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Sepsis/septic shock activates the sympathetic nervous system (SNS) to deal with the infection stress. However, an imbalanced or maladaptive response due to excessive or uncontrolled activation characterizes autonomic dysfunction. Our hypothesis was that reducing this excessive activation of the autonomic nervous system would impact positively in sepsis. Using ganglionic blockers as a pharmacological approach, the main aim of the present report was to assess the role of ganglionic transmission in the vascular dysfunction associated with sepsis.Sepsis was induced in rats by cecal ligation and puncture (CLP). One hour after CLP surgery, rats were treated subcutaneously with hexamethonium (15 mg/kg; ganglionic blocker), pentolinium (5 mg/kg; a blocker with a higher selectivity for sympathetic ganglia compared to hexamethonium), or vehicle (PBS). Basal blood pressure and the response to adrenergic agonists were evaluated at 6 and 24 h after CLP surgery. Reactivity to vasoconstrictors, nitric oxide (NO) synthase 2 (NOS-2) expression, IL-1 and TNF plasma levels, and density of α1 adrenergic receptors were evaluated in the aorta 24 h after CLP.Septic shock resulted in hypotension and hyporesponsiveness to norepinephrine and phenylephrine, increased plasma cytokine levels and NOS-2 expression in the aorta, and decreased α1 receptor density in the same vessel. Pentolinium but not hexamethonium recovered responsiveness and α1 adrenergic receptor density in the aorta. Both blockers normalized the in vivo response to vasoconstrictors, and reduced plasma IL-1 and NOx levels and NOS-2 expression in the aorta.Blockade of ganglionic sympathetic transmission reduced the vascular dysfunction in experimental sepsis. This beneficial effect seems to be, at least in part, due to the preservation of α1 adrenergic receptor density and to reduced NOS-2 expression and may lead to adjuvant ways to treat human sepsis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Hemorrhagic shock (HS), a leading cause of preventable death, is characterized by severe blood loss and inadequate tissue perfusion. Reoxygenation of ischemic tissues exacerbates organ damage through ischemia-reperfusion injury. SUMOylation has been shown to protect neurons after stroke and is upregulated in response to cellular stress. However, the role of SUMOylation in organ protection after HS is unknown. This study aimed to investigate SUMOylation-mediated organ protection following HS. Male Wistar rats were subjected to HS (blood pressure of 40 ± 2 mmHg, for 90 min) followed by reperfusion. Blood, kidney, and liver samples were collected at various time points after reperfusion to assess organ damage and investigate the profile of SUMO1 and SUMO2/3 conjugation. In addition, human kidney cells (HK-2), treated with the SUMOylation inhibitor TAK-981 or overexpressing SUMO proteins, were subjected to oxygen and glucose deprivation to investigate the role of SUMOylation in hypoxia/reoxygenation injury. The animals presented progressive multiorgan dysfunction, except for the renal system, which showed improvement over time. Compared to the liver, the kidneys displayed distinct patterns in terms of oxidative stress, apoptosis activation, and tissue damage. The global level of SUMO2/3 in renal tissue was also distinct, suggesting a differential role. Pharmacological inhibition of SUMOylation reduced cell viability after hypoxia-reoxygenation damage, while overexpression of SUMO1 or SUMO2 protected the cells. These findings suggest that SUMOylation might play a critical role in cellular protection during ischemia-reperfusion injury in the kidneys, a role not observed in the liver. This difference potentially explains the renal resilience observed in HS animals when compared to other systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although studies have suggested an association between lung infections and increased risk of neuronal disorders (e.g., dementia, cognitive impairment, and depressive and anxious behaviors), its mechanisms remain unclear. Thus, an experimental mice model of pulmonary sepsis was developed to investigate the relationship between lung and brain inflammation. Male Swiss mice were randomly assigned to either pneumosepsis or control groups. Pneumosepsis was induced by intratracheal instillation of Klebsiella pneumoniae , while the control group received a buffer solution. The model's validation included assessing systemic markers, as well as tissue vascular permeability. Depression- and anxiety-like behaviors and cognitive function were assessed for 30 days in sepsis survivor mice, inflammatory profiles, including cytokine levels (lungs, hippocampus, and prefrontal cortex) and microglial activation (hippocampus), were examined. Pulmonary sepsis damaged distal organs, caused peripheral inflammation, and increased vascular permeability in the lung and brain, impairing the blood-brain barrier and resulting in bacterial dissemination. After sepsis induction, we observed an increase in myeloperoxidase activity in the lungs (up to seven days) and prefrontal cortex (up to 24 h), proinflammatory cytokines in the hippocampus and prefrontal cortex, and percentage of areas with cells positive for ionized calcium-binding adaptor molecule 1 (IBA-1) in the hippocampus. Also, depression- and anxiety-like behaviors and changes in short-term memory were observed even 30 days after sepsis induction, suggesting a crosstalk between inflammatory responses of lungs and brain., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jamil Assrey reports financial support, equipment, drugs, or supplies, and writing assistance were provided by 10.13039/100017410INCT-INOVAMED. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background: Phosphodiesterase-4 (PDE4) is responsible for terminating cyclic adenosine monophosphate (cAMP) signalling. PDE4 inhibitors, such as roflumilast (RFM), have anti-inflammatory activity and have been studied in inflammation-induced tissue damage in sepsis. However, the role of RFM on cardiovascular derangements induced by sepsis is still unknown. Thus, we aimed to evaluate the potential effects of RFM on cardiovascular collapse and multiorgan damage caused by sepsis., Methods: Sepsis was induced by cecal ligation and puncture (CLP) in male rats. Six hours after the CLP or sham procedure, animals were randomly assigned to receive either RFM (0.3 mg/kg) or vehicle subcutaneously, and cardiovascular parameters were assessed 24 h after the surgery and organ/plasma samples were collected for further analyses., Results: Sepsis induced hypotension, tachycardia, reduced renal blood flow (RBF) and hyporeactivity to vasoconstrictors both in vivo and ex vivo. RFM treatment increased systemic cAMP levels and RBF. RFM also attenuated hypoperfusion and liver damage induced by CLP. Furthermore, RFM reduced systemic nitric oxide (NO) levels in septic rats, while there were no changes in hepatic NOS-2 expression. Nevertheless, RFM exacerbated sepsis-induced hypotension and tachycardia without ameliorating vascular hyporeactivity., Conclusion: Our data show that PDE-4 inhibition protects septic rats from hepatic injury and improves renal perfusion. However, RFM worsened hemodynamic parameters and showed no protection against sepsis-induced cardiovascular dysfunction and mortality. Thus, despite the anti-inflammatory benefits of RFM, its application in sepsis should be approached cautiously., Competing Interests: Declaration of competing interest The authors have no conflicts of interest or disclosures to report., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Abstract: Cecal ligation and puncture (CLP) is the gold standard model for studying septic shock, which is characterized by hypotension and hyporeactivity to vasoconstrictors. However, approximately 30% of CLP animals do not exhibit cardiovascular changes, requiring more replicates because of the high variability of the model. Therefore, biomarkers enabling the early prediction of cardiovascular collapse in sepsis would greatly benefit sepsis nonclinical studies, refining experimental models and improving clinical translation. Thus, this study aimed to test whether the early increase in lactate levels could predict hypotension and hyporesponsiveness to vasoconstrictors in a rat model of sepsis. Male and female Wistar rats were subjected to CLP or sham procedure. Tail blood lactate was measured 6, 12, and 24 h after surgery. Then, inflammatory, biochemical, and hemodynamic parameters were evaluated. Rats subjected to CLP developed hypotension, hyporesponsiveness to vasoconstrictors, an intense inflammatory process, and increased plasma markers of organ dysfunction. By using receiver operating characteristics curve analysis, we have established that a lactate value of 2.45 mmol/L can accurately discriminate between a rat exhibiting a normal vasoconstrictive response and a vasoplegic rat with 84% accuracy (area under the curve: 0.84; confidence interval [CI]: 0.67-1.00). The sensitivity, which is the ability to identify a diseased rat (true positive), was 75% (CI: 41-95), and the true negative rate was 81% (CI: 57-93). Therefore, early measurement of lactate levels in sepsis could serve as a valuable biomarker for distinguishing vasoplegic rats from those exhibiting normal vasoconstrictive responses., Competing Interests: Declaration of conflicting interests: The authors declare that there is no conflict of interest., (Copyright © 2023 by the Shock Society.)

