEF), yet no specific therapies exist for PH associated with HFpEF (PH-HFpEF). We have recently reported on the role of skeletal muscle SIRT3 (sirtuin-3) in modulation of PH-HFpEF, suggesting a novel endocrine signaling pathway for skeletal muscle modulation of pulmonary vascular remodeling.METHODS:Using skeletal muscle-specific Sirt3 knockout mice (Sirt3skm-/-) and mass spectrometry-based comparative secretome analysis, we attempted to define the processes by which skeletal muscle SIRT3 defects affect pulmonary vascular health in PH-HFpEF.RESULTS:Sirt3skm-/- mice exhibited reduced pulmonary vascular density accompanied by pulmonary vascular proliferative remodeling and elevated pulmonary pressures. Comparative analysis of secretome by mass spectrometry revealed elevated secretion levels of LOXL2 (lysyl oxidase homolog 2) in SIRT3-deficient skeletal muscle cells. Elevated circulation and protein expression levels of LOXL2 were also observed in plasma and skeletal muscle of Sirt3skm-/- mice, a rat model of PH-HFpEF, and humans with PH-HFpEF. In addition, expression levels of CNPY2 (canopy fibroblast growth factor signaling regulator 2), a known proliferative and angiogenic factor, were increased in pulmonary artery endothelial cells and pulmonary artery smooth muscle cells of Sirt3skm-/- mice and animal models of PH-HFpEF. CNPY2 levels were also higher in pulmonary artery smooth muscle cells of subjects with obesity compared with nonobese subjects. Moreover, treatment with recombinant LOXL2 protein promoted pulmonary artery endothelial cell migration/proliferation and pulmonary artery smooth muscle cell proliferation through regulation of CNPY2-p53 signaling. Last, skeletal muscle-specific Loxl2 deletion decreased pulmonary artery endothelial cell and pulmonary artery smooth muscle cell expression of CNPY2 and improved pulmonary pressures in mice with high-fat diet-induced PH-HFpEF.CONCLUSIONS:This study demonstrates a systemic pathogenic impact of skeletal muscle SIRT3 deficiency in remote pulmonary vascular remodeling and PH-HFpEF. This study suggests a new endocrine signaling axis that links skeletal muscle health and SIRT3 deficiency to remote CNPY2 regulation in the pulmonary vasculature through myokine LOXL2. Our data also identify skeletal muscle SIRT3, myokine LOXL2, and CNPY2 as potential targets for the treatment of PH-HFpEF.

Acute lung injury (ALI) is a severe form of respiratory failure characterized by altered lung mechanics and refractory hypoxemia. Globally, the condition presents a serious threat to human health. Morin is a potential active monomer that has beneficial therapeutic effects in ALI; however, its mechanism of action remains unclear. Herein, we found significant elevation of inflammation and pyroptosis in the lung tissue of mice with lipopolysaccharide-induced ALI. Additionally, morin blocked the activation of the TLR4/TRAF6/NF-κB pathway and synergically inhibited the entry of p65 into the nucleus by downregulating the expression of Kruppel-like factor 5. Morin also inhibited caspase-1 activation and protected the GSDMD protein from cleavage. These findings are evidence that morin alleviates ALI by blocking the NF-κB pathway, reducing inflammation, and inhibiting macrophage pyroptosis.

BACKGROUND:Abnormal type I collagen (COL1) expression is associated with the development of many cardiovascular diseases. The TGF-beta/Smad signaling pathway and circRNAs have been shown to regulate COL1 gene expression, but the underlying molecular mechanisms are still not fully understood.METHODS:Gain- and loss-of-function experiments were prformed to study the effect of circZBTB46 on the expression of alpha 2 chain of type I collagen (COL1A2). Co-immunoprecipitation assay was performed to observe the interaction between two proteins. RNA immunoprecipitation assay and biotin pull-down assay were performed to observe the interaction of circZBTB46 with PDLIM5.RESULTS:In this study, we investigated the role of circZBTB46 in regulating COL1A2 expression in human vascular smooth muscle cells (VSMCs). We found that circZBTB46 is expressed in VSMCs and that TGF-beta inhibits circZBTB46 formation by downregulating KLF4 expression through activation of the Smad signaling pathway. CircZBTB46 inhibits the expression of COL1A2 induced by TGF-beta. Mechanistically, circZBTB46 mediates the interaction between Smad2 and PDLIM5, resulting in the inhibition of Smad signaling and the subsequent downregulation of COL1A2 expression. Furthermore, we found that the expression of TGF-beta and COL1A2 is decreased, while circZBTB46 expression is increased in human abdominal aortic aneurysm tissues, indicating that circZBTB46-mediated regulation of TGF-beta/Smad signaling and COL1A2 synthesis in VSMCs plays a crucial role in vascular homeostasis and aneurysm development.CONCLUSIONS:CircZBTB46 was identified as a novel inhibitor of COL1 synthesis in VSMCs, highlighting the importance of circZBTB46 and PDLIM5 in regulating TGF-beta/Smad signaling and COL1A2 expression.

Epidemiological studies show an association between inflammatory bowel disease (IBD) and increased risk of thrombosis. However, how IBD influences thrombosis remains unknown. The current study shows that formation of neutrophil extracellular traps (NETs) significantly increased in the dextran sulfate sodium (DSS)-induced IBD mice, which in turn, contributes to thrombus formation in a NETs-dependent fashion. Furthermore, the exosomes isolated from the plasma of the IBD mice induce arterial and venous thrombosis in vivo. Importantly, proinflammatory factors-exposed intestinal epithelial cells (inflamed IECs) promote neutrophils to release NETs through their secreted exosomes. RNA sequencing revealed that LINC00668 is highly enriched in the inflamed IECs-derived exosomes. Mechanistically, LINC00668 facilitates the translocation of neutrophil elastase (NE) from the cytoplasmic granules to the nucleus via its interaction with NE in a sequence-specific manner, thereby inducing NETs release and thrombus formation. Importantly, berberine (BBR) suppresses the nuclear translocation of NE and subsequent NETs formation by inhibiting the interaction of LINC00668 with NE, thus exerting its antithrombotic effects. This study provides a novel pathobiological mechanism linking IBD and thrombosis by exosome-mediated NETs formation. Targeting LINC00668 can serve as a novel molecular treatment strategy to treat IBD-related thrombosis.

Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by the progressive elevation of pulmonary arterial pressures. It is becoming increasingly apparent that inflammation contributes to the pathogenesis and progression of PAH. Several viruses are known to cause PAH, such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), human endogenous retrovirus K(HERV-K), and human immunodeficiency virus (HIV), in part due to acute and chronic inflammation. In this review, we discuss the connections between HERV-K, HIV, SARS-CoV-2, and PAH, to stimulate research regarding new therapeutic options and provide new targets for the treatment of the disease.