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Rhipicephalus microplus poses a significant problem for livestock worldwide and is primarily controlled with synthetic acaricides. The continuous use of acaricides results in the selection of resistance and causes environmental harm. Vaccination presents an alternative solution to this problem, although searching for the suitable antigen is still a work in progress. Salivary proteins hold promise for inclusion in vaccine formulation due to their roles in modulating host responses, assisting blood feeding and pathogen transmission. Serpins are a class of proteinase inhibitors and are among the molecules found in tick saliva that modulate host blood coagulation, inflammation, and adaptive immune responses. Previous studies have demonstrated the potential of R. microplus serpin 17 (RmS-17) to interfere with the host's defenses, and antibodies have been shown to neutralize its effects. This makes RmS-17 an putative target for vaccine development. Epitope mapping of RmS-17 was achieved using in silico approach combining linear B-cell epitope and antigenicity predictor. In addition, epitope mapping using overlapping peptides in an ELISA screening was used. The serpin tridimensional structure and the epitopes spatial location within the molecule were determined. Peptides were synthetized based on the predictions and used for the production of rabbit anti-sera. Purified IgG's were used to assess the antibodies capacity to neutralize RmS-17. Through in silico mapping, nine potential B cell epitope regions were screened, with p1RmS-17 and p2RmS-17 selected for the experiment based on antigen prediction. In the ELISA screening using overlapping peptides, eight antibody-binding regions were identified, and p3RmS-17 and p4RmS-17 were chosen. Antibodies raised against p3RmS-17 and p4RmS-17 partially neutralized RmS-17 activity. It was found that antibodies against a single epitope are sufficient to partially neutralize RmS-17 activity. These findings support the possibility of using an epitope-based vaccine for immunization against R. microplus. •Rhipicephalus microplus serpin 17 in vitro and in vivo epitope mapping was performed.•Two peptides were selected for experimentation based on antigen prediction.•Antibodies against these two peptides partially neutralize RmS-17 activity.

Maspin, a non-inhibitory member of the serine protease inhibitor superfamily, has been characterized as a tumor suppressor gene in multiple cancer types. Among the established anti-tumor effects of Maspin are the inhibition of cancer cell invasion, attachment to extracellular matrices, increased sensitivity to apoptosis, and inhibition of angiogenesis. However, while significant experimental data support the role of Maspin as a tumor suppressor, clinical data regarding the prognostic implications of Maspin expression have led to conflicting results. This highlights the need for a better understanding of the context dependencies of Maspin in normal biology and how these are perturbed in the context of cancer. In this review, we outline the regulation and roles of Maspin in normal and developmental biology while discussing novel evidence and emerging theories related to its functions in cancer. We provide insight into the immense therapeutic potential of Maspin and the challenges related to its successful clinical translation.

It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue–derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK. Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress–induced metabolic dysfunctions.

To evaluate the efficacy of combining polyene phosphatidylcholine (PPC) with liraglutide in the treatment of nonalcoholic fatty liver disease (NAFLD) and investigate its impact on adipokine expression, specifically omentin-1 and vaspin. One hundred twenty NAFLD patients were randomly assigned to either the observation group (n = 60) or the control group (n = 60). The control group received single-dose PPC treatment, while the observation group received a combination of PPC and liraglutide for 12 weeks. Clinical efficacy, adipose-related factors (omentin-1, vaspin, serum fibroblast growth factor 21 (FGF21)), liver enzymes (alanine aminotransferase (ALT), aspartate aminotransferase (AST), glutamyl transpeptidase (GGT)), and adverse reaction rates were compared between the two groups before and after treatment. In the observation group, the clinical effectiveness rate (95.00%) was significantly higher than that in the control group (83.33%) (P < .05). Before treatment, there were no significant differences in omentin-1, vaspin, FGF21, ALT, AST, and GGT between the two groups (P > .05). After treatment, both groups showed decreased levels of vaspin, FGF21, ALT, AST, and GGT, along with increased omentin-1 levels. However, levels of vaspin, FGF21, ALT, AST, and GGT were lower in the observation group compared to the control group, while omentin-1 levels were higher (P < .05). Adverse reaction rates did not significantly differ between the two groups (10.00% vs. 6.67%) (P > .05). The combination therapy of PPC and liraglutide demonstrates efficacy in treating NAFLD, improving adipose-related factors, and reducing liver enzyme activity with high safety. This approach warrants broader clinical implementation.