Background: Hemorrhagic shock (HS), which causes insufficient tissue perfusion, can result in multiple organ failure (MOF) and death. This study aimed to evaluate whether doxycycline (DOX) protects cardiovascular, kidney, and liver tissue from damage in a rat model of HS. Immediately before the resuscitation, DOX (10 mg/kg; i.v.) was administered, and its protective effects were assessed 24 h later. Mean arterial pressure, renal blood flow, heart rate, vasoactive drug response, and blood markers such as urea, creatinine, AST, ALT, CPK, CPR, and NOx levels were determined., Results: We showed that DOX has a significant effect on renal blood flow and on urea, creatinine, AST, ALT, CPK, and NOx. Morphologically, DOX reduced the inflammatory process in the liver tissue., Conclusions: We conclude that DOX protects the liver and kidney against injury and dysfunction in a HS model and could be a strategy to reduce organ damage associated with ischemia-and-reperfusion injury., (© 2024. The Author(s).)

Sepsis is a severe condition secondary to dysregulated host response to infection leading to tissue damage and organ dysfunction. Cannabinoid CB 2 receptor has modulatory effects on the immune response. Therefore, this study investigated the effects of a cannabinoid CB 2 receptor agonist on the local and systemic inflammatory process associated with pneumonia-induced sepsis. Pneumonia-induced sepsis was induced in mice by intratracheal inoculation of Klebsiella pneumoniae. Tissue and bronchoalveolar lavage (BAL) were collected 6, 24, or 48 h after surgery. Mice were treated with CB 2 agonist (AM1241, 0.3 and 3 mg/kg, i.p.) and several parameters of inflammation were evaluated 24 h after sepsis induction. Polymorphonuclear cell migration to the infectious focus peaked 24 h after pneumonia-induced sepsis induction in male and female animals. Septic male mice presented a significant reduction of cannabinoid CB 2 receptor density in the lung tissue after 24 h, which was not observed in females. CB 2 expression in BAL macrophages was also reduced in septic animals. Treatment of septic mice with AM1241 reduced cell migration, local infection, myeloperoxidase activity, protein extravasation, and NOS-2 expression in the lungs. In addition, the treatment reduced plasma IL-1β, increased IL-10 and reduced the severity and mortality of septic animals. These results suggest that AM1241 promotes an interesting balance in the inflammatory response, maintaining lung function and preventing organ injury. Therefore, cannabinoid CB 2 receptors are potential targets to control the excessive inflammatory process that occurs in severe conditions, and agonists of these receptors can be considered promising adjuvants in pneumonia-induced sepsis treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Purpose: Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Because pathogen-derived neuraminidase (NEU) stimulates neutrophils, we investigated whether host NEU can be targeted to regulate the neutrophil dysregulation observed in severe infections., Experimental Approach: The effects of NEU inhibitors on lipopolysaccharide (LPS)-stimulated neutrophils from healthy donors or COVID-19 patients were determined by evaluating the shedding of surface sialic acids, cell activation, and reactive oxygen species (ROS) production. Re-analysis of single-cell RNA sequencing of respiratory tract samples from COVID-19 patients also was carried out. The effects of oseltamivir on sepsis and betacoronavirus-induced acute lung injury were evaluated in murine models., Key Results: Oseltamivir and zanamivir constrained host NEU activity, surface sialic acid release, cell activation, and ROS production by LPS-activated human neutrophils. Mechanistically, LPS increased the interaction of NEU1 with matrix metalloproteinase 9 (MMP-9). Inhibition of MMP-9 prevented LPS-induced NEU activity and neutrophil response. In vivo, treatment with oseltamivir fine-tuned neutrophil migration and improved infection control as well as host survival in peritonitis and pneumonia sepsis. NEU1 also is highly expressed in neutrophils from COVID-19 patients, and treatment of whole-blood samples from these patients with either oseltamivir or zanamivir reduced neutrophil overactivation. Oseltamivir treatment of intranasally infected mice with the mouse hepatitis coronavirus 3 (MHV-3) decreased lung neutrophil infiltration, viral load, and tissue damage., Conclusion and Implications: These findings suggest that interplay of NEU1-MMP-9 induces neutrophil overactivation. In vivo, NEU may serve as a host-directed target to dampen neutrophil dysfunction during severe infections., (© 2022 British Pharmacological Society.)

