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Previous research has identified intravascular platelet thrombi in regions affected by myocardial ischemia-reperfusion (MI/R) injury and neighbouring areas. However, the occurrence of arterial thrombosis in the context of MI/R injury remains unexplored. This study utilizes intravital microscopy to investigate carotid artery thrombosis during MI/R injury in rats, establishing a connection with the presence of prothrombotic cellular fibronectin containing extra domain A (CFN-EDA) protein. Additionally, the study examines samples from patients with coronary artery disease (CAD) both before and after coronary artery bypass grafting (CABG). Levels of CFN-EDA significantly increase following MI with further elevation observed following reperfusion of the ischemic myocardium. Thrombotic events, such as thrombus formation and growth, show a significant increase, while the time to complete cessation of blood flow in the carotid artery significantly decreases following MI/R injury induced by ferric chloride. The acute infusion of purified CFN-EDA protein accelerates in-vivo thrombotic events in healthy rats and significantly enhances in-vitro adenosine diphosphate and collagen-induced platelet aggregation. Treatment with anti-CFN-EDA antibodies protected the rat against MI/R injury and significantly improved cardiac function as evidenced by increased end-systolic pressure-volume relationship slope and preload recruitable stroke work compared to control. Similarly, in a human study, plasma CFN-EDA levels were notably elevated in CAD patients undergoing CABG. Post-surgery, these levels continued to rise over time, alongside cardiac injury biomarkers such as cardiac troponin and B-type natriuretic peptide. The study highlights that increased CFN-EDA due to CAD or MI initiates a destructive positive feedback loop by amplifying arterial thrombus formation, potentially exacerbating MI/R injury. [Display omitted] • The study emphasizes a direct and robust connection between arterial thrombosis and MI/R injury, previously unidentified. • Increased CFN-EDA levels post-CAD or MI injury potentially accelerate arterial thrombosis events in reperfusion injury. • The significant increase in CFN-EDA following CABG, along with elevated cardiac-injury biomarkers, underscores its clinical significance. • Targeting CFN-EDA before treatment may offer promising strategy to alleviate the hastened thrombotic events linked to MI/R injury. [ABSTRACT FROM AUTHOR]

Jiandong Wang,1– 3,* Jinyuan Ma,1,4,* Zongguang Tai,1,4,* Lisha Li,1,4 Tingrui Zhang,1,4 Tingting Cheng,1– 3 Junxia Yu,1– 3 Quangang Zhu,1,4 Leilei Bao,2 Zhongjian Chen1,4 1Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, People’s Republic of China; 2Department of Pharmacy, Third Affiliated Hospital of Naval Medical University, Shanghai, People’s Republic of China; 3School of Pharmacy, Bengbu Medical College, Bengbu, Anhui, People’s Republic of China; 4Shanghai Engineering Research Center of External Chinese Medicine, Shanghai, 200443, People’s Republic of China*These authors contributed equally to this workCorrespondence: Leilei Bao; Zhongjian Chen, Department of Pharmacy, Third Affiliated Hospital of Naval Medical University ; Shanghai Skin Disease Hospital, School of Medicine, Tongji University, 1278 Baode Road, Shanghai, 200443, People’s Republic of China, Tel/Fax +86 21 81875571 ; +86 21 36803007, Email annabao212@126.com; aajian818@163.comAbstract: Melanoma, a highly aggressive skin tumor, exhibits notable features including heterogeneity, a high mutational load, and innate immune escape. Despite advancements in melanoma treatment, current immunotherapies fail to fully exploit the immune system’s maximum potential. Activating immunogenic cell death (ICD) holds promise in enhancing tumor cell immunogenicity, stimulating immune amplification response, improving drug sensitivity, and eliminating tumors. Nanotechnology-enabled ICD has emerged as a compelling therapeutic strategy for augmenting cancer immunotherapy. Nanoparticles possess versatile attributes, such as prolonged blood circulation, stability, and tumor-targeting capabilities, rendering them ideal for drug delivery. In this review, we elucidate the mechanisms underlying ICD induction and associated therapeutic strategies. Additionally, we provide a concise overview of the immune stress response associated with ICD and explore the potential synergistic benefits of combining ICD induction methods with the utilization of nanocarriers.Keywords: immunogenic cell death, melanoma, immunotherapy, damage associated molecular patterns, nanocarrier

Background: The mechanism of action of root resorption in a permanent tooth can be classified as infection‐related (e.g., microbial infection) or non‐infection‐related (e.g., sterile damage). Infection induced root resorption occurs due to bacterial invasion. Non‐infection‐related root resorption stimulates the immune system through a different mechanism. Objectives: The aim of this narrative review is to describe the pathophysiologic process of non‐infection‐related inflammatory processes involved in root resorption of permanent teeth. Methods: A literature search on root resorption was conducted using Scopus (PubMed and Medline) and Google Scholar databases to highlight the pathophysiology of bone and root resorption in non‐infection‐related situations. The search included key words covering the relevant category. It included in vitro and in vivo studies, systematic reviews, case series, reviews, and textbooks in English. Conference proceedings, lectures and letters to the editor were excluded. Results: Three types of root resorption are related to the non‐infection mechanism of action, which includes surface resorption due to either trauma or excessive orthodontic forces, external replacement resorption and external cervical resorption. The triggers are usually damage associated molecular patterns and hypoxia conditions. During this phase macrophages and clastic cells act to eliminate the damaged tissue and bone, eventually enabling root resorption and bone repair as part of wound healing. Discussion: The resorption of the root occurs during the inflammatory phase of wound healing. In this phase, damaged tissues are recognized by macrophages and neutrophiles that secrete interlaukines such as TNF‐α, IL‐1, IL‐6, IL‐8. Together with the hypoxia condition that accelarates the secretion of growth factors, the repair of the damaged perioduntiom, including damaged bone, is initiated. If the precementum and cementoblast are injured, root resorption can occur. Conclusions: Wound healing exhibits different patterns of action that involves immune stimulation in a bio‐physiological activity, that occurs in the proper sequence, with overlapping phases. Two pathologic conditions, DAMPs and hypoxia, can activate the immune cells including clastic cells, eliminating damaged tissue and bone. Under certain conditions, root resorption occurs as a side effect. [ABSTRACT FROM AUTHOR]

Neutrophil extracellular traps (NETs) represent a recently discovered polymorphonuclear leukocyte-associated ancient defence mechanism, and they have also been identified as part of polytrauma patients' sterile inflammatory response. This systematic review aimed to determine the clinical significance of NETs in polytrauma, focusing on potential prognostic, diagnostic and therapeutic relevance. The methodology covered all major databases and all study types, but was restricted to polytraumatised humans. Fourteen studies met the inclusion criteria, reporting on 1967 patients. Ten samples were taken from plasma and four from whole blood. There was no standardisation of methodology of NET detection among plasma studies; however, of all the papers that included a healthy control NET, proxies were increased. Polytrauma patients were consistently reported to have higher concentrations of NET markers in peripheral blood than those in healthy controls, but their diagnostic, therapeutic and prognostic utility is equivocal due to the diverse study population and methodology. After 20 years since the discovery of NETs, their natural history and potential clinical utility in polytrauma is undetermined, requiring further standardisation and research. [ABSTRACT FROM AUTHOR]

