An one-pot two-step automated synthesis of [18F]T807 injection, its biodistribution in mice and monkeys, and a preliminary study in humans.

[18F]T807 is a potent tau protein imaging agent. In order to fulfill the demand from preclinical and clinical studies, we developed an automated one-pot two-step synthesis of this potent tau imaging agent and studied its stability, and dosimetry in mice and monkeys. We also conducted a preliminary study of this imaging agent in humans. Using this one-pot two-step method, the radiochemical yield (RCY) of [18F]T807 was 20.5 ± 6.1% (n = 15) at the end of bombardment (EOB) in a synthesis time of 70±5 min. The chemical and radiochemical purities were >90% and the specific activities were 151 ± 52 GBq/µmol. The quality of [18F]T807 synthesized by this method met the U.S. Pharmacopoeia (USP) criteria. The stability test showed that the [18F]T807 injection was stable at room temperature for up to 4 h after the end of synthesis (EOS). The estimated effective dose of the [18F]T807 injection extrapolated from monkeys was 19 µSv/MBq (n = 2), while the estimated effective doses of the [18F]T807 injection extrapolated from fasted and non-fasted mice were 123 ± 27 (n = 3) and 94 ± 19 (n = 4) µSv/MBq, respectively. This one-pot two-step automated method produced the [18F]T807 injection with high reproducibility and high quality. PET imaging and radiation dosimetry evaluation in mice and Formosan rock monkeys suggested that the [18F]T807 injection synthesized by this method is suitable for use in human PET imaging studies. Thus, this method could fulfill the demand for the [18F]T807 injection in both preclinical and clinical studies of tauopathies, especially for nearby study sites without cyclotrons.

Baicalein increases keratin 1 and 10 expression in HaCaT keratinocytes via TRPV4 receptor activation.

In this study, we characterized the effect of baicalein on the regulation of keratinocyte differentiation and proliferation, which are abnormal in atopic dermatitis or psoriasis. Treatment of HaCaT keratinocytes with 10 µm baicalein slightly inhibited cell growth, caused morphological differentiation and increased expression of keratins 1 and 10 (K1/K10) without affecting ROS generation, cytochrome c release or apoptosis. Baicalein treatment caused growth arrest in G0 /G1 phase and also induced Ca(2+) influx via TRPV4 receptor activation. Phosphorylation of ERK, Akt and p38 MAPK, but not JNK, was increased by baicalein, and inhibition of phosphorylation of ERK, but not that of Akt or p38 MAPK, blocked the baicalein-induced increase in K1/K10 expression, suggesting that ERK activation is involved in this increase. Removal of extracellular Ca(2+) or blockade of Ca(2+) influx by pharmacological inhibition or silencing of the TRPV4 receptor did not affect growth arrest, ROS generation or apoptosis, but inhibited baicalein-induced ERK phosphorylation and K1/K10 expression. Thus, baicalein treatment increases differentiation, and decreases proliferation, of keratinocytes. The mechanism of differentiation of keratinocytes is distinct from that of proliferation, the former being Ca(2+) dependent and the latter Ca(2+) independent.

Histochemical and functional improvement of adipose-derived stem cell-based tissue-engineered cartilage by hyperbaric oxygen/air treatment in a rabbit articular defect model.

Cartilage is exposed to compression forces during joint loading. Therefore, exogenous stimuli are frequently used in cartilage tissue engineering strategies to enhance chondrocyte differentiation and extracellular matrix (ECM) secretion. In this study, human adipose-derived stem cells were seeded on a gelatin/polycaprolactone scaffold to evaluate the histochemical and functional improvement of tissue-engineered cartilage after hyperbaric oxygen/air treatment in a rabbit articular defect model. Behavior tests showed beneficial effects on weight-bearing and rear leg-supporting capacities after treatment of tissue-engineered cartilage with 2.5 ATA oxygen or air. Moreover, positron emission tomography images and immunohistochemistry staining demonstrated hydroxyapatite formation and increased ECM synthesis, respectively, at the tissue-engineered cartilage graft site after high pressure oxygen/air treatment. Based on these results, we concluded that hyperbaric oxygen and air treatment can improve the quality of tissue-engineered cartilage in vivo by increasing the synthesis of ECM.

Disproportionate Reduction of Serotonin Transporter May Predict the Response and Adherence to Antidepressants in Patients with Major Depressive Disorder: A Positron Emission Tomography Study with 4-[18F]-ADAM.

BACKGROUND: Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants. METHODS: We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more. RESULTS: Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders. CONCLUSIONS: The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD.

Enhanced anti-tumor activity of triptolide in combination with irradiation for the treatment of oral cancer.

Advanced oral cancer has a poor prognosis because of the lack of an effective treatment. We explored the efficiency of combined treatment with triptolide and ionizing radiation for treating oral cancer. Human tongue cancer cells were treated with triptolide, ionizing radiation, or triptolide plus ionizing radiation. Cell proliferation, cell cycle arrest, and apoptotic influences were analyzed by FACS and immunohistochemistry. Tumor potency was examined in an in vivo human tongue cancer cells xenograft mouse model. Our results demonstrated that triptolide caused a marked reduction in colony number that was further enhanced with increasing doses of ionizing radiation. Triptolide increased apoptosis and decreased the expression of anti-apoptotic proteins. In vivo, combination treatment synergistically reduced tumor weight and volume possibly via the induction of apoptosis and reduction in anti-apoptotic protein expression. In conclusion, triptolide plus ionizing radiation treatment had synergistic anti-tumor effects, especially in vivo, and may be a promising combined modality therapy for advanced oral cancer.

Three Chinese herbal medicines promote neuroproliferation in vitro, and reverse the effects of chronic mild stress on behavior, the HPA axis, and proliferation of hippocampal precursor cell in vivo.

ETHNOPHARMACOLOGICAL RELEVANCE: The present study investigated whether Chinese herbal medicines (CHMs) could reverse the effects of chronic mild stress (CMS) in a depression-like mouse model. MATERIALS AND METHODS: The effects of three Chinese herbals, Rhizome Chuanxiong, Radix Scutellaria and Radix Phellodendri on promoting neuroproliferation were evaluated in vitro first and followed by in vivo study of mice which were received by an experimental setting of CMS for 14 days. The effects of the three CHMs on depression were evaluated using a behavioral test, named a forced swimming test (FST). The possible anti-depressive mechanisms of these three CHMs, including the modulation of HPA axis and promoting the hippocampal precursor cell proliferation, were evaluated by measuring plasma corticosterone levels and BrdU incorporation. RESULTS: The in vitro results of MTS assay showed that Rhizome Chuanxiong, Radix Scutellaria and Radix Phellodendri could promote the proliferation of neural stem cells (NSCs) in a concentration-dependent manner. The oral administration of these three CHMs for 14 days reversed not only the elevation of plasma corticosterone levels and body weight loss, but also the decreasing of hippocampal precursor cell proliferation and abnormal behavior in the CMS induced depression-like mouse model. CONCLUSION: These results indicated that Rhizome Chuanxiong, Radix Scutellaria and Radix Phellodendri have the potential to ameliorate depression. The possible mechanisms were the inhibition of HPA axis hyperactivity and the increasing of hippocampal precursor cell proliferation. These findings supported the multicomponent and multitargeted approach of Chinese herbal medicine.