Precision Medicine in Rheumatic Diseases: Unlocking the Potential of Antibody-Drug Conjugates.

In the era of precision medicine, antibody-drug conjugates (ADCs) have emerged as a cutting-edge therapeutic strategy. These innovative compounds combine the precision of monoclonal antibodies with the potent cell-killing or immune-modulating abilities of attached drug payloads. This unique strategy not only reduces off-target toxicity but also enhances the therapeutic effectiveness of drugs. Beyond their well established role in oncology, ADCs are now showing promising potential in addressing the unmet needs in the therapeutics of rheumatic diseases. Rheumatic diseases, a diverse group of chronic autoimmune diseases with varying etiologies, clinical presentations, and prognoses, often demand prolonged pharmacological interventions, creating a pressing need for novel, efficient, and low-risk treatment options. ADCs, with their ability to precisely target the immune components, have emerged as a novel therapeutic strategy in this context. This review will provide an overview of the core components and mechanisms behind ADCs, a summary of the latest clinical trials of ADCs for the treatment of rheumatic diseases, and a discussion of the challenges and future prospects faced by the development of next-generation ADCs. SIGNIFICANCE STATEMENT: There is a lack of efficient and low-risk targeted therapeutics for rheumatic diseases. Antibody-drug conjugates, a class of cutting-edge therapeutic drugs, have emerged as a promising targeted therapeutic strategy for rheumatic disease. Although there is limited literature summarizing the progress of antibody-drug conjugates in the field of rheumatic disease, updating the advancements in this area provides novel insights into the development of novel antirheumatic drugs.

Mid1 promotes synovitis in rheumatoid arthritis via ubiquitin-dependent post-translational modification.

INTRODUCTION: Current anti-rheumatic drugs are primarily modulating immune cell activation, yet their effectiveness remained suboptimal. Therefore, novel therapeutics targeting alternative mechanisms, such as synovial activation, is urgently needed. OBJECTIVES: To explore the role of Midline-1 (Mid1) in synovial activation. METHODS: NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) mice were used to establish a subcutaneous xenograft model. Wild-type C57BL/6, Mid1-/-, Dpp4-/-, and Mid1-/-Dpp4-/- mice were used to establish a collagen-induced arthritis model. Cell viability, cell cycle, qPCR and western blotting analysis were used to detect MH7A proliferation, dipeptidyl peptidase-4 (DPP4) and Mid1 levels. Co-immunoprecipitation and proteomic analysis identified the candidate protein of Mid1 substrates. Ubiquitination assays were used to determine DPP4 ubiquitination status. RESULTS: An increase in Mid1, an E3 ubiquitin ligase, was observed in human RA synovial tissue by GEO dataset analysis, and this elevation was confirmed in a collagen-induced mouse arthritis model. Notably, deletion of Mid1 in a collagen-induced arthritis model completely protected mice from developing arthritis. Subsequent overexpression and knockdown experiments on MH7A, a human synoviocyte cell line, unveiled a previously unrecognized role of Mid1 in synoviocyte proliferation and migration, the key aspects of synovial activation. Co-immunoprecipitation and proteomic analysis identified DPP4 as the most significant candidate of Mid1 substrates. Mechanistically, Mid1 promoted synoviocyte proliferation and migration by inducing ubiquitin-mediated proteasomal degradation of DPP4. DPP4 deficiency led to increased proliferation, migration, and inflammatory cytokine production in MH7A, while reconstitution of DPP4 significantly abolished Mid1-induced augmentation of cell proliferation and activation. Additionally, double knockout model showed that DPP4 deficiency abolished the protective effect of Mid1 defect on arthritis. CONCLUSION: Overall, our findings suggest that the ubiquitination of DPP4 by Mid1 promotes synovial cell proliferation and invasion, exacerbating synovitis in RA. These results reveal a novel mechanism that controls synovial activation, positioning Mid1 as a promising target for therapeutic intervention in RA.

