High mobility group box 1 complexed with heparin induced angiogenesis in a matrigel plug assay

Angiogenesis involves complex processes mediated by several factors and is associated with inflammation and wound healing. High mobility group box 1 (HMGB1) is released from necrotic cells as well as macrophages and plays proinflammatory roles. In the present study, we examined whether HMGB1 would exhibit angiogenic activity in a matrigel plug assay in mice. HMGB1 in combination with heparin strongly induced angiogenesis, whereas neither HMGB1 nor heparin alone showed such angiogenic activity. The heparin-dependent induction of angiogenesis by HMGB1 was accompanied by increases in the expression of tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor-A120 (VEGF-A120). It is likely that the dependence of the angiogenic activity of HMGB1 on heparin was due to the efficiency of the diffusion of the HMGB1-heparin complex from matrigel to the surrounding areas. VEGF-A165 possessing a heparin-binding domain showed a pattern of heparin-dependent angiogenic activity similar to that of HMGB1. The presence of heparin also inhibited the degradation of HMGB1 by plasmin in vitro. Taken together, these results suggested that HMGB1 in complex with heparin possesses remarkable angiogenic activity, probably through the induction of TNF-alpha and VEGF-A120.</p

Establishment of in Vitro Binding Assay of High Mobility Group Box-1 and S100A12 to Receptor for Advanced Glycation Endproducts: Heparin's Effect on Binding

Interaction between the receptor for advanced glycation end products (RAGE) and its ligands has been implicated in the pathogenesis of various inflammatory disorders. In this study, we establish an in vitro binding assay in which recombinant human high-mobility group box 1 (rhHMGB1) or recombinant human S100A12 (rhS100A12) immobilized on the microplate binds to recombinant soluble RAGE (rsRAGE). The rsRAGE binding to both rhHMGB1 and rhS100A12 was saturable and dependent on the immobilized ligands. The binding of rsRAGE to rhS100A12 depended on Ca2 and Zn2, whereas that to rhHMGB1 was not. Scatchard plot analysis showed that rsRAGE had higher affinity for rhHMGB1 than for rhS100A12. rsRAGE was demonstrated to bind to heparin, and rhS100A12, in the presence of Ca2, was also found to bind to heparin. We examined the effects of heparin preparations with different molecular sizesunfractionated native heparin (UFH), low molecular weight heparin (LMWH) 5000Da, and LMWH 3000Da on the binding of rsRAGE to rhHMGB1 and rhS100A12. All 3 preparations concentration-dependently inhibited the binding of rsRAGE to rhHMGB1 to a greater extent than did rhS100A12. These results suggested that heparin's anti-inflammatory effects can be partly explained by its blocking of the interaction between HMGB1 or S100A12 and RAGE. On the other hand, heparin would be a promising effective remedy against RAGE-related inflammatory disorders.</p

Global burden of skin cancer and its subtypes: a comprehensive analysis from 1990 to 2021 with projections to 2040

BackgroundSkin cancer represents a significant global public health concern. Comprehensive analysis of its global burden provides critical insights for evidence-based interventions. This study systematically evaluates the global disease burden of skin cancer and its subtypes.MethodsThis study analyzed GBD 2021 data to assess ASIR and ASDR trends for total skin cancer and its subtypes (1990–2021), stratified by geography, age, and sex, using APC modeling, decomposition analysis, and inequality assessments, with projections through 2040.ResultsFirst, skin cancer ASIR increased from 1990 to 2021, while ASDR significantly decreased. Second, geographical heterogeneity existed in distribution of histological subtypes. Third, skin cancer burden demonstrated age-dependent progression with compositional variance in subtypes across age groups. Fourth, sex disparities intensified beyond age 55, with increasing longitudinal divergence. Fifth, both the ASIR and ASDR of total skin cancer showed non‑linear associations with SDI. Sixth, international disparities in skin cancer burden demonstrated a decreasing trend. Finally, projections to 2040 indicate a continued increase in total skin cancer ASIR accompanied by a persistent decline in total skin cancer ASDR.ConclusionASIRs of total skin cancer and its subtypes showed increasing trends, while ASDRs demonstrated decreasing patterns, with significant heterogeneity across regions, age groups, and sex