Objectives: Damage associated molecular patterns (DAMPs) levels are associated with sepsis severity and prognosis. Histone and high mobility group box 1 (HMGB1) levels are also potential indicators of prognosis. We investigated the relationship between serum histone H3 and HMGB1 levels and the illness severity score and prognosis in postoperative patients. Methods: Postoperative serum histone H3 and HMGB1 levels in 39 intensive care unit (ICU) patients treated at our institution were measured. The correlation between peak histone H3 and HMGB1 levels in each patient and clinical data (age, sex, surgical time, length of ICU stay, and survival after ICU discharge), which also included the patients’ illness severity score, was examined. Results: Histone H3 but not HMGB1 levels were positively correlated with surgical time, the Sequential Organ Failure Assessment score, the Japanese Association for Acute Medicine acute phase disseminated intravascular coagulation diagnosis score, and the length of ICU stay. Both histone H3 and HMGB1 levels were negatively correlated with age. However, survival post-ICU discharge was not correlated with histone H3 or HMGB1 levels. Conclusions: Histone H3 levels are correlated with severity scores and the length of ICU stay. Serum histone H3 and HMGB1 levels are elevated postoperatively. These DAMPs, however, are not prognostic indicators in postoperative ICU patients.

Associated with the development of hospital-acquired infections, major traumatic injury results in an immediate and persistent state of systemic immunosuppression, yet the underlying mechanisms are poorly understood. Detected in the circulation in the minutes, days and weeks following injury, damage associated molecular patterns (DAMPs) are a heterogeneous collection of proteins, lipids and DNA renowned for initiating the systemic inflammatory response syndrome. Suggesting additional immunomodulatory roles in the post-trauma immune response, data are emerging implicating DAMPs as potential mediators of post-trauma immune suppression. Discussing the results of in vitro, in vivo and ex vivo studies, the purpose of this review is to summarise the emerging immune tolerising properties of cytosolic, nuclear and mitochondrial-derived DAMPs. Direct inhibition of neutrophil antimicrobial activities, the induction of endotoxin tolerance in monocytes and macrophages, and the recruitment, activation and expansion of myeloid derived suppressor cells and regulatory T cells are examples of some of the immune suppressive properties assigned to DAMPs so far. Crucially, with studies identifying the molecular mechanisms by which DAMPs promote immune suppression, therapeutic strategies that prevent and/or reverse DAMP-induced immunosuppression have been proposed. Approaches currently under consideration include the use of synthetic polymers, or the delivery of plasma proteins, to scavenge circulating DAMPs, or to treat critically-injured patients with antagonists of DAMP receptors. However, as DAMPs share signalling pathways with pathogen associated molecular patterns, and pro-inflammatory responses are essential for tissue regeneration, these approaches need to be carefully considered in order to ensure that modulating DAMP levels and/or their interaction with immune cells does not negatively impact upon anti-microbial defence and the physiological responses of tissue repair and wound healing. [ABSTRACT FROM AUTHOR]

Acute liver injury (ALI) in children, which commonly leads to acute liver failure (ALF) with the need for liver transplantation, is a devastating life-threatening condition. As the orchestrated regulation of immune hemostasis in the liver is essential for resolving excess inflammation and promoting liver repair in a timely manner, in this study we focused on the immune inflammation and regulation with the functional involvement of both innate and adaptive immune cells in acute liver injury progression. In the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, it was also important to incorporate insights from the immunological perspective for the hepatic involvement with SARS-CoV-2 infection, as well as the acute severe hepatitis of unknown origin in children since it was first reported in March 2022. Furthermore, molecular crosstalk between immune cells concerning the roles of damage-associated molecular patterns (DAMPs) in triggering immune responses through different signaling pathways plays an essential role in the process of liver injury. In addition, we also focused on DAMPs such as high mobility group box 1 (HMGB1) and cold-inducible RNA-binding protein (CIRP), as well as on macrophage mitochondrial DNA-cyclic GMP-AMP synthase (cGAS)- stimulator of interferon genes (STING) signaling pathway in liver injury. Our review also highlighted novel therapeutic approaches targeting molecular and cellular crosstalk and cell-based therapy, providing a future outlook for the treatment of acute liver injury. [ABSTRACT FROM AUTHOR]

Snake venom enzymes have a broad range of molecular targets in plasma, tissues, and cells, among which hyaluronan (HA) is outstanding. HA is encountered in the extracellular matrix of diverse tissues and in the bloodstream, and its different chemical configurations dictate the diverse morphophysiological processes in which it participates. Hyaluronidases are highlighted among the enzymes involved in HA metabolism. This enzyme has been detected along the phylogenetic tree, suggesting that hyaluronidases exert multiple biological effects on different organisms. Hyaluronidases have been described in tissues, blood and snake venoms. Snake venom hyaluronidases (SVHYA) contribute to tissue destruction in envenomations and are called spreading factors since their action potentiates venom toxin delivery. Interestingly, SVHYA are clustered in Enzyme Class 3.2.1.35 together with mammalian hyaluronidases (HYAL). Both HYAL and SVHYA of Class 3.2.1.35 act upon HA, generating low molecular weight HA fragments (LMW-HA). LMW-HA generated by HYAL becomes a damage-associated molecular pattern that is recognized by Toll-like receptors 2 and 4, triggering cell signaling cascades culminating in innate and adaptive immune responses that are characterized by lipid mediator generation, interleukin production, chemokine upregulation, dendritic cell activation and T cell proliferation. In this review, aspects of the structures and functions of HA and hyaluronidases in both snake venoms and mammals are presented, and their activities are compared. In addition, the potential immunopathological consequences of HA degradation products generated after snakebite envenoming and their use as adjuvant to enhance venom toxin immunogenicity for antivenom production as well as envenomation prognostic biomarker are also discussed. [ABSTRACT FROM AUTHOR]

Associated with the development of hospital-acquired infections, major traumatic injury results in an immediate and persistent state of systemic immunosuppression, yet the underlying mechanisms are poorly understood. Detected in the circulation in the minutes, days and weeks following injury, damage associated molecular patterns (DAMPs) are a heterogeneous collection of proteins, lipids and DNA renowned for initiating the systemic inflammatory response syndrome. Suggesting additional immunomodulatory roles in the post-trauma immune response, data are emerging implicating DAMPs as potential mediators of post-trauma immune suppression. Discussing the results of in vitro, in vivo and ex vivo studies, the purpose of this review is to summarise the emerging immune tolerising properties of cytosolic, nuclear and mitochondrial-derived DAMPs. Direct inhibition of neutrophil antimicrobial activities, the induction of endotoxin tolerance in monocytes and macrophages, and the recruitment, activation and expansion of myeloid derived suppressor cells and regulatory T cells are examples of some of the immune suppressive properties assigned to DAMPs so far. Crucially, with studies identifying the molecular mechanisms by which DAMPs promote immune suppression, therapeutic strategies that prevent and/or reverse DAMP-induced immunosuppression have been proposed. Approaches currently under consideration include the use of synthetic polymers, or the delivery of plasma proteins, to scavenge circulating DAMPs, or to treat critically-injured patients with antagonists of DAMP receptors. However, as DAMPs share signalling pathways with pathogen associated molecular patterns, and pro-inflammatory responses are essential for tissue regeneration, these approaches need to be carefully considered in order to ensure that modulating DAMP levels and/or their interaction with immune cells does not negatively impact upon anti-microbial defence and the physiological responses of tissue repair and wound healing.