Objective: To evaluate the potential changes in the plasma levels of resolvin D1 (RvD1) in patients with trauma and hemorrhage. Having found that trauma results in a profound reduction in plasma RvD1 in patients, we have then investigated the effects of RvD1 on the organ injury and dysfunction associated with hemorrhagic shock (HS) in the rat., Background: HS is a common cause of death in trauma due to excessive systemic inflammation and multiple organ failure. RvD1 is a member of the resolvin family of pro-resolution mediators., Methods: Blood samples were drawn from critically injured patients (n = 27, ACITII-prospective observational cohort study) within 2 hours of injury for targeted liquid chromatography tandem mass spectrometry. HS rats (removal of blood to reduce arterial pressure to 30 ± 2 mm Hg, 90 minutes, followed by resuscitation) were treated with RvD1 (0.3 or 1 μg/kg intravenous (i.v.)) or vehicle (n = 7). Parameters of organ injury and dysfunction were determined., Results: Plasma levels of RvD1 (mg/dL) were reduced in patients with trauma+HS (0.17 ± 0.08) when compared with healthy volunteers (0.76 ± 0.25) and trauma patients (0.62 ± 0.20). In rats with HS, RvD1 attenuated the kidney dysfunction, liver injury, and tissue ischemia. RvD1 also reduced activation of the nuclear factor (NF)-κB pathway and reduced the expression of pro-inflammatory proteins such as inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β, and interleukin-6., Conclusion: Plasma RvD1 is reduced in patients with trauma-HS. In rats with HS, administration of synthetic RvD1 on resuscitation attenuated the multiple organ failure associated with HS by a mechanism that involves inhibition of the activation of NF-κB., Competing Interests: The authors have no conflicts of interest., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: The aim of this study was to investigate (a) the potential of the Bruton's tyrosine kinase (BTK) inhibitors acalabrutinib and fenebrutinib to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) hemorrhagic shock (HS) rat models and (b) whether treatment with either acalabrutinib or fenebrutinib attenuates BTK, NF-κB and NLRP3 activation in HS., Background: The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. The protein BTK is known to play a role in the activation of the NLRP3 inflammasome, which is a key component of the innate inflammatory response. However, its role in trauma-hemorrhage is unknown., Methods: Acute HS rat models were performed to determine the influence of acalabrutinib or fenebrutinib on MODS. The activation of BTK, NF-κB and NLRP3 pathways were analyzed by western blot in the kidney., Results: We demonstrated that (a) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (b) treatment of HS-rats with either acalabrutinib or fenebrutinib attenuated the organ injury and dysfunction in acute HS models and (c) reduced the activation of BTK, NF- kB and NLRP3 pathways in the kidney., Conclusion: Our results point to a role of BTK in the pathophysiology of organ injury and dysfunction caused by trauma/hemorrhage and indicate that BTK inhibitors may be repurposed as a potential therapeutic approach for MODS after trauma and/or hemorrhage., Competing Interests: Drafting the manuscript for important intellectual content: NMP and CT All authors reviewed and approved the manuscript. The authors report no conflicts of interest., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Sepsis is one of the leading causes of acute kidney injury (AKI), and several mechanisms including microcirculatory alterations, oxidative stress, and endothelial cell dysfunction are involved. Nitric oxide (NO) is one of the common elements to all these mechanisms. Although all three nitric oxide synthase (NOS) isoforms are constitutively expressed within the kidneys, they contribute in different ways to nitrergic signaling. While the endothelial (eNOS) and neuronal (nNOS) isoforms are likely to be the main sources of NO under basal conditions and participate in the regulation of renal hemodynamics, the inducible isoform (iNOS) is dramatically increased in conditions such as sepsis. The overexpression of iNOS in the renal cortex causes a shunting of blood to this region, with consequent medullary ischemia in sepsis. Differences in the vascular reactivity among different vascular beds may also help to explain renal failure in this condition. While most of the vessels present vasoplegia and do not respond to vasoconstrictors, renal microcirculation behaves differently from nonrenal vascular beds, displaying similar constrictor responses in control and septic conditions. The selective inhibition of iNOS, without affecting other isoforms, has been described as the ideal scenario. However, iNOS is also constitutively expressed in the kidneys and the NO produced by this isoform is important for immune defense. In this sense, instead of a direct iNOS inhibition, targeting the NO effectors such as guanylate cyclase, potassium channels, peroxynitrite, and S-nitrosothiols, may be a more interesting approach in sepsis-AKI and further investigation is warranted., (© 2022 The Author(s).)

SUMOylation is described as a posttranslational protein modification (PTM) that is involved in the pathophysiological processes underlying several conditions related to ischemia- and reperfusion-induced damage. Increasing evidence suggests that, under low oxygen levels, SUMOylation might be part of an endogenous mechanism, which is triggered by injury to protect cells within the central nervous system. However, the role of ischemia-induced SUMOylation in the periphery is still unclear. This article summarizes the results of recent studies regarding SUMOylation profiles in several diseases characterized by impaired blood flow to the cardiorenal, gastrointestinal, and respiratory systems. Our review shows that although ischemic injury per se does not always increase SUMOylation levels, as seen in strokes, it seems that in most cases the positive modulation of protein SUMOylation after peripheral ischemia might be a protective mechanism. This complex relationship warrants further investigation, as the role of SUMOylation during hypoxic conditions differs from organ to organ and is still not fully elucidated., (© 2022 Wiley Periodicals LLC.)

Objective: The aim of this study was to investigate (a) macrophage migration inhibitory factor (MIF) levels in polytrauma patients and rats after haemorrhagic shock (HS), (b) the potential of the MIF inhibitor ISO-1 to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) HS rat models and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in HS., Background: The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. MIF is a pleiotropic cytokine which can modulate the inflammatory response, however, its role in trauma is unknown., Methods: The MIF levels in plasma of polytrauma patients and serum of rats with HS were measured by ELISA. Acute HS rat models were performed to determine the influence of ISO-1 on MODS. The activation of NF-κB and NLRP3 pathways were analysed by western blot in the kidney and liver., Results: We demonstrated that (a) MIF levels are increased in polytrauma patients on arrival to the emergency room and in rats after HS, (b) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (c) treatment of HS-rats with ISO-1 attenuated the organ injury and dysfunction in acute HS models and (d) reduced the activation of NF-κB and NLRP3 pathways in the kidney and liver., Conclusion: Our results point to a role of MIF in the pathophysiology of trauma-induced organ injury and dysfunction and indicate that MIF inhibitors may be used as a potential therapeutic approach for MODS after trauma and/or haemorrhage., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Patel, Yamada, Oliveira, Stiehler, Zechendorf, Hinkelmann, Kraemer, Stoppe, Collino, Collotta, Alves, Ramos, Sordi, Marzi, Relja, Marx, Martin and Thiemermann.)