Background Macrophage M2 polarization plays a critical role in type 2 airway inflammation in asthma. We previously reported that serine peptidase inhibitor, clade B, member 10 (SERPINB10) promotes airway eosinophilic inflammation in asthma. Objective To investigate the role of SERPINB10 in macrophage M2 polarization and airway inflammation in asthma. Methods The expression of SERPINB10 was detected in bronchoalveolar lavage (BAL) cells from 15 control subjects and 36 asthma patients. Serpinb10 knockout mice and wild type mice were sensitized and challenged with ovalbumin (OVA). Macrophage polarization and airway inflammation were evaluated. An adoptive transfer experiment of Serpinb10 -deficient macrophages to macrophage-depleted mice was performed to assess the effect of Serpinb10 deficiency in macrophages on the airway inflammation in the model. The role of SERPINB10 in the activation of IL-4 receptor (IL-4R) signaling pathway and macrophage M2 polarization was investigated in cell cultures. Results SERPINB10 expression was markedly elevated in BAL cells from asthmatic patients, and was significantly correlated with fractional exhaled nitric oxide and CD206 , a marker for macrophage M2 polarization. In the OVA-induced allergic airway inflammation mouse model, Serpinb10 deficiency significantly inhibited airway inflammation, mucous cell metaplasia and airway hyperresponsiveness. Moreover, Serpinb10 deficiency suppressed the expression of M2 markers including Cd206 , Arg1 in mouse lung tissues and the protein levels of M2 macrophage effector cytokines including Ccl17 and Ccl22 in BAL fluid. Adoptive transfer of Serpinb10 -deficient bone marrow-derived macrophages (BMDMs) to wild type mice depleted macrophages significantly suppressed the airway inflammation and mucous cell metaplasia. Mechanistically, SERPINB10 suppresses the degradation of IL-4Rα in macrophages, thereby upregulating the phosphorylation of Stat6 and Akt and leading to macrophage M2 polarization. Conclusions SERPINB10 promotes macrophage M2 polarization by suppressing IL-4Rα degradation and upregulating IL-4R signaling. SERPINB10 is a potential therapeutic target for asthma.

Inflammatory caspases (caspase-1, caspase-4, caspase-5 and caspase-11 (caspase-1/-4/-5/-11)) mediate host defense against microbial infections, processing pro-inflammatory cytokines and triggering pyroptosis. However, precise checkpoints are required to prevent their unsolicited activation. Here we report that serpin family B member 1 (SERPINB1) limited the activity of those caspases by suppressing their caspase-recruitment domain (CARD) oligomerization and enzymatic activation. While the reactive center loop of SERPINB1 inhibits neutrophil serine proteases, its carboxy-terminal CARD-binding motif restrained the activation of pro-caspase-1/-4/-5/-11. Consequently, knockdown or deletion of SERPINB1 prompted spontaneous activation of caspase-1/-4/-5/-11, release of the cytokine IL-1β and pyroptosis, inducing elevated inflammation after non-hygienic co-housing with pet-store mice and enhanced sensitivity to lipopolysaccharide- or Acinetobacter baumannii –induced endotoxemia. Our results reveal that SERPINB1 acts as a vital gatekeeper of inflammation by restraining neutrophil serine proteases and inflammatory caspases in a genetically and functionally separable manner. Serpins are a large family of serine protease inhibitors. Jae Jung and colleagues show that SERPINB1 serves an endogenous regulatory role for pro-inflammatory caspases by preventing CARD–CARD polymerization and, hence, inflammasome activation.

Senescence of alveolar type II (ATII) cells, progenitors of the alveolar epithelium, is a pathological feature and contributes importantly to the pathogenesis of idiopathic pulmonary fibrosis. Despite recognition of the importance of ATII cell senescence in idiopathic pulmonary fibrosis pathogenesis, how ATII cell senescence is regulated and how senescent ATII cells contribute to lung fibrogenesis remain unclear. In this study, we show that TGF-β1 (transforming growth factor-β1), a most ubiquitous and potent profibrotic cytokine, induces plasminogen activator inhibitor-1 (PAI-1), a cell senescence and fibrosis mediator, and p16 as well as senescence, but not apoptosis, in primary mouse ATII cells. We also found that senescent ATII cells secrete various cytokines and chemokines, including IL-4 and IL-13, which stimulate the expression of genes associated with a profibrotic phenotype in alveolar macrophages. Similar responses were also observed in TGF-β1-treated rat ATII (L2) and rat macrophage NR8383 cells. Deletion of PAI-1 or inhibition of PAI-1 activity with a small molecule PAI-1 inhibitor, however, blocks TGF-β1-induced senescence as well as a senescence-associated secretory phenotype in ATII and L2 cells and, consequently, the stimulatory effects of the conditioned medium from senescent ATII/L2 cells on macrophages. Moreover, we show that silencing p16 ameliorates PAI-1 protein-induced ATII cell senescence and secretion of profibrotic mediators. Our data suggest that PAI-1 mediates TGF-β1-induced ATII cell senescence and secretion of profibrotic mediators through inducing p16, and they also suggest that senescent ATII cells contribute to lung fibrogenesis in part by activating alveolar macrophages through secreting profibrotic and proinflammatory mediators.