Snake venom enzymes have a broad range of molecular targets in plasma, tissues, and cells, among which hyaluronan (HA) is outstanding. HA is encountered in the extracellular matrix of diverse tissues and in the bloodstream, and its different chemical configurations dictate the diverse morphophysiological processes in which it participates. Hyaluronidases are highlighted among the enzymes involved in HA metabolism. This enzyme has been detected along the phylogenetic tree, suggesting that hyaluronidases exert multiple biological effects on different organisms. Hyaluronidases have been described in tissues, blood and snake venoms. Snake venom hyaluronidases (SVHYA) contribute to tissue destruction in envenomations and are called spreading factors since their action potentiates venom toxin delivery. Interestingly, SVHYA are clustered in Enzyme Class 3.2.1.35 together with mammalian hyaluronidases (HYAL). Both HYAL and SVHYA of Class 3.2.1.35 act upon HA, generating low molecular weight HA fragments (LMW-HA). LMW-HA generated by HYAL becomes a damage-associated molecular pattern that is recognized by Toll-like receptors 2 and 4, triggering cell signaling cascades culminating in innate and adaptive immune responses that are characterized by lipid mediator generation, interleukin production, chemokine upregulation, dendritic cell activation and T cell proliferation. In this review, aspects of the structures and functions of HA and hyaluronidases in both snake venoms and mammals are presented, and their activities are compared. In addition, the potential immunopathological consequences of HA degradation products generated after snakebite envenoming and their use as adjuvant to enhance venom toxin immunogenicity for antivenom production as well as envenomation prognostic biomarker are also discussed.

Diffuse intrinsic pontine glioma (DIPG) is the most lethal tumor involving the pediatric central nervous system. The median survival of children that are diagnosed with DIPG is only 9 to 11 months. More than 200 clinical trials have failed to increase the survival outcomes using conventional cytotoxic or myeloablative chemotherapy. Immunotherapy presents exciting therapeutic opportunities against DIPG that is characterized by unique and heterogeneous features. However, the non-inflammatory DIPG microenvironment greatly limits the role of immunotherapy in DIPG. Encouragingly, the induction of immunogenic cell death, accompanied by the release of damage-associated molecular patterns (DAMPs) shows satisfactory efficacy of immune stimulation and antitumor strategies. This review dwells on the dilemma and advances in immunotherapy for DIPG, and the potential efficacy of immunogenic cell death (ICD) in the immunotherapy of DIPG. [ABSTRACT FROM AUTHOR]

The pathophysiology after polytrauma represents a complex network of interactions. While it was thought for a long time that the direct and indirect effects of hypoperfusion are most relevant due to the endothelial permeability changes, it was discovered that the innate immune response to trauma is equally important in modifying the organ response. Recent multi center studies provided a "genetic storm" theory, according to which certain neutrophil changes are activated at the time of injury. However, a second hit phenomenon can be induced by activation of certain molecules by direct organ injury, or pathogens (damage associated molecular patterns, DAMPS - pathogen associated molecular patterns, PAMPS). The interactions between the four pathogenetic cycles (of shock, coagulopathy, temperature loss and soft tissue injuries) and cross-talk between coagulation and inflammation have also been identified as important modifiers of the clinical status. In a similar fashion, overzealous surgeries and their associated soft tissue injury and blood loss can induce secondary worsening of the patient condition. Therefore, staged surgeries in certain indications represent an important alternative, to allow for performing a "safe definitive surgery" strategy for major fractures. The current review summarizes all these situations in a detailed fashion. [ABSTRACT FROM AUTHOR]

Temporomandibular joint osteoarthritis (TMJOA) is a chronic degenerative disease for which the underlying mechanism still remains unclear. Compared with apoptosis and autophagy, necroptosis causes greater harm to tissue homeostasis by releasing damage‐associated molecular patterns (DAMPs). However, the role of necroptosis and downstream key DAMPs in TMJOA is unknown. Here, rodent models of TMJOA were established by the unilateral anterior crossbite (UAC). Transmission electron microscopy (TEM) and immunohistochemistry of receptor interacting protein kinase 3 (RIPK3)/phosphorylation of mixed lineage kinase domain‐like protein (pMLKL) were conducted to evaluate the occurrence of necroptosis in vivo. The therapeutic effects of blocking necroptosis were achieved by intra‐articularly injecting RIPK3 or MLKL inhibitors and using RIPK3 or MLKL knockout mice. In vitro necroptosis of condylar chondrocyte was induced by combination of tumor necrosis factor alpha (TNFα), second mitochondria‐derived activator of caspases (SMAC) mimetics and carbobenzoxy‐valyl‐alanyl‐aspartyl‐[O‐methyl]‐ fluoromethylketone (z‐VAD‐fmk). The possible DAMPs released by necroptotic chondrocytes were screened by quantitative proteomics and blocked by specific antibody. Translucent cytosol, swollen organelles, and ruptured cell membranes, features of necroptosis, were frequently manifested in chondrocytes at the early stage of condylar cartilage degeneration in TMJOA, which was accompanied by upregulation of RIPK3/pMLKL. Inhibiting or knocking out RIPK3/MLKL significantly prevented cartilage degeneration. DAMPs released by necroptotic condylar chondrocytes, such as syndecan 4 (SDC4) and heat shock protein 90 (HSP90), were verified. Furthermore, blocking the function of SDC4 significantly attenuated the expression of TNFα in cartilage and synovium, and accordingly increased cartilage thickness and reduced synovial inflammation. Thus, the necroptotic vicious cycle of TNFα‐SDC4‐TNFα contributes to cartilage degeneration and synovitis, and can serve as a potential therapeutic target for treating TMJOA. © 2022 American Society for Bone and Mineral Research (ASBMR). [ABSTRACT FROM AUTHOR]