Sepsis and septic shock are associated with high mortality and are considered one of the major public health concerns. The onset of sepsis is known as a hyper-inflammatory state that contributes to organ failure and mortality. Recent findings suggest a potential role of two non-receptor protein tyrosine kinases, namely Focal adhesion kinase (FAK) and Proline-rich tyrosine kinase 2 (Pyk2), in the inflammation associated with endometriosis, cancer, atherosclerosis and asthma. Here we investigate the role of FAK-Pyk2 in the pathogenesis of sepsis and the potential beneficial effects of the pharmacological modulation of this pathway by administering the potent reversible dual inhibitor of FAK and Pyk2, PF562271 (PF271) in a murine model of cecal ligation and puncture (CLP)-induced sepsis. Five-month-old male C57BL/6 mice underwent CLP or Sham surgery and one hour after the surgical procedure, mice were randomly assigned to receive PF271 (25 mg/kg, s.c.) or vehicle. Twenty-four hours after surgery, organs and plasma were collected for analyses. In another group of mice, survival rate was assessed every 12 h over the subsequent 5 days. Experimental sepsis led to a systemic cytokine storm resulting in the formation of excessive amounts of both pro-inflammatory cytokines (TNF-α, IL-1β, IL-17 and IL-6) and the anti-inflammatory cytokine IL-10. The systemic inflammatory response was accompanied by high plasma levels of ALT, AST (liver injury), creatinine, (renal dysfunction) and lactate, as well as a high, clinical severity score. All parameters were attenuated following PF271 administration. Experimental sepsis induced an overactivation of FAK and Pyk2 in liver and kidney, which was associated to p38 MAPK activation, leading to increased expression/activation of several pro-inflammatory markers, including the NLRP3 inflammasome complex, the adhesion molecules ICAM-1, VCAM-1 and E-selectin and the enzyme NOS-2 and myeloperoxidase. Treatment with PF271 inhibited FAK-Pyk2 activation, thus blunting the inflammatory abnormalities orchestrated by sepsis. Finally, PF271 significantly prolonged the survival of mice subjected to CLP-sepsis. Taken together, our data show for the first time that the FAK-Pyk2 pathway contributes to sepsis-induced inflammation and organ injury/dysfunction and that the pharmacological modulation of this pathway may represents a new strategy for the treatment of sepsis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alves, Aimaretti, Einaudi, Mastrocola, de Oliveira, Collotta, Porchietto, Aragno, Cifani, Sordi, Thiemermann, Fernandes and Collino.)

Sepsis activates the renin-angiotensin system and the production of angiotensin II, which has a key role in the regulation of blood pressure through AT 1 receptors. However, excessive activation of AT 1 receptor is associated with deleterious effects. We investigated the consequences of a differential blockade of AT 1 receptor caused by two doses of losartan (0.25 mg/kg or 15 mg/kg, s.c), a selective AT 1 receptor antagonist on sepsis outcome. These doses reduced the effect of angiotensin II in normal rats by 30% and >90% 8 h after administration, respectively, but only the higher dose maintained its inhibitory effect (~70%) 24 h after injection. Sepsis was induced by cecal ligation and puncture (CLP). Losartan was injected 2 h after CLP and parameters were evaluated 6 and 24 h after CLP. Septic rats developed hypotension and hyporesponsiveness to vasoconstrictors, an intense inflammatory process and increase in plasma markers of organ dysfunction. The lower dose of losartan improved the vasoconstrictive response to phenylephrine and angiotensin II, reduced lung myeloperoxidase and prevented leukopenia 24 h after CLP, but it did not reduce NOS-2 expression, plasma IL-6 levels or organ injury parameters of septic rats. On the other hand, the higher dose of losartan worsened the response to vasoconstrictors, potentiated the hypotension and increased further levels of creatine, urea and lactate in septic rats. Therefore, an early and partial blockade of AT 1 receptor with a low dose of losartan may counteract sepsis-induced refractoriness to vasoconstrictors thus providing an opportunity to improve the outcome of this condition., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Previous studies have shown that phagocytosis of apoptotic cells can tune the macrophage phenotype and trigger the resolution of inflammation. This mechanism is largely dependent on the recognition of phosphatidylserine (PS) residues on the outer membrane of dying cells. Therefore, we sought to assess the effects of PS-containing liposomes (mimics of apoptotic cells) on the leukocyte migration profile during the inflammatory process in vivo. Inflammation was induced by carrageenan injection into air pouches created on the dorsal region of mice, as this model enables convenient access to the exudates for further investigation. Mice were treated with PBS, PS-containing or phosphatidylcholine (PC)-containing liposomes (10, 30 or 100 mg/kg intraperitoneally [i.p.]). Starting 8 h after carrageenan injection, the level of leukocyte infiltration was monitored over three days. The PS-containing, but not PC-containing, liposomes reduced the polymorphonuclear (PMN) and mononuclear (MN) leukocyte influx into the inflamed pouches in a dose-dependent fashion. Most notably, these effects could also be adoptively transferred; that is, they were also found in mice injected with a liposome-free peritoneal lavage obtained from the mice that had received the intraperitoneal PS-liposome treatment. The effect of treatment with the PS-induced soluble mediators (PS-ISMs) was found to be dependent on the presence of peritoneal macrophages and was susceptible to heat, trypsin degradation, and cycloheximide treatment. The PS-containing liposomes promoted the reduction of PMN leukocyte influx by triggering the release of anti-inflammatory autacoids with a proteinaceous nature that were produced de novo after PS exposure., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Abstract: Sepsis is a life-threatening condition widely studied by animal models. Cecal ligation and puncture (CLP) is still regarded as the gold standard model for sepsis. However, CLP has limitations due to its invasiveness and variability. Cecal slurry (CS) model is a nonsurgical and thus less invasive alternative. However, the lack of standardization of the CS model in the literature limits its practical application. Additionally, it is not well studied whether CS model reproduces septic cardiovascular dysfunction in rats, which is a crucial issue in septic patients. Thus, this study aimed to standardize the CS model in Wistar rats and evaluate sepsis-induced cardiovascular dysfunction compared to CLP. Our results showed that CS model induced important features of sepsis cardiovascular dysfunction 24 h after its onset, such as hypotension, tachycardia, and decreased contractile response to vasoconstrictors both in vivo and ex vivo as well changes in renal blood flow. Increases in blood lactate, AST, ALT, creatinine, and urea indicated organ dysfunction. CS model also induced increased production of nitric oxide metabolites and bacterial spread to tissues. CS model causes less animal suffering, it is a nonsurgical model, and, more importantly, it replicates the cardiovascular dysfunction induced by sepsis with better homogeneity than CLP. Therefore, CS model serves as an alternative and possibly as a better model for sepsis research., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Objectives: Patients with breast cancer who receive weekly paclitaxel therapy may experience deleterious effects associated with prophylactic dexamethasone use for 12 consecutive weeks. Approximately 90% of paclitaxel hypersensitivity reactions (HSRs) occur within the first 10 to 15 min of the first two infusions. We investigated the feasibility of dexamethasone withdrawal between weeks 3 and 12 (W3 and W12) in early stage breast cancer patients treated with weekly paclitaxel at the standard dose (80 mg/m 2 )., Methods: All patients received intravenous prophylaxis of dexamethasone 20 mg, ranitidine 50 mg, and diphenhydramine 50 mg in the first 2 weeks (W1 and W2) of treatment. Provided that no serious (G3/G4) HSRs events occurred, dexamethasone was omitted between W3 and W12, while ranitidine and diphenhydramine were continued. The primary end point was the incidence of any grade HSRs during the treatment period, and the secondary end points were quality of life and weight changes., Results: Twenty-five patients were included in the study, and 300 infusion cycles of paclitaxel were evaluated for HSRs. The overall incidence of HSRs was 0.6% (2 events), and both of these events occurred in the first week. There were no incidents of serious HSRs or anaphylaxis and no G3 or G4 toxicities. Scores from the EORTC QLQ-C30 questionnaire did not change significantly for the global health status/quality of life scale or for the symptoms scales, although changes in scores differed significantly for the functional scales. There were no clinically relevant weight changes during the treatment period., Conclusions: Dexamethasone withdrawal from W3 to W12 in early stage breast cancer patients treated with weekly paclitaxel is feasible. The incidence of all grades of HSRs was comparable to that reported in trials with dexamethasone for 12 consecutive weeks, and no serious events (G3/G4) occurred. Studies with larger sample sizes are needed to confirm our results which are important, especially for patients for whom corticosteroids are contraindicated.

