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1.
Oncotarget ; 8(26): 42098-42115, 2017 Jun 27.
Article in English | MEDLINE | ID: mdl-28431400

ABSTRACT

Fracture nonunion and delayed union continue to pose challenges for orthopedic surgeons. In the present study, we combined HMGB1 gelatin sponges with MSC sheets to promote bone healing after surgical treatment of rat tibial fractures. The HMGB1 gelatin sponge scaffolds supported the expansion of mesenchymal stem cells (MSCs) and promoted the osteogenic differentiation of MSCs and MSC sheets. Lentiviral vectors were then used to overexpress HMGB1 in MSCs. The results indicated that HMGB1 promotes the osteogenic differentiation of MSCs through the STAT3 pathway. Both siRNA and a STAT3 inhibitor downregulated STAT3, further confirming that HMGB1 induces the osteogenic differentiation of MSCs partly via the STAT3 signal pathway. In a rat tibial osteotomy model, we demonstrated the ability of HMGB1 gelatin sponge scaffolds to increase bone formation. The addition of MSC sheets further enhanced fracture healing. These findings support the use of HMGB1-loaded gelatin sponge scaffolds combined with MSC sheets to enhance fracture healing after surgical intervention.


Subject(s)
Fracture Healing , Gelatin , HMGB1 Protein/administration & dosage , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Tissue Scaffolds , Animals , Biomarkers , Calcification, Physiologic , Cell Differentiation , HMGB1 Protein/pharmacokinetics , Immunohistochemistry , Male , Mesenchymal Stem Cell Transplantation , Osteogenesis , Radiography , Rats , Tissue Engineering , X-Ray Microtomography
2.
Yakugaku Zasshi ; 132(10): 1171-7, 2012.
Article in Japanese | MEDLINE | ID: mdl-23037703

ABSTRACT

An initial loading procedure has been recommended to enable teicoplanin to promptly reach an effective serum concentration for the treatment of methicillin-resistant Staphylococcus aureus (MRSA). The mean trough concentrations were 13.2 mg/L for patients with eradication of MRSA. I showed that the administration of ≥36 mg/kg during the first 3 days was effective in promptly obtaining a trough concentration target of ≥13 mg/L for the initial treatment of MRSA infections. The major adverse effect associated with linezolid treatment is reversible myelosuppression, primarily thrombocytopenia. I demonstrated that the incidence of linezolid-induced thrombocytopenia was higher among patients with renal failure than in patients with normal renal function. A statistically significant (p<0.01) and strong correlation (r=0.933) was observed between linezolid and creatinine clearance. A negative correlation (r=-0.567) was also shown between linezolid clearance and blood urea nitrogen. Voriconazole trough plasma concentration has been reported to correlate with hepatotoxicity. Logistic regression analysis revealed that the therapeutic range for the voriconazole trough concentration should be 2-4 mg/L. Nonlinear pharmacokinetic analysis suggested that voriconazole therapy should be initiated with a dose of 7.2-8.9 mg/kg/day for CYP2C19 wild type and 4.4-6.5 mg/kg/day for the non-wild type in patients. Anaemia and thrombocytopenia are major side effects of liposomal amphotericin B. I demonstrated that the doses of liposomal amphotericin B estimated to cause side effects of a low red blood cell count, anaemia and thrombocytopenia with 50% probability are 4.0, 3.3 and 3.0 mg/kg/day, respectively.


Subject(s)
Anti-Bacterial Agents/administration & dosage , Antifungal Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacokinetics , Anti-Bacterial Agents/pharmacology , Antifungal Agents/adverse effects , Antifungal Agents/pharmacokinetics , Antifungal Agents/pharmacology , Female , HMGB1 Protein/administration & dosage , HMGB1 Protein/pharmacokinetics , HMGB1 Protein/pharmacology , Humans , Liposomes , Male , Pyrimidines/administration & dosage , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Teicoplanin/administration & dosage , Teicoplanin/pharmacokinetics , Teicoplanin/pharmacology , Triazoles/administration & dosage , Triazoles/pharmacokinetics , Triazoles/pharmacology , Voriconazole
3.
Am J Physiol Lung Cell Mol Physiol ; 289(4): L583-90, 2005 Oct.
Article in English | MEDLINE | ID: mdl-15937067