Objective To detect the expression levels of six mitochondrial N-formyl peptides (NFPs) in plasma and formyl peptide receptor 1 (FPR1) in pancreas of rats with severe acute pancreatitis (SAP), and to explore the correlation between them and the progression of SAP. Methods Thirty male SD rats were divided into the sham operation group, the SAP model 3 h group and the SAP model 6 h group by random number table method, with 10 rats in each group. In the sham operation group, the pancreas was turned slightly after laparotomy, and then the abdominal cavity was closed. SAP rat model was prepared in the SAP groups by retrograde injection of 5% sodium taurocholate (50 mg/kg) into the biliary duct. The expression levels of six mitochondrial NFPs in plasma were detected by Western Blotting. The pathological changes of pancreatic tissue were observed by hematoxylin-eosin staining. Immunohistochemistry was used to detect the protein expression of FPR1 in pancreas. Results Compared with the sham operation group, pancreatic hemorrhage, acinoid cell necrosis, inflammatory cell infiltration, edema and other pathological changes occurred in the SAP model 3 h group and the SAP model 6 h group, and the pathological scores were significantly increased, especially in the SAP model 6 h group (P＜ 0.05). Immunohistochemical results showed that the expression levels of FPR1 in pancreatic tissue were significantly higher in the SAP model 3 h group and the SAP model 6 h group than that of the sham group, especially in the SAP model 6 h group (P＜0.05). The expression levels of six mitochondrial NFPs were varied. The expression levels of MT-ND1, MT-ND3 and MT-ND6 were gradually increased with the prolonging of SAP modeling time (P＜0.05), while MT-ND4 showed a decreasing trend (P＜0.05). There was no significant difference in the expression of MT-ND5 between the three groups. [ABSTRACT FROM AUTHOR]

Abstract Background Cell wall degrading enzymes (CWDEs) induce plant immune responses and E3 ubiquitin ligases are known to play important roles in regulating plant defenses. Expression of the rice E3 ubiquitin ligase, OsPUB41, is enhanced upon treatment of leaves with Xanthomonas oryzae pv. oryzae (Xoo) secreted CWDEs such as Cellulase and Lipase/Esterase. However, it is not reported to have a role in elicitation of immune responses. Results Expression of the rice E3 ubiquitin ligase, OsPUB41, is induced when rice leaves are treated with either CWDEs, pathogen associated molecular patterns (PAMPs), damage associated molecular patterns (DAMPs) or pathogens. Overexpression of OsPUB41 leads to induction of callose deposition, enhanced tolerance to Xoo and Rhizoctonia solani infection in rice and Arabidopsis respectively. In rice, transient overexpression of OsPUB41 leads to enhanced expression of PR genes and SA as well as JA biosynthetic and response genes. However, in Arabidopsis, ectopic expression of OsPUB41 results in upregulation of only JA biosynthetic and response genes. Transient overexpression of either of the two biochemically inactive mutants (OsPUB41C40A and OsPUB41V51R) of OsPUB41 in rice and stable transgenics in Arabidopsis ectopically expressing OsPUB41C40A failed to elicit immune responses. This indicates that the E3 ligase activity of OsPUB41 protein is essential for induction of plant defense responses. Conclusion The results presented here suggest that OsPUB41 is possibly involved in elicitation of CWDE triggered immune responses in rice.

Diffuse intrinsic pontine glioma (DIPG) is the most lethal tumor involving the pediatric central nervous system. The median survival of children that are diagnosed with DIPG is only 9 to 11 months. More than 200 clinical trials have failed to increase the survival outcomes using conventional cytotoxic or myeloablative chemotherapy. Immunotherapy presents exciting therapeutic opportunities against DIPG that is characterized by unique and heterogeneous features. However, the non-inflammatory DIPG microenvironment greatly limits the role of immunotherapy in DIPG. Encouragingly, the induction of immunogenic cell death, accompanied by the release of damage-associated molecular patterns (DAMPs) shows satisfactory efficacy of immune stimulation and antitumor strategies. This review dwells on the dilemma and advances in immunotherapy for DIPG, and the potential efficacy of immunogenic cell death (ICD) in the immunotherapy of DIPG.

Coronary artery bypass grafting (CABG) is the standard treatment modality in revascularization of the myocardium. However, the graft failure remains the major complication following CABG procedure. Involvement of mitochondrial damage-associated molecular patterns (mt-DAMPs) in the pathogenesis of vein-graft failure is largely unknown. Here, we investigated the expression of major protein-mt-DAMPs, cytochrome-C (Cyt-C), heat shock protein-60 (Hsp-60), mitochondrial transcription factor A (mtTFA), in the occluded graft and associated tissues, including distal left anterior descending (LAD), LAD adjacent to anastomosis, and left internal mammary artery (LIMA) in the microswine CABG model. The protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was significantly decreased in the graft and LIMA, whereas the protein expression of hypoxia inducible factor-1 alpha (HIF-1α) and Cyt-C was decreased and that of mtTFA and Hsp60 was increased in all tissues compared to controls. There was no significant difference in the protein expression of citrate synthase, complex-1, and mitochondrial pyruvate dehydrogenase in the graft and associated tissues compared to control. Hypoxia in cultured smooth muscle cells (SMCs) significantly upregulated all mitochondrial biomarkers and mt-DAMPs compared to normoxia. The increased reactive oxygen species (ROS) content and compromised membrane integrity in the hypoxic SMCs correlated well with increased mt-DAMPs in the graft and associated tissues, suggesting a possible role of mt-DAMPs in the pathogenesis of graft failure. These findings suggest that the pathological signals elicited by mt-DAMPs could reveal targets for better therapeutic approaches and diagnostic strategies in the management of CABG graft failure. [ABSTRACT FROM AUTHOR]

The endothelial glycocalyx (EG) is involved in critical regulatory mechanisms that maintain endothelial vascular integrity. We hypothesized that prolonged cardiopulmonary bypass (CPB) may be associated with EG degradation. We performed an analysis of soluble syndecan-1 levels in relation to duration of CPB, as well as factors associated with cell stress and damage, such as mitochondrial DNA (mtDNA) and inflammation. Blood samples from subjects undergoing cardiac surgery with CPB (n = 54) were obtained before and during surgery, 4-8 h and 24 h after completion of CPB, and on postoperative day 4. Flow cytometry was used to determine subpopulations of white blood cells. Plasma levels of mtDNA were determined using quantitative polymerase chain reaction and plasma content of shed syndecan-1 was measured. To determine whether syndecan-1 was signaling white blood cells, the effect of recombinant syndecan-1 on mobilization of neutrophils from bone marrow was tested in mice. CPB is associated with increased mtDNA during surgery, increased syndecan-1 blood levels at 4-8 h, and increased white blood cell count at 4-8 h and 24 h. Correlation analysis revealed significant positive associations between time on CPB and syndecan-1 (r s = 0.488, P < 0.001) and level of syndecan-1 and neutrophil count (r s = 0.351, P = 0.038) at 4-8 h. Intravenous administration of recombinant syndecan-1 in mice resulted in a 2.5-fold increase in the number of circulating neutrophils, concurrent with decreased bone marrow neutrophil number. Longer duration of CPB is associated with increased plasma levels of soluble syndecan-1, a signal for EG degradation, which can induce neutrophil egress from the bone marrow. Development of therapy targeting EG shedding may be beneficial in patients with prolonged CPB. [ABSTRACT FROM AUTHOR]