Objective: Periodontitis is associated with endothelial dysfunction, which is clinically characterized by a reduction in endothelium-dependent relaxation. However, we have previously shown that impairment in endothelium-dependent relaxation is transient. Therefore, we evaluated which mediators are involved in endothelium-dependent relaxation recovery., Material and Methods: Rats were subjected to ligature-induced experimental periodontitis. Twenty-one days after the procedure, the animals were prepared for blood pressure recording, and the responses to acetylcholine or sodium nitroprusside were obtained before and 30 minutes after injection of a nitric oxide synthase inhibitor (L-NAME), cyclooxygenase inhibitor (Indomethacin, SC-550 and NS- 398), or calcium-dependent potassium channel blockers (apamin plus TRAM- 34). The maxilla and mandible were removed for bone loss analysis. Blood and gingivae were obtained for C-reactive protein (CRP) and myeloperoxidase (MPO) measurement, respectively., Results: Experimental periodontitis induces bone loss and an increase in the gingival MPO and plasmatic CRP. Periodontitis also reduced endothelium-dependent vasodilation, a hallmark of endothelial dysfunction, 14 days after the procedure. However, the response was restored at day 21. We found that endothelium-dependent vasodilation at day 21 in ligature animals was mediated, at least in part, by the activation of endothelial calcium-activated potassium channels., Conclusions: Periodontitis induces impairment in endothelial-dependent relaxation; this impairment recovers, even in the presence of periodontitis. The recovery is mediated by the activation of endothelial calcium-activated potassium channels in ligature animals. Although important for maintenance of vascular homeostasis, this effect could mask the lack of NO, which has other beneficial properties.

Chronic kidney disease (CKD) is a major public health concern, underscoring a need to identify pathogenic mechanisms and potential therapeutic targets. Reactive oxygen species (ROS) are derivatives of oxygen molecules that are generated during aerobic metabolism and are involved in a variety of cellular functions that are governed by redox conditions. Low levels of ROS are required for diverse processes, including intracellular signal transduction, metabolism, immune and hypoxic responses, and transcriptional regulation. However, excess ROS can be pathological, and contribute to the development and progression of chronic diseases. Despite evidence linking elevated levels of ROS to CKD development and progression, the use of low-molecular-weight antioxidants to remove ROS has not been successful in preventing or slowing disease progression. More recent advances have enabled evaluation of the molecular interactions between specific ROS and their targets in redox signalling pathways. Such studies may pave the way for the development of sophisticated treatments that allow the selective control of specific ROS-mediated signalling pathways., (© 2023. Springer Nature Limited.)

Septic shock, which is triggered by microbial products, is mainly characterised by inadequate tissue perfusion, which can lead to multiple organ dysfunction and death. An intense release of vasoconstrictors agents occurs in the early stages of shock, which can lead to ischemic injury. In this scenario, cGMP could play a key role in counterbalancing these agents and preventing tissue damage. Sildenafil, which is a phosphodiesterase-5 inhibitor, increases cGMP in smooth muscle cells and promotes vasodilation. Thus, the purpose of this study was to investigate the effect of treatment with sildenafil in the early stages of sepsis. Male rats were submitted to either cecal ligation and puncture (CLP) or a sham procedure. Eight h after the procedure, the CLP and sham groups were randomly assigned to receive sildenafil (10mg/kg, gavage) or vehicle, and twelve or twenty-four h later the inflammatory, biochemical and haemodynamic parameters were evaluated. Sepsis significantly increased levels of plasma nitrate/nitrite (NOx), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, creatine kinase and lactate. Additionally, sepsis led to hypotension, hyporesponsiveness to vasoconstrictor, renal blood flow reduction and also increased lung and kidney myeloperoxidase. Sildenafil increased renal blood flow and reduced the plasma levels of creatinine, lactate and creatine kinase, as well as reducing lung myeloperoxidase. Thus, phosphodiesterase inhibition may be a useful therapeutic strategy if administered at the proper time., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Acute kidney injury (AKI) is a major risk factor for the development of chronic kidney disease. Nuclear factor-κB is a nuclear transcription factor activated post-ischemia, responsible for the transcription of proinflammatory proteins. The role of nuclear factor-κB in the renal fibrosis post-AKI is unknown., Methods and Results: We used a rat model of AKI caused by unilateral nephrectomy plus contralateral ischemia (30 minutes) and reperfusion injury (up to 28 days) to show impairment of renal function (peak: 24 hours), activation of nuclear factor-κB (peak: 48 hours), and fibrosis (28 days). In humans, AKI is diagnosed by a rise in serum creatinine. We have discovered that the IκB kinase inhibitor IKK16 (even when given at peak serum creatinine) still improved functional and structural recovery and reduced myofibroblast formation, macrophage infiltration, transforming growth factor-β expression, and Smad2/3 phosphorylation. AKI resulted in fibrosis within 28 days (Sirius red staining, expression of fibronectin), which was abolished by IKK16. To confirm the efficacy of IKK16 in a more severe model of fibrosis, animals were subject to 14 days of unilateral ureteral obstruction, resulting in tubulointerstitial fibrosis, myofibroblast formation, and macrophage infiltration, all of which were attenuated by IKK16., Conclusions: Inhibition of IκB kinase at peak creatinine improves functional recovery, reduces further injury, and prevents fibrosis., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Objective: To evaluate the effects of artesunate on organ injury and dysfunction associated with hemorrhagic shock (HS) in the rat., Background: HS is still a common cause of death in severely injured patients and is characterized by impairment of organ perfusion, systemic inflammatory response, and multiple organ failure. There is no specific therapy that reduces organ injury/dysfunction. Artesunate exhibits pharmacological actions beyond its antimalarial activity, such as anticancer, antiviral, and anti-inflammatory effects., Methods: Rats were submitted to HS. Mean arterial pressure was reduced to 30 mm Hg for 90 minutes, followed by resuscitation. Rats were randomly treated with artesunate (2.4 or 4.8 mg/kg i.v.) or vehicle upon resuscitation. Four hours later, parameters of organ injury and dysfunction were assessed., Results: Artesunate attenuated the multiple organ injury and dysfunction caused by HS. Pathway analysis of RNA sequencing provided good evidence to support an effect of artesunate on the Akt-survival pathway, leading to downregulation of interleukin-1 receptor-associated kinase 1. Using Western blot analysis, we confirmed that treatment of HS rats with artesunate enhanced the phosphorylation (activation) of Protein kinase B (Akt) and endothelial nitric oxide synthase and the phosphorylation (inhibition) of glycogen synthase kinase-3β (GSK-3β). Moreover, artesunate attenuated the HS-induced activation of nuclear factor kappa B and reduced the expression of proinflammatory proteins (inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin 6)., Conclusions: Artesunate attenuated the organ injury/dysfunction associated with HS by a mechanism that involves the activation of the Akt-endothelial nitric oxide synthase survival pathway, and the inhibition of glycogen synthase kinase-3β and nuclear factor kappa B. A phase II clinical trial evaluating the effects of good manufacturing practice-artesunate in patients with trauma and severe hemorrhage is planned.