Simultaneous quantitative LC-MS/MS analysis of 13 apolipoproteins and lipoprotein (a) in human plasma.

Numerous studies have revealed a close correlation between the levels of apolipoproteins (Apos) (including lipoprotein(a) [Lp(a)]) and an increased risk of cardiovascular disease in recent decades. However, clinically, lipid profiling remains limited to the conventional plasma levels of cholesterol, triglyceride, ApoA1, and ApoB, which brings the necessity to quantify more apolipoproteins in human plasma. In this study, we simultaneously quantified 13 apolipoproteins and Lp(a) in 5 µL of human plasma using the LC-MS/MS platform. A method was developed for the precise detection of Lp(a), ApoA1, A2, A5, B, C1, C2, C3, D, E, H, L1, M, and J. Suitable peptides were selected and optimized to achieve clear separation of each peak. Method validation consisting of linearity, sensitivity, accuracy and precision, recovery, and matrix effects was evaluated. The intra-day CV ranged from 0.58% to 14.2% and the inter-day CV ranged from 0.51% to 13.3%. The recovery rates ranged from 89.8% to 113.7%, while matrix effects ranged from 85.4% to 113.9% for all apolipoproteins and Lp(a). Stability tests demonstrated that these apolipoproteins remained stable for 3 days at 4 °C and 7 days at -20 °C. This validated method was successfully applied to human plasma samples obtained from 45 volunteers. The quantitative results of ApoA1, ApoB, and Lp(a) exhibited a close correlation with the results from the immunity transmission turbidity assay. Collectively, we developed a robust assay that can be used for high-throughput quantification of apolipoproteins and Lp(a) simultaneously for investigating related risk factors in patients with dyslipidemia.

MRP14 enhances the ability of macrophage to recruit T cells and promotes obesity-induced insulin resistance.

OBJECTIVE: Myeloid-related protein-14 (MRP14) and its binding partner MRP8 play an essential role in innate immune function and have been implicated in a variety of inflammatory diseases. However, the role of MRP14 in obesity-induced inflammation and insulin resistance is not well defined. This study investigated the role of MRP14 in macrophage-mediated adipose tissue inflammation and obesity-induced insulin resistance. SUBJECTS AND RESULTS: Wild-type (WT) and Mrp14-/- mice were fed with a high-fat diet or normal chow for 12 weeks. Tissue-resident macrophages in both adipose tissue and liver from obese WT mice expressed higher levels of MRP14 in the visceral adipose fat and liver compared with the lean mice. Mrp14-/- mice demonstrated a significantly improved postprandial insulin sensitivity, as measured by intraperitoneal glucose tolerance test and insulin tolerance testing. Macrophages secreted MRP14 in response to inflammatory stimuli, such as LPS. Extracellular MRP8/14 induced the production of CCL5 and CXCL9. Deficiency of MRP14 did not affect macrophage proliferation, mitochondrial respiration, and glycolytic function, but Mrp14-/- macrophages showed a reduced ability to attract T cells. Depletion of the extracellular MRP14 reduced the T cell attracting ability of WT macrophages to a level similar to Mrp14-/- macrophages. CONCLUSION: Our data indicate that MRP14 deficiency decreases obesity-induced insulin resistance and MRP8/14 regulates T-cell recruitment through the induction of T-cell chemoattractant production from macrophages.

Environmental stressors and cardio-metabolic disease: part II-mechanistic insights.

Environmental factors can act as facilitators of chronic non-communicable diseases. Ambient noise and air pollution collectively outrank all other environmental risk factors in importance, contributing to over 75% of the disease and disability burden associated with known environmental risk factors. In the first part of this review, we discussed the global burden and epidemiologic evidence supporting the importance of these novel risk factors as facilitators of cardiometabolic disease. In this part, we will discuss pathophysiological mechanisms responsible for noise and air pollution-mediated effects. Akin to traditional cardiovascular risk factors, a considerable body of evidence suggests that these environmental agents induce low-grade inflammation, oxidative stress, vascular dysfunction, and autonomic nervous system imbalance, thereby facilitating the development of diseases such as hypertension and diabetes. Through their impact on traditional risk factors and via additional novel mechanisms, environmental risk factors may have much larger impact on cardiovascular events than currently appreciated. In the second part of this review, we discuss deficiencies and gaps in knowledge and opportunities for new research.