Several chemoimmunotherapies have been approved by the FDA for the treatment of various cancers. Chemotherapy has the potential to improve the efficacy of immunotherapy by inducing immunogenic cell death (ICD) of tumor cells, promoting the release of tumor associated antigens (TAAs), tumor specific antigens (TSAs) and damage associated molecular patterns (DAMPs), and disrupting immunosuppressive microenvironments by tumor debulking. Unfortunately, systemic administration of chemotherapeutics carries side effects of blunting anti -cancer immune response through systemic immunosuppression, which deserves to be explored as an inner contradiction in chemoimmunotherapy. Here, we proposed the hypothesis of "immunogenicity equivalence" in chemoimmunotherapy that chemotherapeutics-induced immunogenic antigens and DAMPs in vitro that can subsequently be incorporated into nanovaccines, which will possess comparable immunostimulatory potential when compared to tumors treated with systemic chemotherapy in vivo. The proteomic analysis confirmed that our nanovaccines contained TAAs, TSAs and DAMPs. Improvement in treatment outcomes in tumor-bearing mice receiving anti -PD-1 and chemotherapy-induced nanovaccines was then observed. Furthermore, we demonstrated the feasibility of replacing long-term chemotherapy with nanovaccines in chemoimmunotherapy. Our nanovaccine strategy would be a general choice for formulating cancer vaccines in personalized medicine. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are innate cytotoxic lymphoid cells that actively prevent neoplastic development, growth, and metastatic dissemination in a process called cancer immunosurveillance. An equilibrium between immune control and tumor growth is maintained as long as cancer cells evade immunosurveillance. Therapies designed to kill cancer cells and to simultaneously sustain host antitumor immunity are an appealing strategy to control tumor growth. Several chemotherapeutic agents, depending on which drugs and doses are used, give rise to DNA damage and cancer cell death by means of apoptosis, immunogenic cell death, or other forms of non-apoptotic death (i.e., mitotic catastrophe, senescence, and autophagy). However, it is becoming increasingly clear that they can trigger additional stress responses. Indeed, relevant immunostimulating effects of different therapeutic programs include also the activation of pathways able to promote their recognition by immune effector cells. Among stress-inducible immunostimulating proteins, changes in the expression levels of NK cell-activating and inhibitory ligands, as well as of death receptors on tumor cells, play a critical role in their detection and elimination by innate immune effectors, including NK cells. Here, we will review recent advances in chemotherapy-mediated cellular stress pathways able to stimulate NK cell effector functions. In particular, we will address how these cytotoxic lymphocytes sense and respond to different types of drug-induced stresses contributing to anticancer activity. [ABSTRACT FROM AUTHOR]

Background: There is an intimate crosstalk between cancer formation, dissemination, treatment response and the host immune system, with inducing tumour cell death the ultimate therapeutic goal for most anti-cancer treatments. However, inducing a purposeful synergistic response between conventional therapies and the immune system remains evasive. The release of damage associated molecular patterns (DAMPs) is indicative of immunogenic cell death and propagation of established immune responses. However, there is a gap in the literature regarding the importance of DAMP expression in oesophageal adenocarcinoma (OAC) or by immune cells themselves., Aim: To investigate the effects of conventional therapies on DAMP expression and to determine whether OAC is an immunogenic cancer., Methods: We investigated the levels of immunogenic cell death-associated DAMPs, calreticulin (CRT) and HMGB1 using an OAC isogenic model of radioresistance. DAMP expression was also assessed directly using ex vivo cancer patient T cells ( n = 10) and within tumour biopsies ( n = 9) both pre and post-treatment with clinically relevant chemo(radio)therapeutics., Results: Hypoxia in combination with nutrient deprivation significantly reduces DAMP expression by OAC cells in vitro . Significantly increased frequencies of T cell DAMP expression in OAC patients were observed following chemo(radio)therapy, which was significantly higher in tumour tissue compared with peripheral blood. Patients with high expression of HMGB1 had a significantly better tumour regression grade (TRG 1-2) compared to low expressors., Conclusion: In conclusion, OAC expresses an immunogenic phenotype with two distinct subgroups of high and low DAMP expressors, which correlated with tumour regression grade and lymphatic invasion. It also identifies DAMPs namely CRT and HMGB1 as potential promising biomarkers in predicting good pathological responses to conventional chemo(radio)therapies currently used in the multimodal management of locally advanced disease., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Acute liver injury (ALI) in children, which commonly leads to acute liver failure (ALF) with the need for liver transplantation, is a devastating life-threatening condition. As the orchestrated regulation of immune hemostasis in the liver is essential for resolving excess inflammation and promoting liver repair in a timely manner, in this study we focused on the immune inflammation and regulation with the functional involvement of both innate and adaptive immune cells in acute liver injury progression. In the context of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, it was also important to incorporate insights from the immunological perspective for the hepatic involvement with SARS-CoV-2 infection, as well as the acute severe hepatitis of unknown origin in children since it was first reported in March 2022. Furthermore, molecular crosstalk between immune cells concerning the roles of damage-associated molecular patterns (DAMPs) in triggering immune responses through different signaling pathways plays an essential role in the process of liver injury. In addition, we also focused on DAMPs such as high mobility group box 1 (HMGB1) and cold-inducible RNA-binding protein (CIRP), as well as on macrophage mitochondrial DNA-cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway in liver injury. Our review also highlighted novel therapeutic approaches targeting molecular and cellular crosstalk and cell-based therapy, providing a future outlook for the treatment of acute liver injury., 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 © 2023 Duan, Liu, Yang, Zhang, Wu, Lv and Lei.)

Objectives: Damage associated molecular patterns (DAMPs) levels are associated with sepsis severity and prognosis. Histone and high mobility group box 1 (HMGB1) levels are also potential indicators of prognosis. We investigated the relationship between serum histone H3 and HMGB1 levels and the illness severity score and prognosis in postoperative patients., Methods: Postoperative serum histone H3 and HMGB1 levels in 39 intensive care unit (ICU) patients treated at our institution were measured. The correlation between peak histone H3 and HMGB1 levels in each patient and clinical data (age, sex, surgical time, length of ICU stay, and survival after ICU discharge), which also included the patients' illness severity score, was examined., Results: Histone H3 but not HMGB1 levels were positively correlated with surgical time, the Sequential Organ Failure Assessment score, the Japanese Association for Acute Medicine acute phase disseminated intravascular coagulation diagnosis score, and the length of ICU stay. Both histone H3 and HMGB1 levels were negatively correlated with age. However, survival post-ICU discharge was not correlated with histone H3 or HMGB1 levels., Conclusions: Histone H3 levels are correlated with severity scores and the length of ICU stay. Serum histone H3 and HMGB1 levels are elevated postoperatively. These DAMPs, however, are not prognostic indicators in postoperative ICU patients.