Severe hemorrhage can lead to global ischemia and hemorrhagic shock (HS), resulting in multiple organ failure (MOF) and death. Restoration of blood flow and re-oxygenation is associated with an exacerbation of tissue injury and inflammatory response. The neuronal nitric oxide synthase (nNOS) has been implicated in vascular collapse and systemic inflammation of septic shock; however, the role of nNOS in HS is poorly understood. The aim of this study was to evaluate the role of nNOS in the MOF associated with HS.Rats were subjected to HS under anesthesia. Mean arterial pressure was reduced to 30  mmHg for 90  min, followed by resuscitation with shed blood. Rats were randomly treated with two chemically distinct nNOS inhibitors [ARL 17477 (1 mg/kg) and 7-nitroindazol (5 mg/kg)] or vehicle upon resuscitation. Four hours later, parameters of organ injury and dysfunction were assessed.HS was associated with MOF development. Inhibition of nNOS activity at resuscitation protected rats against the MOF and vascular dysfunction. In addition, treatment of HS rats with nNOS inhibitors attenuated neutrophil infiltration into target organs and decreased the activation of NF-κB, iNOS expression, NO production, and nitrosylation of proteins. Furthermore, nNOS inhibition also reduced the levels of pro-inflammatory cytokines TNF-α and IL-6 in HS rats.In conclusion, two distinct inhibitors of nNOS activity reduced the MOF, vascular dysfunction, and the systemic inflammation associated with HS. Thus, nNOS inhibitors may be useful as an adjunct therapy before fluids and blood administration in HS patients to avoid the MOF associated with reperfusion injury during resuscitation.

Background and Purpose Kinins are pro-inflammatory peptides that are released during tissue injury, including that caused by inflammatory bowel disease. Herein, we assessed the role and underlying mechanisms through which the absence of kinin B1 receptors exacerbates the development of dextran sulfate sodium ( DSS)-induced colitis in mice. Experimental Approach B1 and B2 receptor antagonists and B1 receptor knockout mice ( B1−/−) were used to assess the involvement of B1 and B2 receptor signalling in a DSS-colitis. B1 receptor, B2 receptor, occludin and claudin-4 expression, cytokine levels and cell permeability were evaluated in colon from wild-type ( WT) and B1−/− mice. Key Results DSS-induced colitis was significantly exacerbated in B1−/− compared with WT mice. IL-1β, IFN-γ, keratinocyte-derived chemokine and macrophage inflammatory protein-2 were markedly increased in the colon from DSS-treated B1−/− compared with DSS-treated WT mice. Treatment of WT mice with a selective B1 receptor antagonist, DALBK or SSR240612, had no effect on DSS-induced colitis. Of note, B2 receptor mRNA expression was significantly up-regulated in colonic tissue from the B1−/− mice after DSS administration. Moreover, treatment with a selective B2 receptor antagonist prevented the exacerbation of colitis in B1−/− mice following DSS administration. The water- or DSS-treated B1−/− mice showed a decrease in occludin gene expression, which was partially prevented by the B2 receptor antagonist. Conclusions and Implications A loss of B1 receptors markedly exacerbates the severity of DSS-induced colitis in mice. The increased susceptibility of B1−/− may be associated with compensatory overexpression of B2 receptors, which, in turn, modulates tight junction expression. [ABSTRACT FROM AUTHOR]

Septic vascular dysfunction is characterized by hypotension and hyporeactivity to vasoconstrictors and nitric oxide (NO), reactive oxygen species and peroxynitrite have a prominent role in this condition. However, the mechanism whereby the vascular dysfunction is initiated is poorly understood. Based on previous studies of our group and the literature,we hypothesize that constitutive nitric oxide synthases (c-NOS) and peroxynitrite may play a role in the development of septic vascular dysfunction. Bacterial lipopolysaccharide (LPS) and interferon-γ (IFN) were used to stimulate rat aorta smooth muscle cells (A7r5) and rat aorta slices. This stimulation led to a rapid (within minutes) production of NO and superoxide anion, which led to peroxynitrite formation. When this rapid initial burst was reduced, through the inhibition of c-NOS and NADPH oxidases (NOX) or the scavenging of NO and superoxide the NF-κB activation, NOS-2 expression and nitrite production were significantly attenuated. Although vascular smooth muscle cells express both c-NOS isoforms, gene knockdown revealed that only NOS-1-dependent NO and peroxynitrite formation are important for the later NOS-2 expression. Similar findings were obtained by knockdown NOX-1 gene, one source of superoxide for peroxynitrite formation. Taking together, we show that smooth muscle cell activation by LPS/IFN leads to a rapid formation of NOS-1-derived NO and NOX-1-derived superoxide, forming peroxynitrite; and that this species act as a trigger for NOS-2 expression through NF-κB activation. Therefore, our findings suggest a critical role for NOS-1 and NOX-1 in the initiation of the vascular dysfunction associated with sepsis and septic shock., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Nuclear factor-kappa B (NF-κB) activation is widely implicated in multiple organ failure (MOF); however, a direct inhibitor of IκB kinase (IKK), which plays a pivotal role in the activation of NF-κB, has not been investigated in shock. Thus, the aim of the present work was to investigate the effects of an IKK inhibitor on the MOF associated with hemorrhagic shock (HS). Therefore, rats were subjected to HS and were resuscitated with the shed blood. Rats were treated with the inhibitor of IKK or vehicle at resuscitation. Four hours later, blood and organs were assessed for organ injury and signaling events involved in the activation of NF-κB. Additionally, survival following serum deprivation was assessed in HK-2 cells treated with the inhibitor of IKK. HS resulted in renal dysfunction, lung, liver and muscular injury, and increases in serum inflammatory cytokines. Kidney and liver tissue from HS rats revealed increases in phosphorylation of IKKαβ and IκBα, nuclear translocation of NF-κB and expression of inducible isoform of nitric oxide synthase (iNOS). IKK16 treatment upon resuscitation attenuated NF-κB activation and activated the Akt survival pathway, leading to a significant attenuation of all of the above parameters. Furthermore, IKK16 exhibited cytoprotective effects in human kidney cells. In conclusion, the inhibitor of IKK complex attenuated the MOF associated with HS. This effect may be due to the inhibition of the NF-κB pathway and activation of the survival kinase Akt. Thus, the inhibition of the IKK complex might be an effective strategy for the prevention of MOF associated with HS.