Neuropathic Pain in Rats with a Partial Sciatic Nerve Ligation Is Alleviated by Intravenous Injection of Monoclonal Antibody to High Mobility Group Box-1

High mobility group box-1 (HMGB1) is associated with the pathogenesis of inflammatory diseases. A previous study reported that intravenous injection of anti-HMGB1 monoclonal antibody significantly attenuated brain edema in a rat model of stroke, possibly by attenuating glial activation. Peripheral nerve injury leads to increased activity of glia in the spinal cord dorsal horn. Thus, it is possible that the anti-HMGB1 antibody could also be efficacious in attenuating peripheral nerve injury-induced pain. Following partial sciatic nerve ligation (PSNL), rats were treated with either anti-HMGB1 or control IgG. Intravenous treatment with anti-HMGB1 monoclonal antibody (2 mg/kg) significantly ameliorated PSNL-induced hind paw tactile hypersensitivity at 7, 14 and 21 days, but not 3 days, after ligation, whereas control IgG had no effect on tactile hypersensitivity. The expression of HMGB1 protein in the spinal dorsal horn was significantly increased 7, 14 and 21 days after PSNL; the efficacy of the anti-HMGB1 antibody is likely related to the presence of HMGB1 protein. Also, the injury-induced translocation of HMGB1 from the nucleus to the cytosol occurred mainly in dorsal horn neurons and not in astrocytes and microglia, indicating a neuronal source of HMGB1. Markers of astrocyte (glial fibrillary acidic protein (GFAP)), microglia (ionized calcium binding adaptor molecule 1 (Iba1)) and spinal neuron (cFos) activity were greatly increased in the ipsilateral dorsal horn side compared to the sham-operated side 21 days after PSNL. Anti-HMGB1 monoclonal antibody treatment significantly decreased the injury-induced expression of cFos and Iba1, but not GFAP. The results demonstrate that nerve injury evokes the synthesis and release of HMGB1 from spinal neurons, facilitating the activity of both microglia and neurons, which in turn leads to symptoms of neuropathic pain. Thus, the targeting of HMGB1 could be a useful therapeutic strategy in the treatment of chronic pain

HMGB1 Translocation in Neurons after Ischemic Insult: Subcellular Localization in Mitochondria and Peroxisomes

High mobility group box-1 (HMGB1), a nonhistone chromatin DNA-binding protein, is released from neurons into the extracellular space under ischemic, hemorrhagic, and traumatic insults. However, the details of the time-dependent translocation of HMGB1 and the subcellular localization of HMGB1 through the release process in neurons remain unclear. In the present study, we examined the subcellular localization of HMGB1 during translocation of HMGB1 in the cytosolic compartment using a middle cerebral artery occlusion and reperfusion model in rats. Double immunofluorescence microscopy revealed that HMGB1 immunoreactivities were colocalized with MTCO1(mitochondrially encoded cytochrome c oxidase I), a marker of mitochondria, and catalase, a marker of peroxisomes, but not with Rab5/Rab7 (RAS-related GTP-binding protein), LC3A/B (microtubule-associated protein 1 light chain 3), KDEL (KDEL amino acid sequence), and LAMP1 (Lysosomal Associated Membrane Protein 1), which are endosome, phagosome, endoplasmic reticulum, and lysosome markers, respectively. Immunoelectron microscopy confirmed that immune-gold particles for HMGB1 were present inside the mitochondria and peroxisomes. Moreover, HMGB1 was found to be colocalized with Drp1 (Dynamin-related protein 1), which is involved in mitochondrial fission. These results revealed the specific subcellular localization of HMGB1 during its release process under ischemic conditions

Histamine induced high mobility group box-1 release from vascular endothelial cells through H-1 receptor

