Biology subjects

Serezani, C. H.

Publications and source records attributed to Serezani, C. H..

5 recordsLinked to original sources

bioRxiv2026

Transcriptomic Profiling of Diabetic Porcine Wound Healing Model Identifies Key Metabolic, Inflammatory, and Oxidative Stress Pathways

Diabetic foot ulcers (DFUs) remain a major clinical challenge as diabetes prevalence rises, emphasizing the need for improved therapeutics and relevant preclinical models. Common rodent wound-healing models poorly recapitulate human skin anatomy and repair. Although porcine skin is comparable to human skin, many studies employ young, healthy pigs that do not reflect typical chronic human wounds. Here, we evaluated wound healing in full-thickness skin wounds in non-diabetic and diabetic Yucatan minipigs. RNA sequencing identified key transcriptional differences in wounds of diabetic versus non-diabetic animals, including pathways linked to increased inflammation and oxidative stress, as well as decreased metabolism and extracellular matrix organization, known hallmarks of DFUs. These findings support this preclinical model as a powerful approach for discovery and therapeutic testing in diabetic wounds and provide a novel data set for further mining of potential gene targets for diabetic wound intervention.

pathology↗

bioRxiv2022

Hyperglycemia increases the severity of Staphylococcus aureus osteomyelitis and influences bacterial genes required for survival in bone.

Hyperglycemia, or elevated blood glucose, renders individuals more prone to developing severe Staphylococcus aureus infections. S. aureus is the most common etiological agent of musculoskeletal infection, which is a common manifestation of disease in hyperglycemic patients. However, the mechanisms by which S. aureus causes severe musculoskeletal infection during hyperglycemia are incompletely characterized. To examine the influence of hyperglycemia on S. aureus virulence during invasive infection, we used a murine model of osteomyelitis and induced hyperglycemia with streptozotocin. We discovered that hyperglycemic mice exhibited increased bacterial burdens in bone and enhanced dissemination compared to control mice. Furthermore, infected hyperglycemic mice sustained increased bone destruction relative to euglycemic controls, suggesting that hyperglycemia exacerbates infection-associated bone loss. To identify genes contributing to S. aureus pathogenesis during osteomyelitis in hyperglycemic animals relative to euglycemic controls, we used transposon sequencing (TnSeq). We identified 71 genes uniquely essential for S. aureus survival in osteomyelitis in hyperglycemic mice and another 61 mutants with compromised fitness. Among the genes essential for S. aureus survival in hyperglycemic mice was superoxide dismutase A (sodA), one of two S. aureus superoxide dismutases involved in detoxifying reactive oxygen species (ROS). We determined that a sodA mutant exhibits attenuated growth in vitro in high glucose and in vivo during osteomyelitis in hyperglycemic mice. SodA therefore serves an important role during growth in high glucose and promotes S. aureus survival in bone. Collectively, these studies demonstrate that hyperglycemia increases the severity of osteomyelitis and identify genes contributing to S. aureus survival during hyperglycemic infection.

microbiology↗

bioRxiv2020

Macrophage-derived miR-21 drives overwhelming glycolytic and inflammatory response during sepsis via repression of the PGE2/IL-10 axis.

Myeloid cells play a critical role in the development of systemic inflammation and organ damage during sepsis. The mechanisms the development of aberrant inflammatory response remains to be elucidated. MicroRNAs are small non-coding RNAs that could prevent the expression of inflammatory molecules. Although the microRNA-21 (miR-21) is abundantly expressed in macrophages, the role of miR-21 in sepsis is controversial. Here we showed that miR-21 is upregulated in neutrophils and macrophages from septic mice. We found that myeloid-specific miR-21 deletion enhances animal survival, followed by decreased bacterial growth and organ damage during sepsis. Increased resistance against sepsis was associated with a reduction of aerobic glycolysis (as determined by reduced extracellular acidification rate (ECAR) and expression of glycolytic enzymes) and systemic inflammatory response (IL-1{beta}TNF and IL-6). While miR-21-/- macrophages failed to induce aerobic glycolysis and production of pro-inflammatory cytokines, we observed increased levels of the anti-inflammatory mediators prostaglandin E2 (PGE2) and IL10. Using blocking antibodies and pharmacological tools, we further discovered that increased survival and decreased systemic inflammation in miR21{Delta}myel during sepsis is dependent on the PGE2/IL10-mediated glycolysis inhibition. Together, we are showing a heretofore unknown role of macrophage miR21 in the orchestrating the balance between anti-inflammatory mediators and metabolic reprogramming that drives cytokine storm and tissue damage during sepsis.

immunology↗

bioRxiv2020

Leukotriene B4 licenses inflammasome activation to enhance skin host defense

The initial production of inflammatory mediators dictates host defense as well as tissue injury. Inflammasome activation is a constituent of the inflammatory response by recognizing pathogen and host-derived products and eliciting the production of IL-1{beta}, IL-18 as well as inducing a type of inflammatory cell death termed "pyroptosis". Leukotriene B4 (LTB4) is a lipid mediator produced quickly (seconds to minutes) by phagocytes and induces chemotaxis, enhances cytokine/chemokine production, and enhances antimicrobial effector functions. Whether LTB4 directly activates the inflammasome is not well understood. Our data show that endogenously produced LTB4 is required for the expression of pro-IL-1{beta} in vivo and in vitro and enhances inflammasome assembly. Furthermore, LTB4-mediated Brutons tyrosine kinase (BTK) activation is required for inflammasome assembly in vivo as well for IL-1{beta}-enhanced skin host defense. Together, these data unveil a new role for LTB4 in enhancing the expression and assembly of inflammasome components and suggest that while blocking LTB4 actions could be a promising therapeutic strategy to prevent inflammasome-mediated diseases, exogenous LTB4 can be used as an adjuvant to boost inflammasome-dependent host defense.

immunology↗

bioRxiv2019

Palmitate induces apoptotic cell death and inflammasome activation in human placental macrophages

IntroductionThere is an increasing prevalence of non-communicable diseases worldwide. Metabolic diseases such as obesity and gestational diabetes mellitus (GDM) increasingly affect women during pregnancy, which can harm pregnancy outcomes and the long-term health and wellbeing of exposed offspring. Both obesity and GDM have been associated with proinflammatory effects within the placenta, the critical organ governing fetal development.\n\nMethodsThe purpose of these studies was to model, in vitro, the effects of metabolic stress (high levels of glucose, insulin and saturated lipids) on placental macrophage biology, since these cells are the primary innate immune phagocyte within the placenta with roles in governing maternofetal immune tolerance and antimicrobial host defense. Macrophages were isolated from the villous core of term, human placentae delivered through nonlaboring, elective Cesarean sections and exposed to combinations of elevated glucose (30 mM), insulin (10 nM) and the saturated lipid palmitic acid (palmitate, 0.4 mM).\n\nResultsWe found that palmitate alone induced the activation of the nucleotide-binding oligomerization domain-like receptor (NLR) Family Pyrin Domain Containing 3 (NLRP3) inflammasome in placental macrophages, which was associated with increased interleukin 1 beta release and an increase in apoptotic cell death. Glucose and insulin neither provoked these effects nor augmented the impact of palmitate itself.\n\nDiscussionOur findings confirm an impact of saturated fat on placental macrophage immune activation and could be relevant to the impact of metabolic stress in vivo.

immunology↗