Methods: Male rats were 'pretreated' with phosphate-buffered saline (PBS; i.p.) or LPS (1 mg/kg; i.p.) 24 h prior to HS. Mean arterial pressure (MAP) was maintained at 30 ± 2 mmHg for 90 min or until 25% of the shed blood had to be re-injected to sustain MAP. This was followed by resuscitation with the remaining shed blood. Four hours after resuscitation, parameters of organ dysfunction and systemic inflammation were assessed., Results: HS resulted in renal dysfunction, and liver and muscular injury. At a first glance, LPS preconditioning attenuated organ dysfunction. However, we discovered that HS-rats that had been preconditioned with LPS (a) were not able to sustain a MAP at 30 mmHg for more than 50 min and (b) the volume of blood withdrawn in these animals was significantly less than in the PBS-control group. This effect was associated with an enhanced formation of the nitric oxide (NO) derived from inducible NO synthase (iNOS). Thus, a further control group in which all animals were resuscitated after 50 min of hemorrhage was performed. Then, LPS preconditioning aggravated both circulatory failure and organ dysfunction. Most notably, HS-rats pretreated with LPS exhibited a dramatic increase in NF-κB activation and pro-inflammatory cytokines., Conclusion: In conclusion, LPS preconditioning predisposed animals to an earlier vascular decompensation, which may be mediated by an excess of NO production secondary to induction of iNOS and activation of NF-κB. Moreover, LPS preconditioning increased the formation of pro-inflammatory cytokines, which is likely to have contributed to the observed aggravation of organ injury/dysfunction caused by HS.

The formylpeptide receptor 2 (FPR2/ALX) is a very promiscuous receptor, utilized by lipid and protein ligands that trigger pro- or anti-inflammatory responses. FPR2/ALX expression is increased in lung tissues of septic animals and its activation has a beneficial therapeutic effect by controlling exacerbated inflammation. Although FPR2/ALX expression was observed in vascular smooth muscle cells, its role in vascular reactivity in inflammatory conditions has not been studied. In this study, we report that LPS increases FPR2/ALX expression in vascular smooth muscle cells (A7r5 cells) and aorta tissue, and that the selective agonist WKYMVm reverses LPS-induced vascular hyporeactivity in mouse aorta rings. Mice bearing pneumosepsis by Klebsiella pneumoniae and treated with WKYMVm recovered the reactivity to vasoconstrictors and the survival improved by 40%. As for the mechanisms involved, FPR2/ALX activation decreases NO production in LPS-stimulated cells and aorta, but it does not seem involve the regulation of NOS-2 expression. The molecular mechanism by which the peptide inhibits NO production still needs to be elucidated, but our data suggests an important role for NO in the WKYMVm beneficial effect observed in LPS injury and sepsis. In conclusion, our data suggest, for the first time, that a receptor, primarily described as a mediator of immune responses, may have an important role in the vascular dysfunctions observed in sepsis and may be a possible target for new therapeutic interventions., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Hepatic hypoxia/reoxygenation (H/R) insult is a critical issue in hepatic transplant and surgeries, profoundly influencing postoperative prognosis. One crucial pathomechanism in this condition is impaired autophagy flux, which disrupts liver homeostasis. Artesunate, an antimalarial drug, has shown potential in providing hepatoprotection against H/R injury; however, whether it can modulate disrupted autophagy to enhance hepatoprotection remains unclear. Purpose of the study: Accordingly, we delved into the potential mechanism(s) through which artesunate modulates the autophagy process in a hepatic H/R injury model. Methods and results: Rats were categorized into three groups, viz. sham operated, H/R, and artesunate-treated (50 mg/kg, i.p). Disease regression was evaluated microscopically, and molecular alternations were assessed biochemically using ELISA and western blotting techniques. Mechanistic analysis revealed that artesunate administration at reperfusion time significantly upregulated the gene expression of GLP1R protein expression of p-AMPK, accompanied by a downregulation in those of p-mTOR, and its target molecule p-ULK1, presenting the first trail to initiate autophagy. Additionally, artesunate reduced H/R-induced hepatic upregulated protein expression of p-mTOR/P70S6K cue, and cyclin D1 content, which positively correlated with the mTOR/P70S6K axis. Moreover, artesunate sharply upregulated active p-Akt, which in turn phosphorylated/inactivated GSK3β, a cascade that indirectly promotes autophagy. Consequently, artesunate increased the hepatic beclin-1 and LC3-II to further uphold its autophagic capacity. The hepato-therapeutic effectiveness of artesunate was further evidenced by reduced serum ALT and AST levels, along with diminished hepatic histopathological alterations. Conclusion: Artesunate protected liver by triggering autophagy partly by modulating the GLP1R/AMPK/mTOR/ULK1, GLP1R/AMPK/mTOR/P70S6K, cyclin D1, and Akt/GSK3β trajectories providing a significant therapeutic potential in managing hepatic H/R insult. [ABSTRACT FROM AUTHOR]

Emerging and reemerging fungal infections are very common in nosocomial and non-nosocomial settings in people having poor immunogenic profiles either due to hematopoietic stem cell transplants or are using immunomodulators to treat chronic inflammatory disease or autoimmune disorders, undergoing cancer therapy or suffering from an immune weakening disease like HIV. The refractory behavior of opportunistic fungi has necessitated the discovery of unconventional antifungals. The emergence of black fungus infection during COVID-19 also triggered the antifungal discovery program. Natural products are one of the alternative sources of antifungals. Endophytic fungi reside and co-evolve within their host plants and, therefore, offer a unique bioresource of novel chemical scaffolds with an array of bioactivities. Hence, immense possibilities exist that these unique chemical scaffolds expressed by the endophytic fungi may play a crucial role in overcoming the burgeoning antimicrobial resistance. These chemical scaffolds so expressed by these endophytic fungi comprise an array of chemical classes beginning from cyclic peptides, sesquiterpenoids, phenols, anthraquinones, coumarins, etc. In this study, endophytic fungi reported in the last six years (2018–2023) have been explored to document the antifungal entities they produce. Approximately 244 antifungal metabolites have been documented in this period by different groups of fungi existing as endophytes. Various aspects of these antifungal metabolites, such as antifungal potential and their chemical structures, have been presented. Yet another unique aspect of this review is the exploration of volatile antifungal compounds produced by these endophytic fungi. Further strategies like epigenetic modifications by chemical as well as biological methods and OSMAC to induce the silent gene clusters have also been presented to generate unprecedented bioactive compounds from these endophytic fungi. [ABSTRACT FROM AUTHOR]