Environmental stressors and cardio-metabolic disease: part I-epidemiologic evidence supporting a role for noise and air pollution and effects of mitigation strategies.

Traffic noise and air pollution together represent the two most important environmental risk factors in urbanized societies. The first of this two-part review discusses the epidemiologic evidence in support of the existence of an association between these risk factors with cardiovascular and metabolic disease. While independent effects of these risk factors have now clearly been shown, recent studies also suggest that the two exposures may interact with each other and with traditional risk factors such as hypertension and type 2 diabetes. From a societal and policy perspective, the health effects of both air pollution and traffic noise are observed for exposures well below the thresholds currently accepted as being safe. Current gaps in knowledge, effects of intervention and their impact on cardiovascular disease, will be discussed in the last section of this review. Increased awareness of the societal burden posed by these novel risk factors and acknowledgement in traditional risk factor guidelines may intensify the efforts required for effective legislation to reduce air pollution and noise.

Airborne Particulate Matter Induces Nonallergic Eosinophilic Sinonasal Inflammation in Mice.

Exposure to airborne particulate matter (PM) has been linked to aggravation of respiratory symptoms, increased risk of cardiovascular disease, and all-cause mortality. Although the health effects of PM on the lower pulmonary airway have been extensively studied, little is known regarding the impact of chronic PM exposure on the upper sinonasal airway. We sought to test the impact of chronic airborne PM exposure on the upper respiratory system in vivo. Mice were subjected, by inhalation, to concentrated fine (2.5 µm) PM 6 h/d, 5 d/wk, for 16 weeks. Mean airborne fine PM concentration was 60.92 µm/m3, a concentration of fine PM lower than that reported in some major global cities. Mice were then killed and analyzed for evidence of inflammation and barrier breakdown compared with control mice. Evidence of the destructive effects of chronic airborne PM on sinonasal health in vivo, including proinflammatory cytokine release, and macrophage and neutrophil inflammatory cell accumulation was observed. A significant increase in epithelial barrier dysfunction was observed, as assessed by serum albumin accumulation in nasal airway lavage fluid, as well as decreased expression of adhesion molecules, including claudin-1 and epithelial cadherin. A significant increase in eosinophilic inflammation, including increased IL-13, eotaxin-1, and eosinophil accumulation, was also observed. Collectively, although largely observational, these studies demonstrate the destructive effects of chronic airborne PM exposure on the sinonasal airway barrier disruption and nonallergic eosinophilic inflammation in mice.

DPP4 inhibitors and cardiovascular outcomes: safety on heart failure.

Diabetes is an important risk factor for cardiovascular disease. However, clinical data suggests intensive glycemic control significantly increase rather than decrease cardiovascular mortality, which is largely due to the fact that a majority of oral anti-diabetic drugs have adverse cardiovascular effect. There are several large-scale clinical trials evaluating the cardiovascular safety of DPP4 inhibitors, a novel class of oral anti-diabetic medications, which have been recently completed. They were proven to be safe with regard to cardiovascular outcomes. However, concerns on the safety of heart failure have been raised as the SAVOR-TIMI 53 trial reported a 27% increase in the risk for heart failure hospitalization in diabetic patients treated with DPP4 inhibitor saxagliptin. In this review, we will discuss recent advances in the heart failure effects of DPP4 inhibition and GLP-1 agonism.

The regulatory role of DPP4 in atherosclerotic disease.

