Painful Diabetic Neuropathy Is Associated with Compromised Microglial IGF-1 Signaling Which Can Be Rescued by Green Tea Polyphenol EGCG in Mice.

Background: Painful diabetic neuropathy (PDN) is a frequent and troublesome complication of diabetes, with little effective treatment. PDN is characterized by specific spinal microglia-mediated neuroinflammation. Insulin-like growth factor 1 (IGF-1) primarily derives from microglia in the brain and serves a vital role in averting the microglial transition into the proinflammatory M1 phenotype. Given that epigallocatechin-3-gallate (EGCG) is a potent anti-inflammatory agent that can regulate IGF-1 signaling, we speculated that EGCG administration might reduce spinal microglia-related neuroinflammation and combat the development of PDN through IGF-1/IGF1R signaling. Methods: Type 1 diabetes mellitus (T1DM) was established by a single intraperitoneal (i.p.) injection of streptozotocin (STZ) in mice. The protein expression level of IGF-1, its receptor IGF1R, interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) was determined by Western blot or immunofluorescence. Results: The spinal IGF-1 expression markedly decreased along with the presence of pain-like behaviors, the spinal genesis of neuroinflammation (increased IL-1ß, TNF-α, and Iba-1+ microglia), and the intensified M1 microglia polarization (increased iNOS+Iba-1+ microglia) in diabetic mice. IGF-1 could colocalize with neurons, astrocytes, and microglia, but only microglial IGF-1 was repressed in T1DM mice. Furthermore, we found that i.t. administration of mouse recombinant IGF-1 (rIGF-1) as well as i.t. or i.p. treatment with EGCG alleviated the diabetes-induced pain-like behaviors, reduced neuroinflammation (suppressed IL-1ß, TNF-α, and Iba-1+ microglia), prevented the M1 microglia polarization (less iNOS+Iba-1+ microglia), and restored the microglial IGF-1 expression. Conclusions: Our data highlighted the importance of maintaining spinal IGF-1 signaling in treating microglia-related neuroinflammation in PDN. This study also provides novel insights into the neuroprotective mechanisms of EGCG against neuropathic pain and neuroinflammation through IGF-1 signaling, indicating that this agent may be a promising treatment for PDN in the clinical setting.

Transesophageal echocardiography detection of air embolism during endoscopic surgery and validity of hyperbaric oxygen therapy: Case report.

INTRODUCTION: Air embolism has the potential to be serious and fatal. In this paper, we report 3 cases of air embolism associated with endoscopic medical procedures in which the patients were treated with hyperbaric oxygen immediately after diagnosis by transesophageal echocardiography. In addition, we systematically review the risk factors for air embolism, clinical presentation, treatment, and the importance of early hyperbaric oxygen therapy efficacy after recognition of air embolism. PATIENT CONCERNS: We present 3 patients with varying degrees of air embolism during endoscopic procedures, one of which was fatal, with large amounts of gas visible in the right and left heart chambers and pulmonary artery, 1 showing right heart enlargement with increased pulmonary artery pressure and tricuspid regurgitation, and 1 showing only a small amount of gas images in the heart chambers. DIAGNOSES: Based on ETCO2 and transesophageal echocardiography (TEE), diagnoses of air embolism were made. INTERVENTIONS: The patients received symptomatic supportive therapy including CPR, 100% O2 ventilation, cerebral protection, hyperbaric oxygen therapy and rehabilitation. OUTCOMES: Air embolism can causes respiratory, circulatory and neurological dysfunction. After aggressive treatment, one of the 3 patients died, 1 had permanent visual impairment, and 1 recovered completely without comorbidities. CONCLUSIONS: While it is common for small amounts of air/air bubbles to enter the circulatory system during endoscopic procedures, life-threatening air embolism is rare. Air embolism can lead to serious consequences, including respiratory, circulatory, and neurological impairment. Therefore, early recognition of severe air embolism and prompt hyperbaric oxygen therapy are essential to avoid its serious complications.

Original research paper. A superior preparation method for daidzein-hydroxypropyl-ß-cyclodextrin complexes with improved solubility and dissolution: Supercritical fluid process.

Advantages of the supercritical fluid (SCF) process compared to the conventional solution stirring method (CSSM) in the preparation of daidzein-hydroxypropyl-ß-cyclodextrin (HPßCD) complexes were investigated. Formation of daidzein/ HPßCD inclusion complexes was confirmed by Fourier transformed-infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray diffraction (XRD) and scanning electron microscopy (SEM). Particle size, inclusion yield, drug solubility and dissolution of daidzein/HPßCD complexes were evaluated. Compared to CSSM, the SCF process resulted in higher inclusion yield and higher solubility. Also, extended dissolution of daidzein from the SCF processed HPßCD inclusion complexes was observed, with only 22.94 % released in 45 min, compared to its rapid release from those prepared by CSSM, with 98.25 % drug release in 15 min. This extended release of daidzein from SCF prepared inclusion complexes was necessary to avoid drug precipitation and improve drug solubilisation in the gastrointestinal tract. The results showed that the SCF process is a superior preparation method for daidzein-hydroxypropyl-ß-cyclodextrin complexes.

Curcumin suppresses malignant glioma cells growth and induces apoptosis by inhibition of SHH/GLI1 signaling pathway in vitro and vivo.

AIMS: To study the role of curcumin on glioma cells via the SHH/GLI1 pathway in vitro and vivo. METHODS: The effects of curcumin on proliferation, migration, apoptosis, SHH/GLI1 signaling, and GLI1 target genes expression were evaluated in multiple glioma cell lines in vitro. A U87-implanted nude mice model was used to study the role of curcumin on tumor volume and the suppression efficacy of GLI1. RESULTS: Curcumin showed cytotoxic effects on glioma cell lines in vitro. Both mRNA and protein levels of SHH/GLI1 signaling (Shh, Smo, GLI1) were downregulated in a dose- and time-dependent manner. Several GLI1-dependent target genes (CyclinD1, Bcl-2, Foxm1) were also downregulated. Curcumin treatment prevented GLI1 translocating into the cell nucleus and reduced the concentration of its reporter. Curcumin suppressed cell proliferation, colony formation, migration, and induced apoptosis which was mediated partly through the mitochondrial pathway after an increase in the ratio of Bax to Bcl2. Intraperitoneal injection of curcumin in vivo reduced tumor volume, GLI1 expression, the number of positively stained cells, and prolonged the survival period compared with the control group. CONCLUSION: This study shows that curcumin holds a great promise for SHH/GLI1 targeted therapy against gliomas.