ABSTRACT

High mobility group box 1 (HMGB1) protein, a late mediator of lethality in sepsis, can induce acute inflammatory lung injury. Here, we identify the critical role of alpha-chemokine receptors in the HMGB1-induced inflammatory injury and show that alpha-chemokine receptor inhibition increases survival in sepsis, in a clinically relevant time frame. Intratracheal instillation of recombinant HMGB1 induces a neutrophilic leukocytosis, preceded by alveolar accumulation of the alpha-chemokine macrophage inflammatory protein-2 and accompanied by injury and increased inflammatory potential within the air spaces. To investigate the role of alpha-chemokine receptors in the injury, we instilled recombinant HMGB1 (0.5 microg) directly into the lungs and administered a subcutaneous alpha-chemokine receptor inhibitor, Antileukinate (200 microg). alpha-Chemokine receptor blockade reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 +/- 3.2 vs. 8.1 +/- 2.4 x 10(4) cells; total protein: 120 +/- 48 vs. 311 +/- 129 microg/ml; reactive nitrogen species: 2.3 +/- 0.3 vs. 3.5 +/- 1.3 microM; and macrophage migration inhibitory factor: 6.4 +/- 4.2 vs. 37.4 +/- 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1-induced inflammation and injury are alpha-chemokine mediated. Because HMGB1 can mediate late septic lethality, we administered Antileukinate to septic mice and observed increased survival (from 58% in controls to 89%) even when the inhibitor treatment was initiated 24 h after the induction of sepsis. These data demonstrate that alpha-chemokine receptor inhibition can reduce HMGB1-induced lung injury and lethality in established sepsis and may provide a novel treatment in this devastating disease.


Subject(s)
HMGB1 Protein , Oligopeptides/pharmacology , Pneumonia/drug therapy , Receptors, Chemokine/antagonists & inhibitors , Sepsis/drug therapy , Animals , Chemokine CXCL2 , Chemokines/metabolism , Chemokines, CXC/metabolism , Female , HMGB1 Protein/pharmacokinetics , Mice , Mice, Inbred BALB C , Neutrophils/immunology , Pneumonia/chemically induced , Pneumonia/immunology , Pneumonia/mortality , Pulmonary Alveoli/drug effects , Pulmonary Alveoli/immunology , Pulmonary Alveoli/metabolism , Receptors, Chemokine/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/immunology , Respiratory Distress Syndrome/mortality , Sepsis/immunology , Sepsis/mortality
4.
Pain ; 94(3): 231-244, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11731060

ABSTRACT

Immune activation near healthy peripheral nerves may have a greater role in creating pathological pain than previously recognized. We have developed a new model of sciatic inflammatory neuritis to assess how such immune activation may influence somatosensory processing. The present series of experiments reveal that zymosan (yeast cell walls) acutely injected around the sciatic nerve of awake unrestrained rats rapidly (within 3h) produces low threshold mechanical allodynia in the absence of thermal hyperalgesia. Low (4 microg) doses of zymosan produce both territorial and extra-territorial allodynia restricted to the ipsilateral hindpaw. Higher (40-400 microg) doses of zymosan again produce both territorial and extra-territorial allodynia. However, allodynia is now expressed both in the ipsilateral as well as contralateral hindpaws. Several lines of evidence are provided that the appearance of this contralateral ('mirror') allodynia reflects local actions of zymosan on the sciatic nerve rather than spread of this immune activator to the general circulation. Since many clinical neuropathies result from inflammation/infection of peripheral nerves rather than frank physical trauma, understanding how immune activation alters pain processing may suggest novel approaches to pain control.


Subject(s)
Disease Models, Animal , Rats, Sprague-Dawley , Sciatic Neuropathy/immunology , Sciatic Neuropathy/physiopathology , Acute Disease , Animals , Catheterization , Dose-Response Relationship, Drug , HMGB1 Protein/pharmacokinetics , Hyperalgesia/chemically induced , Hyperalgesia/immunology , Hyperalgesia/physiopathology , Lymph Nodes/anatomy & histology , Male , Organ Size , Physical Stimulation , Rats , Sciatic Neuropathy/chemically induced , Sciatica/chemically induced , Sciatica/immunology , Sciatica/physiopathology , Specific Pathogen-Free Organisms , Spleen/anatomy & histology , Zymosan/pharmacokinetics
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