The increasing prevalence of atherosclerosis has become a worldwide health concern. Although significant progress has been made in the understanding of atherosclerosis pathogenesis, the underlying mechanisms are not fully understood. Recent studies suggest dipeptidyl peptidase-4 (DPP4), a regulator of inflammation and metabolism, may be involved in the development of atherosclerotic diseases. There has been increasing clinical and pre-clinical evidence showing DPP4-incretin axis is involved in cardiovascular disease. Although the cardiovascular outcome of DPP4 inhibition or incretin analogues has been or being evaluated by several large scale clinical trials, the exact role of DPP4 in atherosclerotic diseases is not completely understood. In the current review, we will summarize the recent advances in direct and indirect regulatory role of DPP4 in atherosclerosis.

CD36-dependent 7-ketocholesterol accumulation in macrophages mediates progression of atherosclerosis in response to chronic air pollution exposure.

RATIONALE: Air pollution exposure has been shown to potentiate plaque progression in humans and animals. Our previous studies have suggested a role for oxidized lipids in mediating adverse vascular effect of air pollution. However, the types of oxidized lipids formed in response to air pollutants and how this occurs and their relevance to atherosclerosis are not fully understood. OBJECTIVE: To investigate the mechanisms by which particulate matter <2.5 µm (PM2.5) induces progression of atherosclerosis. METHODS AND RESULTS: Atherosclerosis-prone ApoE(-/-) or LDLR(-/-) mice were exposed to filtered air or concentrated ambient PM2.5 using a versatile aerosol concentrator enrichment system for 6 months. PM2.5 increased 7-ketocholesterol (7-KCh), an oxidatively modified form of cholesterol, in plasma intermediate density lipoprotein/low-density lipoprotein fraction and in aortic plaque concomitant with progression of atherosclerosis and increased CD36 expression in plaque macrophages from PM2.5-exposed mice. Macrophages isolated from PM2.5-exposed mice displayed increased uptake of oxidized lipids without alterations in their efflux capacity. Consistent with these finding, CD36-positive macrophages displayed a heightened capacity for oxidized lipid uptake. Deficiency of CD36 on hematopoietic cells diminished the effect of air pollution on 7-KCh accumulation, foam cell formation, and atherosclerosis. CONCLUSIONS: Our results suggest a potential role for CD36-mediated abnormal accumulations of oxidized lipids, such as 7-KCh, in air pollution-induced atherosclerosis progression.

Repeated ozone exposure exacerbates insulin resistance and activates innate immune response in genetically susceptible mice.

BACKGROUND: Inhaled ozone (O3) has been demonstrated as a harmful pollutant and associated with chronic inflammatory diseases such as diabetes and vascular disorders. However, the underlying mechanisms by which O3 mediates harmful effects are poorly understood. OBJECTIVES: To investigate the effect of O3 exposure on glucose intolerance, immune activation and underlying mechanisms in a genetically susceptible mouse model. METHODS: Diabetes-prone KK mice were exposed to filtered air (FA), or O3 (0.5 ppm) for 13 consecutive weekdays (4 h/day). Insulin tolerance test (ITT) was performed following the last exposure. Plasma insulin, adiponectin, and leptin were measured by ELISA. Pathologic changes were examined by H&E and Oil-Red-O staining. Inflammatory responses were detected using flow cytometry and real-time PCR. RESULTS: KK mice exposed to O3 displayed an impaired insulin response. Plasma insulin and leptin levels were reduced in O3-exposed mice. Three-week exposure to O3 induced lung inflammation and increased monocytes/macrophages in both blood and visceral adipose tissue. Inflammatory monocytes/macrophages increased both systemically and locally. CD4 + T cell activation was also enhanced by the exposure of O3 although the relative percentage of CD4 + T cell decreased in blood and adipose tissue. Multiple inflammatory genes including CXCL-11, IFN-γ, TNFα, IL-12, and iNOS were up-regulated in visceral adipose tissue. Furthermore, the expression of oxidative stress-related genes such as Cox4, Cox5a, Scd1, Nrf1, and Nrf2, increased in visceral adipose tissue of O3-exposed mice. CONCLUSIONS: Repeated O3 inhalation induces oxidative stress, adipose inflammation and insulin resistance.

