Ameliorative effect of bofutsushosan (Fangfengtongshengsan) extract on the progression of aging-induced obesity.

This study aimed to compare fat accumulation in young and aged mice raised on a high-fat diet and to characterize the obesity-reducing effects of a Kampo medicine, bofutsushosan (BTS; fangfengtongshengsan in Chinese). Aged mice fed a high-fat diet containing 2% BTS extract for 28 days exhibited a significant reduction in weight gain and accumulation of visceral and subcutaneous fat, which were greater degree of reduction than those of the young mice. When the treatment period was extended to two months, the serum aspartate aminotransferase and alanine aminotransferase levels and the accumulation of fat droplets in the hepatocytes decreased. The mRNA expression of mitochondrial uncoupling protein 1 (UCP1) in the brown adipose tissue was significantly reduced in the aged mice compared to the young mice but increased by 2% in the BTS-treated aged mice. Additionally, the effect of BTS extract on oleic acid-albumin-induced triglyceride accumulation in hepatoblastoma-derived HepG2 cells was significantly inhibited in a concentration-dependent manner. Evaluation of the single crude drug extracts revealed that Forsythia Fruit, Schizonepeta Spike, and Rhubarb were the active components in BTS extract. These results suggest that BTS extract is effective against visceral, subcutaneous, and ectopic fats in the liver, which tend to accumulate with aging. Thus, BTS extract is useful in preventing and ameliorating the development of obesity and metabolic syndrome.

A triple minimally invasive surgery combination for subacute osteoporotic lower lumbar vertebral collapse with neurological compromise: a potential alternative to the vertebral corpectomy/expandable cage strategy.

OBJECTIVE: Acute/subacute osteoporotic vertebral collapses (OVCs) in the lower lumbar spine with neurological compromise, although far less well documented than those in the thoracolumbar junction, may often pose greater treatment challenges. The authors clarified the utility of 3 familiar combined techniques of minimally invasive surgery for this condition as an alternative to the corpectomy/expandable cage strategy. METHODS: This report included the authors' first 5 patients with more than 2 years (range 27-48 months) of follow-up. The patients were between 68 and 91 years of age, and had subacute painful L4 OVC with neurological compromise and preexisting lumbar spinal stenosis. The authors' single-stage minimally invasive surgery combination consisted of the following: step 1, balloon kyphoplasty for the L4 OVC to restore its strength, followed by L4-percutaneous pedicle screw (PPS) placement with patients in the prone position; step 2, tubular lateral lumbar interbody fusion (LLIF) at the adjacent disc space involved with endplate injury, with patients in the lateral position; and step 3, supplemental PPS-rod fixation with patients in the prone position. RESULTS: Estimated blood loss ranged from 20 to 72 mL. Neither balloon kyphoplasty-related nor LLIF-related potentially serious complications occurred. With CT measurements at the 9 LLIF levels, the postoperative increases averaged 3.5 mm in disc height and 3.7 mm in bilateral foraminal heights, which decreased by only 0.2 mm and 0 mm at the latest evaluation despite their low bone mineral densities, with a T-score of -3.8 to -2.6 SD. Canal compromise by fracture retropulsion decreased from 33% to 23% on average. As indicated by MRI measurements, the dural sac progressively enlarged and the ligamentum flavum increasingly shrank over time postoperatively, consistent with functional improvements assessed by the physician-based, patient-centered measures. CONCLUSIONS: The advantages of this method over the corpectomy/expandable cage strategy include the following: 1) better anterior column stability with a segmentally placed cage, which reduces stress concentration at the cage footplate-endplate interface as an important benefit for patients with low bone mineral density; 2) indirect decompression through ligamentotaxis caused by whole-segment spine lengthening with LLIF, pushing back both the retropulsed fragments and the disc bulge anteriorly and unbuckling the ligamentum flavum to diminish its volume posteriorly; and 3) eliminating the need for segmental vessel management and easily bleeding direct decompressions. The authors' recent procedural modification eliminated step 3 by performing loose PPS-rod connections in step 1 and their tight locking after LLIF in step 2, reducing to only once the number of times the patient was repositioned.

Human recombinant erythropoietin improves motor function in rats with spinal cord compression-induced cervical myelopathy.