BackgroundSystemic allergic reaction is characterized by vasodilation and vascular leakage, which causes a rapid, precipitous and sustained decrease in arterial blood pressure with a concomitant decrease of cardiac output. Histamine is a major mediator released by mast cells in allergic inflammation and response. It causes a cascade of inflammation and strongly increases vascular permeability within minutes through its four G-protein-coupled receptors (GPCRs) on endothelial cells. High mobility group box-1 (HMGB1), a nonhistone chromatin-binding nuclear protein, can be actively secreted into the extracellular space by endothelial cells. HMGB1 has been reported to exert pro-inflammatory effects on endothelial cells and to increase vascular endothelial permeability. However, the relationship between histamine and HMGB1-mediated signaling in vascular endothelial cells and the role of HMGB1 in anaphylactic-induced hypotension have never been studied. Methods and resultsEA.hy 926 cells were treated with different concentrations of histamine for the indicated periods. The results showed that histamine induced HMGB1 translocation and release from the endothelial cells in a concentration- and time-dependent manner. These effects of histamine were concentration-dependently inhibited by d-chlorpheniramine, a specific H-1 receptor antagonist, but not by H-2 or H-3/4 receptor antagonists. Moreover, an H-1-specific agonist, 2-pyridylethylamine, mimicked the effects of histamine, whereas an H-2-receptor agonist, 4-methylhistamine, did not. Adrenaline and noradrenaline, which are commonly used in the clinical treatment of anaphylactic shock, also inhibited the histamine-induced HMGB1 translocation in endothelial cells. We therefore established a rat model of allergic shock by i.v. injection of compound 48/80, a potent histamine-releasing agent. The plasma HMGB1 levels in compound 48/80-injected rats were higher than those in controls. Moreover, the treatment with anti-HMGB1 antibody successfully facilitated the recovery from compound 48/80-induced hypotension. ConclusionHistamine induces HMGB1 release from vascular endothelial cells solely through H-1 receptor stimulation. Anti-HMGB1 therapy may provide a novel treatment for life-threatening systemic anaphylaxis

Case Report: a 28-year-old female with anomalous origin of the left coronary artery from the pulmonary artery syndrome presented as atrial fibrillation and pulmonary hypertension

Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) typically manifests in the first weeks of life. We report a 28-year-old woman with atrial fibrillation and pulmonary hypertension which were later found to be associated with ALCAPA syndrome. Despite a history free of traditional cardiovascular risk factors, her symptoms included exercise intolerance, palpitations, and an ischemic stroke. Echocardiography and further examination revealed pulmonary artery origin of the left coronary artery and extensive collateral formation between the left and right coronary arteries, contributing to her symptoms

Numerical Modeling of Mineralizing Processes During the Formation of the Yangzhuang Kiruna-Type Iron Deposit, Middle and Lower Yangtze River Metallogenic Belt, China: Implications for the Genesis and Longevity of Kiruna-Type Iron Oxide-Apatite Systems

The Yangzhuang iron deposit is a Kiruna-type iron oxide-apatite (IOA) deposit within the Ningwu mining district of the Middle and Lower Yangtze River Metallogenic Belt (MLYRMB), China. This study applies a numerical modeling approach to identify the key processes associated with the formation of the deposit that cannot be easily identified using traditional analytical approaches, including the duration of the mineralizing process and the genesis of iron orebodies within intrusions associated with the deposit. This approach highlights the practical value of numerical modeling in quantitatively analyzing mineralizing processes during the formation of mineral deposits and assesses how these methods can be used in future geological research. Our numerical model links heat transfer, pressure, fluid flow, chemical reactions, and the movement of ore-forming material. Results show that temperature anomaly and structure (occurrence of the contact of intrusion and the Triassic Xujiashan group) are two key factors controlling the formation of the Yangzhuang deposit. This modeling also indicates that the formation of the Yangzhuang deposit only took some 8000 years, a reaction that is likely to be controlled by temperature and diffusion rates within the system. The dynamic changes of temperature and the distribution of mineralization also indicate that the orebodies located inside the intrusions most likely formed after magma ascent rather than representing blocks of existing mineralization that descended into the magma as a result of stoping or other similar processes. All these data form the basis for future research into the forming processes of Kiruna-type IOA systems as well as magmatic–hydrothermal systems more broadly, including providing useful insights for future exploration for these systems. The simulation approach used in this study has several limitations, such as oversimplified chemical reactions, uncertainty of pre-metallogenic conditions and limitation of 2D model. Future development into both theories and methods will definitely improve the practical significance of numerical simulation of ore-forming processes and provide quantitative results for more geological issues