IL-6 Inhibition Reduces STAT3 Activation and Enhances the Antitumor Effect of Carboplatin.

Recent studies suggest that tumor-associated macrophage-produced IL-6 is an important mediator within the tumor microenvironment that promotes tumor growth. The activation of IL-6/STAT3 axis has been associated with chemoresistance and poor prognosis of a variety of cancers including colorectal carcinoma and thus serves as a potential immunotherapeutic target for cancer treatment. However, it is not fully understood whether anticytokine therapy could reverse chemosensitivity and enhance the suppressive effect of chemotherapy on tumor growth. In this study, we aimed to investigate the effect of IL-6 inhibition therapy on the antitumor effect of carboplatin. Enhanced expression of IL-6 and activation of STAT3 were observed in human colorectal carcinoma samples compared to normal colorectal tissue, with higher levels of IL-6/STAT3 in low grade carcinomas. Treatment of carboplatin (CBP) dose-dependently increased IL-6 production and STAT3 activation in human colorectal LoVo cells. Blockade of IL-6 with neutralizing antibody enhanced chemosensitivity of LoVo cells to carboplatin as evidenced by increased cell apoptosis. IL-6 blockade abolished carboplatin-induced STAT3 activation. IL-6 blockade and carboplatin synergistically reduced cyclin D1 expression and enhanced caspase-3 activity in LoVo cells. Our results suggest that inhibition of IL-6 may enhance chemosensitivity of colon cancers with overactive STAT3 to platinum agents.

Ambient air pollution: an emerging risk factor for diabetes mellitus.

Growing evidence supports that air pollution has become an important risk factor for developing diabetes mellitus. Understanding the contributing effect of air pollution in population studies, elucidating the potential mechanisms involved, and identifying the most responsible pollutants are all required in order to promulgate successful changes in policy and to help formulate preventive measures in an effort to reduce the risk for diabetes. This review summarizes recent findings from epidemiologic studies and mechanistic insights that provide links between exposure to air pollution and a heightened risk for diabetes.

MBD2 regulates TH17 differentiation and experimental autoimmune encephalomyelitis by controlling the homeostasis of T-bet/Hlx axis.

Unlike genetic alterations, epigenetic modifications are reversible and amenable to pharmacological interventions, which make them appealing targets for clinical therapy. However, little is known about epigenetic regulation in experimental autoimmune encephalomyelitis (EAE). Here we demonstrated that methyl-CpG-binding domain protein 2 (MBD2), an epigenetic regulator, controls autoimmunity and EAE through T-bet/Hlx. Tbx21 and Hlx underwent a DNA methylation turnover upon polarizations and a unique methylation pattern was essential for TH17 development. Loss of Mbd2 resulted in a defect for reading the information encoded by this methylation turnover, which disrupted the homeostasis of T-bet/Hlx axis and suppressed TH17 differentiation. DNA demethylation induced similar effect on helper T cell differentiation. Therefore, Mbd2(-/-) mice were completely protected from EAE. Pathogenic splenocytes isolated from wild-type mice challenged with MOG35-55 could adoptively transfer disease to Mbd2(-/-) mice. In addition, Mbd2(-/-) mice reconstituted with unstimulated wild-type splenocytes developed EAE as wild-type mice did. These data would provide novel insights into epigenetic regulation of EAE.

Air Pollution in Cardio-Oncology and Unraveling the Environmental Nexus: JACC: CardioOncology State-of-the-Art Review.

Although recent advancements in cancer therapies have extended the lifespan of patients with cancer, they have also introduced new challenges, including chronic health issues such as cardiovascular disease arising from pre-existing risk factors or cancer therapies. Consequently, cardiovascular disease has become a leading cause of non-cancer-related death among cancer patients, driving the rapid evolution of the cardio-oncology field. Environmental factors, particularly air pollution, significantly contribute to deaths associated with cardiovascular disease and specific cancers, such as lung cancer. Despite these statistics, the health impact of air pollution in the context of cardio-oncology has been largely overlooked in patient care and research. Notably, the impact of air pollution varies widely across geographic areas and among individuals, leading to diverse exposure consequences. This review aims to consolidate epidemiologic and preclinical evidence linking air pollution to cardio-oncology while also exploring associated health disparities and environmental justice issues.