Snake venom enzymes have a broad range of molecular targets in plasma, tissues, and cells, among which hyaluronan (HA) is outstanding. HA is encountered in the extracellular matrix of diverse tissues and in the bloodstream, and its different chemical configurations dictate the diverse morphophysiological processes in which it participates. Hyaluronidases are highlighted among the enzymes involved in HA metabolism. This enzyme has been detected along the phylogenetic tree, suggesting that hyaluronidases exert multiple biological effects on different organisms. Hyaluronidases have been described in tissues, blood and snake venoms. Snake venom hyaluronidases (SVHYA) contribute to tissue destruction in envenomations and are called spreading factors since their action potentiates venom toxin delivery. Interestingly, SVHYA are clustered in Enzyme Class 3.2.1.35 together with mammalian hyaluronidases (HYAL). Both HYAL and SVHYA of Class 3.2.1.35 act upon HA, generating low molecular weight HA fragments (LMW-HA). LMW-HA generated by HYAL becomes a damage-associated molecular pattern that is recognized by Toll-like receptors 2 and 4, triggering cell signaling cascades culminating in innate and adaptive immune responses that are characterized by lipid mediator generation, interleukin production, chemokine upregulation, dendritic cell activation and T cell proliferation. In this review, aspects of the structures and functions of HA and hyaluronidases in both snake venoms and mammals are presented, and their activities are compared. In addition, the potential immunopathological consequences of HA degradation products generated after snakebite envenoming and their use as adjuvant to enhance venom toxin immunogenicity for antivenom production as well as envenomation prognostic biomarker are also discussed., 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 © 2023 Silva de França and Tambourgi.)

Endoplasmic reticulum (ER) chaperones (e.g., calreticulin, heat shock proteins, and isomerases) perform a multitude of functions within the ER. However, many of these chaperones can translocate to the cytosol and eventually the surface of cells, particularly during ER stress induced by e.g., drugs, UV irradiation, and microbial stimuli. Once on the cell surface or in the extracellular space, the ER chaperones can take on immunogenic characteristics, as mostly described in the context of cancer, appearing as damage-associated molecular patterns recognized by the immune system. How ER chaperones relocate to the cell surface and interact with other intracellular proteins appears to influence whether a tumor cell is targeted for cell death. The relocation of ER proteins to the cell surface can be exploited to target cancer cells for elimination by immune mechanism. Here we evaluate the evidence for the different mechanisms of ER protein translocation and binding to the cell surface and how ER protein translocation can act as a signal for cancer cells to undergo killing by immunogenic cell death and other cell death pathways. The release of chaperones can also exacerbate underlying autoimmune conditions, such as rheumatoid arthritis and multiple sclerosis, and the immunomodulatory role of extracellular chaperones as potential cancer immunotherapies requires cautious monitoring, particularly in cancer patients with underlying autoimmune disease. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose can cause acute liver failure. Although it is well known that APAP-induced liver injury (AILI) is caused by toxic mechanism, recently it is also reported to be immune related. However, the detail of the mechanism has been unclear. Therefore, elucidation of the pathophysiology is required. In AILI model rats (800 mg/kg), the levels of AST, ALT and Caspase (C)-3/-8/-9 levels were measured. In in vitro study using human hepatocyte cells (FLC-4) and THP-1 cells, APAP (0.03-1.0 mM) were added to FLC-4 and the cell viability, C-9, cytochrome c , mitochondria membrane potential, and glutathione levels of FLC-4 and inflammasome activation of THP-1 were evaluated. In AILI model rats, the levels of AST and ALT were increased only at 12–24 h. C-3/-9 levels rose at 6–9 h, whereas C-8 level rose hours later, moreover, 24 h after; C-3/-8/-9 levels re-rose. In FLC-4 cells, cytochrome c was released from the mitochondria which is promoted by oxidative stress due to drug metabolism and C-9 was activated. Thus, AILI was caused mitochondrial damage by NAPQI as early reaction (first stage). In the next stage, inflammasomes of human antigen presenting cells, which released inflammatory cytokines were activated by damage-associated molecular patterns (DAMPs) released from damaged hepatocyte by APAP. It is confirmed that AILI includes immune related mechanism. Thereby, in case of N -acetylcysteine refractory, additional administration of steroid hormones should be effective and recommended as a novel strategy for AILI with immune related adverse event (irAE). [ABSTRACT FROM AUTHOR]

Evidences accumulated that the death of neutrophils are not the end of their missions. The neutrophil extracellular traps (NETs), web-like structure, formed after neutrophils dying contribute greatly to immune defense, in both innate and adaptive immunity. Interestingly, previous studies revealed that the generation and activation of NETs do not only rely on bacteria induction, but also in patients with sterile inflammatory diseases, implying an undeniable correlation between NETs and these diseases. This review summarized the latest findings that the crucial roles of NETs in sterile inflammatory diseases, as well as novel targeted therapy based on these new discoveries. [ABSTRACT FROM AUTHOR]

Ischemic acute kidney injury (AKI) contributes to considerable morbidity and mortality in hospitalized patients and can contribute to rejection during kidney transplantation. Maladaptive immune responses can exacerbate injury, and targeting these responses holds promise as therapy for AKI. In the last decade, a number of molecules and receptors were identified in the innate immune response to ischemia-reperfusion injury. This review primarily focuses on one pathway that leads to maladaptive inflammation: toll-like receptor 4 (TLR4) and one of its ligands, high mobility group box protein 1 (HMGB1). The temporal-spatial roles and potential therapeutics targeting this particular receptor-ligand interaction are also explored. [ABSTRACT FROM AUTHOR]

Abstract: Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US and UK. Recent studies implied that APAP-induced injury is partially mediated by interleukin-1β (IL-1β), which can activate and recruit neutrophils, exacerbating injury. Mature IL-1β is formed by caspase-1, dependent on inflammasome activation. The objective of this invetstigation was to evaluate the role of the Nalp3 inflammasome on release of damage associated molecular patterns (DAMPs), hepatic neutrophil accumulation and liver injury (ALT, necrosis) after APAP overdose. Mice deficient for each component of the Nalp3 inflammasome (caspase-1, ASC and Nalp3) were treated with 300mg/kg APAP for 24h; these mice had similar neutrophil recruitment and liver injury as APAP-treated C57Bl/6 wildtype animals. In addition, plasma levels of DAMPs (DNA fragments, keratin-18, hypo- and hyper-acetylated forms of high mobility group box-1 protein) were similarly elevated with no significant difference between wildtype and gene knockout mice. In addition, aspirin treatment, which has been postulated to attenuate cytokine formation and the activation of the Nalp3 inflammasome after APAP, had no effect on release of DAMPs, hepatic neutrophil accumulation or liver injury. Together, these data confirm the release of DAMPs and a sterile inflammatory response after APAP overdose. However, as previously reported minor endogenous formation of IL-1β and the activation of the Nalp3 inflammasome have little impact on APAP hepatotoxicity. It appears that the Nalp3 inflammasome is not a promising therapeutic target to treat APAP overdose. [Copyright &y& Elsevier]