Type 2 diabetes (T2D), a growing global health concern, is often exacerbated by obesity and is linked to severe complications. Serpins, a superfamily of serine protease inhibitors, that includes SerpinA3 in humans and its homolog SerpinA3k in mice. SerpinA3k regulates angiogenesis, reactive oxygen species (ROS) production, inflammation, and fibrosis particularly in the context of experimental ocular injury. Furthermore, we have previously demonstrated that urinary SerpinA3 serves as an early biomarker of kidney damage, including diabetic nephropathy; however, its functional role in renal damage, obesity, and T2D remains largely unexplored. This study explored the impact of SerpinA3k deficiency on obesity and T2D and its associated metabolic dysfunctions. Wild-type (WT, n  = 27) and SerpinA3k knockout (KO n  = 26) male mice were randomly assigned to three groups: standard chow diet (SD), high-fat diet (HFD) to induce obesity, and HFD combined with streptozotocin to induce T2D (D2). All the mice were followed and studied after 27 weeks. As expected, WT + D2 mice presented severe hyperglycemia, hyperinsulinemia, increased fat tissue, visceral adipocyte hypertrophy, and renal hyperfiltration. In sharp contrast, diabetic SerpinA3k-deficient mice were protected against these alterations, displaying improved glycemic control, greater pancreatic insulin content, reduced insulin resistance, and favorable adipocyte size remodeling characterized by a lower proportion of medium and large adipocytes. Additionally, these mice showed preserved lipolytic function, and attenuated renal hyperfiltration. Our findings indicate that targeting SerpinA3k mitigates hyperglycemia and insulin resistance, preserves adipose tissue functionality, and potentially prevents metabolic complications. These results highlight SerpinA3k as a promising therapeutic target for T2D.

Kallistatin, a plasma protein, protects against vascular and organ injury. This study is aimed to investigate the role and mechanism of kallistatin in endothelial senescence. Kallistatin inhibited H2O2‐induced senescence in human endothelial cells, as indicated by reduced senescence‐associated‐β‐galactosidase activity, p16INK4a and plasminogen activator inhibitor‐1 expression, and elevated telomerase activity. Kallistatin blocked H2O2‐induced superoxide formation, NADPH oxidase levels and VCAM‐1, ICAM‐1, IL‐6 and miR‐34a synthesis. Kallistatin reversed H2O2‐mediated inhibition of endothelial nitric oxide synthase (eNOS), SIRT1, catalase and superoxide dismutase (SOD)‐2 expression, and kallistatin alone stimulated the synthesis of these antioxidant enzymes. Moreover, kallistatin's anti‐senescence and anti‐oxidant effects were attributed to SIRT1‐mediated eNOS pathway. Kallistatin, via interaction with tyrosine kinase, up‐regulated Let‐7g, whereas Let‐7g inhibitor abolished kallistatin's effects on miR‐34a and SIRT1/eNOS synthesis, leading to inhibition of senescence, oxidative stress and inflammation. Furthermore, lung endothelial cells isolated from endothelium‐specific kallistatin knockout mice displayed marked reduction in mouse kallistatin levels. Kallistatin deficiency in mouse endothelial cells exacerbated senescence, oxidative stress and inflammation compared to wild‐type mouse endothelial cells, and H2O2 treatment further magnified these effects. Kallistatin deficiency caused marked reduction in Let‐7g, SIRT1, eNOS, catalase and SOD‐1 mRNA levels, and elevated miR‐34a synthesis in mouse endothelial cells. These findings indicate that endogenous kallistatin through novel mechanisms protects against endothelial senescence by modulating Let‐7g‐mediated miR‐34a‐SIRT1‐eNOS pathway.

Early therapeutic interventions are essential to prevent Alzheimer Disease (AD). The association of several inflammation-related genetic markers with AD and the early activation of pro-inflammatory pathways in AD suggest inflammation as a plausible therapeutic target. Inflammatory Caspase-1 has a significant impact on AD-like pathophysiology and Caspase-1 inhibitor, VX-765, reverses cognitive deficits in AD mouse models. Here, a one-month pre-symptomatic treatment of Swedish/Indiana mutant amyloid precursor protein (APP Sw/Ind ) J20 and wild-type mice with VX-765 delays both APP Sw/Ind - and age-induced episodic and spatial memory deficits. VX-765 delays inflammation without considerably affecting soluble and aggregated amyloid beta peptide (Aβ) levels. Episodic memory scores correlate negatively with microglial activation. These results suggest that Caspase-1-mediated inflammation occurs early in the disease and raise hope that VX-765, a previously Food and Drug Administration-approved drug for human CNS clinical trials, may be a useful drug to prevent the onset of cognitive deficits and brain inflammation in AD. Previous work showed that the caspase 1 inhibitor VX-765 rescued cognitive deficits in the J20 mouse model of Alzheimer’s disease, and this may occur via reduced inflammation. Here the authors show that administration of the drug prior to onset of cognitive deficits and pathology in mice delays the onset of deficits.