Regulatory effect of rapamycin on recruitment and function of myeloid-derived suppressor cells in heart failure.

BACKGROUND: Immune response and inflammation play important roles in the physiological and pathophysiological processes of heart failure (HF). In our previous study, myeloid-derived suppressor cells (MDSCs), a heterogeneous group of immature myeloid cells with anti-inflammatory and immunosuppressive functions, were shown to exert cardioprotective effects in HF. The pharmacological targeting of MDSCs using rapamycin may emerge as a promising strategy for the prevention and treatment of HF. However, the specific mechanisms underlying rapamycin-induced MDSC accumulation remain unclear. Our study aimed to clarify the effects of rapamycin on the recruitment and function of MDSCs in HF, exploring new therapeutic options for the prevention and treatment of HF. METHODS: We used transverse aortic constriction surgery and isoproterenol injection to establish HF models. Flow cytometry, reverse transcription polymerase chain reaction, transcriptomics and western blot were used to explore the regulation of rapamycin on recruitment and function of MDSCs in HF. Furthermore, rapamycin and granulocyte-macrophage colony-stimulating factor (GM-CSF) were combined to induce exogenous MDSCs from bone marrow cells. RESULTS: Rapamycin promotes the recruitment of MDSCs by inhibiting their maturation and differentiation via suppression of the Wnt signaling in HF mice and enhanced the immunosuppressive function of MDSCs via the NF-κB signaling. Furthermore, exogenous MDSCs induced by rapamycin and GM-CSF can significantly alleviate transverse aortic constriction-induced cardiac dysfunction. CONCLUSIONS: The pharmacological targeting of MDSCs using rapamycin is a promising strategy for the prevention and treatment of HF.

Sex differences in particulate air pollution-related cardiovascular diseases: A review of human and animal evidence.

Cardiovascular disease (CVD) is the leading cause of mortality globally. In the past several decades, researchers have raised significant awareness about the sex differences in CVD and the importance of heart disease in women. Besides physiological disparities, many lifestyles and environmental factors such as smoking and diet may affect CVD in a sex-dependent manner. Air pollution is a well-recognized environmental risk factor for CVD. However, the sex differences in air pollution-related CVD have been largely neglected. A majority of the previously completed studies have either evaluated only one sex (generally male) as study subjects or did not compare the sex differences. Some epidemiological and animal studies have shown that there are sex differences in the sensitivity to particulate air pollution as evidenced by the different morbidity and mortality rates of CVD induced by particulate air pollution, although this was not conclusive. In this review, we attempt to evaluate the sex differences in air pollution-related CVD and the underlying mechanisms by reviewing both epidemiological and animal studies. This review may provide a better understanding of the sex differences in environmental health research, enabling improved prevention and therapeutic strategies for human health in the future.

Particulate air pollution exaggerates diet-induced insulin resistance through NLRP3 inflammasome in mice.