Toll-like receptor (TLR) signaling is a crucial step in initiating adaptive immune responses. In addition to recognizing endotoxin, TLR4 also recognizes endogenous ligands ('damage-associated structures'), which are released into the circulation in the peri-transplantation period. TLR2 to a lesser extent also recognizes these endogenous ligands. Multiple studies involving solid organ transplants demonstrate a clear association between TLR4 and allograft rejection. In the present study we assessed whether an association exists between TLR4 and TLR2-dependent responses and acute liver allograft rejection. The sample included 26 liver transplant recipients. Blood was taken pre-transplant and at multiple points over the first 14 days post-transplant. Monocytes were stimulated with TLR4 and TLR2 ligands, lipopolysaccharide and Pam-3-Cys, respectively. Monocyte TLR expression was determined using flow cytometry; enzyme-linked immunosorbent assays measured tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) production. Nine (34.6%) patients experienced rejection. No differences existed in age, sex, disease or immunosuppression between rejectors and non-rejectors. Baseline TLR4 expression was significantly higher in rejectors (1.36 vs 1.02, P = 0.01). There was no difference in TLR2 expression. In rejectors, baseline TLR4- and TLR2-dependent production of TNF-α and IL-6 was also significantly increased. Post-transplant, the two groups differed with regard to TLR4-dependent TNF-α production, with rejectors demonstrating progressive downregulation over the first week. Prior to liver transplantation, patients who subsequently experience rejection demonstrate robust TLR4-dependent immune responses, which are not seen in those who do not reject. This supports the theory that damage-associated structures signaling through TLR4 may be responsible for the early activation of alloimmune T-cells, favoring allograft rejection. [ABSTRACT FROM AUTHOR]

Apoptosis is an important contributor to the pathophysiology of lung diseases such as acute lung injury (ALI) and chronic obstructive pulmonary disease (COPD). Furthermore, the cellular environment of these acute and chronic lung diseases favors the delayed clearance of apoptotic cells. This dysfunctional efferocytosis predisposes to the release of endogenous ligands from dying cells. These so-called damage-associated molecular patterns (DAMPs) play an important role in the stimulation of innate immunity as well as in the induction of adaptive immunity, potentially against autoantigens. In this review, we explore the role of apoptosis in ALI and COPD, with particular attention to the contribution of DAMP release in augmenting the inflammatory response in these disease states. [ABSTRACT FROM AUTHOR]

Extracellular ATP (eATP) is a potent damage associated molecular pattern (DAMP) molecule known to exert profound effects on the innate and adaptive immune responses. As such, it has become an important biomarker for studying means to pro-actively modulate inflammatory processes. Unfortunately, traditional methodologies employed for measuring eATP require cumbersome supernatant sampling, onerous time courses, or unnecessary duplication of effort. Here we describe a new reagent that is tolerable to test cells in extended exposures and enables a fully homogeneous assay method for real-time determinations of extracellular ATP levels. The reagent is introduced into assay plates containing cells at the time of stimulus introduction. The real-time feature of the format allows for sensitive, continuous accounting of eATP levels in the test model over at least 24 h. This work details our efforts to create and characterize this new reagent and to validate utility by demonstrating its use with multiple cell lines and chemically diverse eATP induction stimuli. • The method measures eATP release in real-time throughout at least a 24 h exposure with conventional luminometers. • Is delivered in a fully homogeneous, "add-mix-measure" format at the time of dosing or at time zero of the insult. • The reagent measures release potential and potency from test agents as a function of time. • The method can deliver total ATP viability measure by an endpoint method. • The method was bench marked versus conventional endpoint chemistries. [ABSTRACT FROM AUTHOR]

• Nanoparticles mediate dual chemotherapy and photothermal therapy. • Doxorubicin and indocyanine green act as chemotherapeutic and photothermal agents. • Dual treatment with nanoparticles results in highest cancer cell growth inhibition. • Dual therapy leads to highest presentation of damage associated molecular patterns. • ATP release, calreticulin presentation, and low intracellular HMGB1 were observed. The use of nanomedicines to induce immunogenic cell death is a new strategy that aims to increase tumor immunogenicity and thereby prime tumors for further immunotherapies. In this study, we developed a nanoparticle formulation for combinatory chemotherapy and photothermal therapy based only on materials previously used in FDA-approved products and investigated the effect of the combinatory therapy on the growth inhibition and induction of immunogenic cell death in human MDA-MB-231 breast cancer cells. The formulation consists of ~108-nm nanoparticles made of poly(lactic acid)- b -methoxy poly(ethylene glycol) which carry doxorubicin for chemotherapy and indocyanine green for photothermal therapy. A 0.3 mg/mL suspension of NPs increased the medium temperature up to 10 °C upon irradiation with an 808-nm diode laser. In vitro studies showed that combination of laser assisted indocyanine green-mediated photothermal therapy and doxorubicin-mediated chemotherapy effectively eradicated cancer cells and resulted in the highest level of damage-associated molecular pattern presentation (calreticulin, high mobility group box 1, and adenosine triphosphate) compared to the individual treatments alone. These results demonstrate that our nanoparticle-mediated combinatory approach led to the most intense immunogenic cell death when compared to individual chemotherapy or photothermal therapy, making it a potent option for future in vivo studies in combination with cancer immunotherapies. [ABSTRACT FROM AUTHOR]

Coronary artery bypass grafting (CABG) is the standard treatment modality in revascularization of the myocardium. However, the graft failure remains the major complication following CABG procedure. Involvement of mitochondrial damage-associated molecular patterns (mt-DAMPs) in the pathogenesis of vein-graft failure is largely unknown. Here, we investigated the expression of major protein-mt-DAMPs, cytochrome-C (Cyt-C), heat shock protein-60 (Hsp-60), mitochondrial transcription factor A (mtTFA), in the occluded graft and associated tissues, including distal left anterior descending (LAD), LAD adjacent to anastomosis, and left internal mammary artery (LIMA) in the microswine CABG model. The protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) was significantly decreased in the graft and LIMA, whereas the protein expression of hypoxia inducible factor-1 alpha (HIF-1α) and Cyt-C was decreased and that of mtTFA and Hsp60 was increased in all tissues compared to controls. There was no significant difference in the protein expression of citrate synthase, complex-1, and mitochondrial pyruvate dehydrogenase in the graft and associated tissues compared to control. Hypoxia in cultured smooth muscle cells (SMCs) significantly upregulated all mitochondrial biomarkers and mt-DAMPs compared to normoxia. The increased reactive oxygen species (ROS) content and compromised membrane integrity in the hypoxic SMCs correlated well with increased mt-DAMPs in the graft and associated tissues, suggesting a possible role of mt-DAMPs in the pathogenesis of graft failure. These findings suggest that the pathological signals elicited by mt-DAMPs could reveal targets for better therapeutic approaches and diagnostic strategies in the management of CABG graft failure., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Introduction: Legg-Calvé-Perthes disease is a juvenile ischemic osteonecrosis which produces extensive necrotic cell debris and release of damage associated molecular patterns (DAMPs) in the femoral head. The necrotic bone environment induces a chronic inflammatory repair response with excessive bone resorption leading to deformity and early osteoarthritis. Currently there is no minimally invasive method to clear the necrotic materials from the bone to decrease the inflammatory burden of the necrotic environment and to improve the healing process., Hypothesis: We hypothesized that a novel minimally invasive two-needle saline washing technique would be effective to remove cell debris, proteins, and fat from the marrow space of porcine cadaveric humeral heads (HHs)., Materials and Methods: Twenty-two HHs were subjected to three freeze-thaw cycles to simulate osteonecrosis prior to the wash procedure which consisted of placement of two 15-gauge intraosseous needles followed by incremental saline wash. After the washout procedure, the solutions were collected for measurements of turbidity, protein concentration, and cell count. The HHs were analyzed by optical scanning and histology., Results: The solution collected after each wash showed a significant decrease in the turbidity, cell count, and protein concentration (p<0.05). Histologic assessment showed significantly decreased cell debris and adipocytes in the washed group compared to the unwashed group (p<0.001)., Discussion/conclusion: The two-needle intraosseous wash technique effectively removed cell debris and proteins from the marrow space. The technique may be used to reduce the necrotic cell debris and DAMPs present in the necrotic bone., Level of Evidence: III, in vitro comparative study., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Cell wall degrading enzymes (CWDEs) induce plant immune responses and E3 ubiquitin ligases are known to play important roles in regulating plant defenses. Expression of the rice E3 ubiquitin ligase, OsPUB41, is enhanced upon treatment of leaves with Xanthomonas oryzae pv. oryzae (Xoo) secreted CWDEs such as Cellulase and Lipase/Esterase. However, it is not reported to have a role in elicitation of immune responses. Results: Expression of the rice E3 ubiquitin ligase, OsPUB41, is induced when rice leaves are treated with either CWDEs, pathogen associated molecular patterns (PAMPs), damage associated molecular patterns (DAMPs) or pathogens. Overexpression of OsPUB41 leads to induction of callose deposition, enhanced tolerance to Xoo and Rhizoctonia solani infection in rice and Arabidopsis respectively. In rice, transient overexpression of OsPUB41 leads to enhanced expression of PR genes and SA as well as JA biosynthetic and response genes. However, in Arabidopsis, ectopic expression of OsPUB41 results in upregulation of only JA biosynthetic and response genes. Transient overexpression of either of the two biochemically inactive mutants (OsPUB41C40A and OsPUB41V51R) of OsPUB41 in rice and stable transgenics in Arabidopsis ectopically expressing OsPUB41C40A failed to elicit immune responses. This indicates that the E3 ligase activity of OsPUB41 protein is essential for induction of plant defense responses. Conclusion: The results presented here suggest that OsPUB41 is possibly involved in elicitation of CWDE triggered immune responses in rice. [ABSTRACT FROM AUTHOR]