Caffeine is the most popular and widely consumed behaviourally active substance in the world. This review describes the influence of caffeine on the cardiovascular system, with a special focus on blood platelets. For many years, caffeine was thought to have a negative effect on the cardiovascular system mainly due to increasing blood pressure. However, more recent data suggest that habitual caffeine consumption may reduce the risk of cardiovascular disease and hypertension. This could be a significant finding as cardiovascular disease is the leading cause of death worldwide. Caffeine is known to inhibit A1 adenosine receptors, through which it is believed to modulate inter alia coronary blood flow, total peripheral resistance, diuresis, and heart rate. It has been shown that coffee possesses antiplatelet activity, but depending on the dose and the term of its use, caffeine may stimulate or inhibit platelet reactivity. Also, chronic exposure to caffeine may sensitize or upregulate the adenosine receptors in platelets causing increased cAMP accumulation and anti-aggregatory effects and decrease calcium levels elicited by AR agonists. The search for new, selective, and safe AR agonists is one of the new strategies for improving antiplatelet therapy involving targeting multiple pathways of platelet activation. Therefore, this review examines the AR-dependent impact of caffeine on blood platelets in the presence of adenosine receptor agonists. [ABSTRACT FROM AUTHOR]

Background and objectives: The main problem of vascular preservation is the maintenance of vessel graft quality and function following extended storage. Conventional preservation solutions such as histidine–tryptophan–ketoglutarate (HTK) solution, Phosphate-Buffer Solution (PBS), or sodium chloride 0.9% has been shown to be inadequate in preserving vascular physiological function after 3 days of cold storage. This study aimed to evaluate whether adenosine and lidocaine (AL) in a modified Krebs–Henseleit (KH) solution can preserve the function and histological structure of rat aortic rings after 6 days. Materials and Methods: Thirty-five aortic rings from male Wistar rats (200–300 g) were harvested and immediately immersed in one of the assigned cold preservation solutions: standard KH, modified KH (mod KH) with lower calcium (Ca2+) and higher magnesium content (Mg2+) with or without adenosine and lidocaine (mod KH-AL), and modified KH with AL, insulin, and melatonin (Mod KH-ALMI). The contraction and relaxation function of the aortic rings were examined using an isometric force transducer after 6 days of cold preservation. Hematoxylin and eosin staining were used to analyze the rings' histological structure. Results: Vascular contraction and relaxation functions were severely affected after a 6-day cold storage period in standard KH. Modifying the KH solution by reducing the Ca2+ and increasing the Mg2+ levels greatly recovered the vessel functions. The addition of AL or ALMI to the modified KH did not further recover vascular contractility. However, only the addition of AL to the modified KH increased the ACh-induced relaxation at 6 days when compared to the conventional KH, suggesting that endothelium preservation is improved. From histological analysis, it was found that the addition of AL but not ALMI further improved the endothelial lining and the structure of the elastic membrane layers of the preserved vessels after 6 days of cold preservation. Conclusions: The addition of AL to low calcium-high magnesium KH solution significantly enhanced endothelial preservation and improved endothelial-induced relaxation of preserved vessels after 6 days of cold storage. [ABSTRACT FROM AUTHOR]

Lipoxin A4 (LXA4) is an endogenous lipid mediator with potent anti-inflammatory actions but its role in infectious processes is not well understood. We investigated the involvement of LXA4 and its receptor FPR2/ALX in the septic inflammatory dysregulation. Pneumosepsis was induced in mice by inoculation of Klebsiella pneumoniae. LXA4 levels and FPR2/ALX expression in the infectious focus as well as the effects of treatment with receptor agonists (LXA4 and BML-111) and antagonists (BOC-2 and WRW(4)) in early (1h) and late (24h) sepsis were studied. Sepsis induced an early increase in LXA4, FPR2/ALX lung expression, local and systemic infection and inflammation, and mortality. Treatment with BOC-2 in early sepsis increased leukocyte migration to the focus, and reduced bacterial load and dissemination. Inhibition of 5- and 15-lipoxygenase in early sepsis also increased leukocyte migration. Early treatment with WRW(4) and BOC-2 improved survival. Treatment with authentic LXA4 or BML-111 in early sepsis decreased cell migration and worsened the infection. In late sepsis, treatment with BOC-2 had no effect, but LXA4 improved the survival rate by reducing the excessive inflammatory response, this effect being abolished by pretreatment with BOC-2. Thus, the anti-inflammatory and pro-resolution mediator LXA4 and its receptor FPR2/ALX levels were increased in the early phase of sepsis, contributing to the septic inflammatory dysregulation. In addition, LXA4 has a dual role in sepsis and that its beneficial or harmful effects are critically dependent on the time. Therefore, a proper interference with LXA4 system may be a new therapeutic avenue to treat sepsis., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objectives: This study aimed to evaluate the systemic inflammatory response and cardiovascular changes induced by experimental periodontitis in rats., Design: Experimental periodontitis was induced by placing a cotton ligature around the cervix of both sides of mandibular first molars and maxillary second molars in each male rat. Sham-operated rats had the ligature removed immediately after the procedure. Seven, 14 or 28 days after procedure, the effects of acetylcholine, sodium nitroprusside and phenylephrine were evaluated on blood pressure, aortic rings and isolated and perfused mesenteric bed. The blood was obtained for plasma Interleukin-6 (IL-6), C-reactive protein (CRP) and lipid evaluation. The mesenteric vessels were obtained to evaluate superoxide production and nitric oxide synthase 3 (NOS-3) expression., Results: Ligature induced periodontitis reduced endothelium-dependent vasodilatation, a hallmark of endothelial dysfunction. This effect was associated with an increase in systemic inflammatory markers (IL-6 and CRP), worsens on lipid profile, increased vascular superoxide production and reduced NOS-3 expression. It is interesting to note that many of these effects were transitory., Conclusion: Periodontitis induced a transient systemic and vascular inflammation which leads to endothelial dysfunction, an initial step for cardiovascular diseases. Moreover, the animal model of periodontitis used here may represent a valuable tool for studying the relationship between periodontitis and endothelial dysfunction., (Copyright © 2013 Elsevier Ltd. All rights reserved.)