Air particulate matter 2.5 (PM2.5) has been demonstrated to exaggerate insulin resistance in both human and animal studies. However, the exact molecular mechanisms remain elusive. This study sought to assess the role of NLRP3 inflammasome in PM2.5 exposure-induced insulin resistance and explore the underlying mechanisms. Wild-type (WT), Nlrp3-/-, Tlr4Lps-d, or Nrf2-/- mice, on a normal diet or high-fat diet (HFD), were exposed to PM2.5 or filtered air (FA) in a whole-body exposure facility. Priming (first signal) and assembly (second signal) of NLRP3 inflammasome activation were assessed by measuring the transcription of Nlrp3/Il-1ß and detecting the activity of caspase-1 and secretion of IL-1ß. We found PM2.5 exposure exaggerated insulin resistance and increased IL-1ß production in the HFD-fed WT mice, but not Nlrp3-/- mice. Gene expressions of Nlrp3 and Il-1ß in the lungs and peritoneal macrophages were upregulated in WT mice exposed to PM2.5. When stimulated with LPS (first signal) or monosodium urate (second signal), PM2.5 exposure was able to enhance the activity of caspase-1 and IL-1ß secretion, suggesting that PM2.5 may serve as a stimulus of either the first or second signal for NLRP3 inflammasome activation. Effects of PM2.5 on caspase-1 activation and IL-1ß secretion were partially blocked in Tlr4Lps-d mice. Reactive oxygen species (ROS), co-localization of NLRP3 and mitochondria, and secondary lysosomes in macrophages were increased after PM2.5 exposure, while deficiency of antioxidant gene Nrf2 in mice significantly enhanced PM2.5-induced secretion of IL-1ß. Imaging flow cytometry and transmission electron microscopy demonstrated an engulfment of PM2.5 particles by macrophages, while suppression of phagocytosis by cytochalasin D abolished PM2.5-induced transcription of Nlrp3/Il-1ß. Our results demonstrated a critical role of NLRP3 inflammasome in PM2.5 exaggerated insulin resistance, and multiple pathways in the first and second signals of NLRP3 inflammasome activation may be involved.

Unleashing the Potential of Nrf2: A Novel Therapeutic Target for Pulmonary Vascular Remodeling.

Pulmonary vascular remodeling, characterized by the thickening of all three layers of the blood vessel wall, plays a central role in the pathogenesis of pulmonary hypertension (PH). Despite the approval of several drugs for PH treatment, their long-term therapeutic effect remains unsatisfactory, as they mainly focus on vasodilation rather than addressing vascular remodeling. Therefore, there is an urgent need for novel therapeutic targets in the treatment of PH. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a vital transcription factor that regulates endogenous antioxidant defense and emerges as a novel regulator of pulmonary vascular remodeling. Growing evidence has suggested an involvement of Nrf2 and its downstream transcriptional target in the process of pulmonary vascular remodeling. Pharmacologically targeting Nrf2 has demonstrated beneficial effects in various diseases, and several Nrf2 inducers are currently undergoing clinical trials. However, the exact potential and mechanism of Nrf2 as a therapeutic target in PH remain unknown. Thus, this review article aims to comprehensively explore the role and mechanism of Nrf2 in pulmonary vascular remodeling associated with PH. Additionally, we provide a summary of Nrf2 inducers that have shown therapeutic potential in addressing the underlying vascular remodeling processes in PH. Although Nrf2-related therapies hold great promise, further research is necessary before their clinical implementation can be fully realized.

Dipeptidyl Peptidase 4/Midline-1 Axis Promotes T Lymphocyte Motility in Atherosclerosis.

T cells play a crucial role in atherosclerosis, with its infiltration preceding the formation of atheroma. However, how T-cell infiltration is regulated in atherosclerosis remains largely unknown. Here, this work demonstrates that dipeptidyl peptidase-4 (DPP4) is a novel regulator of T-cell motility in atherosclerosis. Single-cell ribonucleic acid (RNA) sequencing and flow cytometry show that CD4+ T cells in atherosclerotic patients display a marked increase of DPP4. Lack of DPP4 in hematopoietic cells or T cells reduces T-cell infiltration and atherosclerotic plaque volume in atherosclerosis mouse models. Mechanistically, DPP4 deficiency reduces T-cell motility by suppressing the expression of microtubule associated protein midline-1 (Mid1) in T cells. Deletion of either DPP4 or Mid1 inhibits chemokine-induced shape change and motility, while restitution of Mid1 in Dpp4-/- T cell largely restores its migratory ability. Thus, DPP4/Mid1, as a novel regulator of T-cell motility, may be a potential inflammatory target in atherosclerosis.