Background: Although inflammatory cytokines are established biomarkers of mood disorders, their molecular mechanism is not known. We hypothesized that circulating mitochondrial DNA (mtDNA) contributes to inflammation and could be used as biomarkers. We investigated if circulating mtDNA level is associated with inflammatory cytokines and can be used as a biomarker of mood disorders., Methods: Plasma mtDNA concentration was measured with real-time quantitative PCR targeting two regions of the mtDNA and plasma levels of four cytokines (GM-CSF, IL-2, IL-4, and IL-6) were measured with a multiplex immunoassay method in 109 patients with major depressive disorder (MDD). The most significantly correlated cytokine was verified with an enzyme-linked immunosorbent assay (ELISA). The data from 28 patients with bipolar disorder (BD), 17 patients with schizophrenia (SZ), and 29 healthy controls were compared., Results: MtDNA levels showed a nominal positive correlation with GM-CSF, IL-2 and IL-4 in patients with MDD. The most significant correlation with IL-4 (ρ = 0.38, P < 0.00005) was verified with an ELISA (ρ = 0.19, P = 0.049). Unexpectedly, patients with MDD and BD showed significantly lower plasma mtDNA levels than controls. MtDNA levels were lower in the depressive state than in the euthymic state in patients with MDD. Patients with depression, bipolar disorder, and schizophrenia did not show significantly higher levels of these four cytokines than controls., Limitations: There is a possibility that the patients in this study are different from previous studies in which increased cytokine levels were reported. MtDNA levels should be measured in patients showing elevated plasma cytokine levels. A larger sample is required to generalize the results., Conclusions: The present findings coincide with our hypothesis that circulating mtDNA contributes to the inflammation in MDD. Further studies are needed to conclude whether plasma mtDNA would be a biomarker of mood disorders., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

The proportion of elderly people rises in the developed countries. The increased susceptibility of the elderly to infectious diseases is caused by immune dysfunction, especially T cell functional decline. Age-related hematopoietic stem cells deviate from lymphoid lineage to myeloid lineage. Thymus shrinks early in life, which is followed by the decline of naïve T cells. T-cell receptor repertoire diversity declines by aging, which is caused by cytomegalovirus-driven T cell clonal expansion. Functional decline of B cell induces antibody affinity declines by aging. Many effector functions including phagocytosis of myeloid cells are down regulated by aging. The studies of aging of myeloid cells have some controversial results. Although M1 macrophages have been shown to be replaced by anti-inflammatory (M2) macrophages by advanced age, many human studies showed that pro-inflammatory cytokines are elevated in older human. To solve this discrepancy here we divide age-related pathological changes into two categories. One is an aging of immune cell itself. Second is involvement of immune cells to age-related pathological changes. Cellular senescence and damaged cells in aged tissue recruit pro-inflammatory M1 macrophages, which produce pro-inflammatory cytokines and proceed to age-related diseases. Underlying biochemical and metabolic studies will open nutritional treatment., Competing Interests: Conflict-of-interest statement: There are no conflict of interest.

Macrophages, and more broadly inflammation, have been considered for a long time as bad markers of tissue homeostasis. However, if it is indisputable that macrophages are associated with many diseases in a deleterious way, new roles have emerged, showing beneficial properties of macrophages during tissue repair and regeneration. This discrepancy is likely due to the high plasticity of macrophages, which may exhibit a wide range of phenotypes and functions depending on their environment. Therefore, regardless of their role in immunity, macrophages play a myriad of roles in the maintenance and recovery of tissue homeostasis. They take a major part in the resolution of inflammation. They also exert various effects of parenchymal cells, including stem and progenitor cell, of which they regulate the fate. In the present review, few examples from various tissues are presented to illustrate that, beyond their specific properties in a given tissue, common features have been described that sustain a role of macrophages in the recovery and maintenance of tissue homeostasis., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Background: Discoid lupus erythematosus (DLE) is a cutaneous autoimmune inflammatory disease in which the role of conventional dendritic cells (cDCs) in skin damage has not been evaluated., Objective: To evaluate the involvement of cDCs in DLE pathogenesis., Material & Methods: Skin biopsies from 42 patients with DLE were embedded in paraffin or placed in culture. The dermis was separated and cell suspensions were characterized by flow cytometry., Results: We found an increase in cDCs with inflammatory characteristics in the skin of DLE patients, compared with control skins. Interestingly, cDCs from the DLE patients expressed low levels of the inhibitory molecule PD-L1 and showed a high expression of CCR6, which correlated with disease activity. Increased cellular death was observed in the skin of DLE patients compared with control skin and remarkably we found that damage-associated molecular patterns could be responsible for CCR6 expression on cDCs in the skin., Conclusions: Our results indicate the presence of pathogenic CCR6+ cDCs in the skin lesions of DLE patients, which could result from in situ phenotypic changes.