OBJECTIVE: Erythropoietin (EPO) is a clinically available hematopoietic cytokine. EPO has shown beneficial effects in the context of spinal cord injury and other neurological conditions. The aim of this study was to evaluate the effect of EPO on a rat model of spinal cord compression-induced cervical myelopathy and to explore the possibility of its use as a pharmacological treatment. METHODS: To develop the compression-induced cervical myelopathy model, an expandable polymer was implanted under the C5-C6 laminae of rats. EPO administration was started 8 weeks after implantation of a polymer. Motor function of rotarod performance and grip strength was measured after surgery, and motor neurons were evaluated with H-E, NeuN and choline acetyltransferase staining. Apoptotic cell death was assessed with TUNEL and Caspase-3 staining. The 5HT, GAP-43 and synaptophysin were evaluated to investigate the protection and plasticity of axons. Amyloid beta precursor protein (APP) was assessed to evaluate axonal injury. To assess transfer of EPO into spinal cord tissue, the EPO levels in spinal cord tissue were measured with an ELISA for each group after subcutaneous injection of EPO. RESULTS: High-dose EPO maintained motor function in the compression groups. EPO significantly prevented the loss of motor neurons and significantly decreased neuronal apoptotic cells. Expression of 5HT and synaptophysin was significantly preserved in the EPO group. APP expression was partly reduced in the EPO group. The EPO levels in spinal cord tissue were significantly higher in the high-dose EPO group than other groups. CONCLUSION: EPO improved motor function in rats with compression-induced cervical myelopathy. EPO suppressed neuronal cell apoptosis, protected motor neurons, and induced axonal protection and plasticity. The neuroprotective effects were produced following transfer of EPO into the spinal cord tissue. These findings suggest that EPO has high potential as a treatment for degenerative cervical myelopathy.

Autologous Transfusion of Blood Aspirated during Suction Decompression in Clipping of Large or Giant Cerebral Aneurysm.

The suction decompression (SD) method, which proactively aspirates the blood flowing into the aneurysm and reduces the internal pressure of the aneurysm, is useful for clipping surgery of large and giant cerebral aneurysm. However, there has been little discussion on re-utilization of blood aspirated during SD. This study aimed to examine the safety, convenience, and usefulness of autologous transfusion of aspirated blood using a transfusion bag. At the time of craniotomy, the cervical carotid artery is fully exposed. An angiocatheter sheath was inserted into the carotid artery and placed in the internal carotid artery. In SD, blood was aspirated from the sheath at a constant speed and quickly stored in a blood transfusion storage bag. Blood aspiration was repeated with a new syringe; once the transfusion bag was full, the blood was re-administered to the patient. Changes in vital sign and hemoglobin/hematocrit values before and after SD were examined in five cases performed in this procedure. The aspirated blood volumes of five cases ranged from 130 to 400 mL, and all aspirated blood was successfully re-transfused. There was no critical change in vital sign, and no significant decrease in the hemoglobin/hematocrit value. No findings suggestive of complications of thrombus formation, infection, and hemolysis were noted. Re-transfusion of aspirated blood during SD using a transfusion bag is a simple and safe method, which can minimize potential risk of re-utilizing aspirated blood, and enables the safe and easy execution of SD regardless of aspirated blood volume.

Optimized Dosing Schedule Based on Circadian Dynamics of Mouse Breast Cancer Stem Cells Improves the Antitumor Effects of Aldehyde Dehydrogenase Inhibitor.

Although malignant phenotypes of triple-negative breast cancer (TNBC) are subject to circadian alterations, the role of cancer stem cells (CSC) in defining this circadian change remains unclear. CSC are often characterized by high aldehyde dehydrogenase (ALDH) activity, which is associated with the malignancy of cancer cells and is used for identification and isolation of CSC. Here, we show that the population of ALDH-positive cells in a mouse 4T1 breast tumor model exhibits pronounced circadian alterations. Alterations in the number of ALDH-positive cells were generated by time-dependent increases and decreases in the expression of Aldh3a1 Importantly, circadian clock genes were rhythmically expressed in ALDH-negative cells, but not in ALDH-positive cells. Circadian expression of Aldh3a1 in ALDH-positive cells was dependent on the time-dependent release of Wingless-type mmtv integration site family 10a (WNT10a) from ALDH-negative cells. Furthermore, antitumor and antimetastatic effects of ALDH inhibitor N,N-diethylaminobenzaldehyde were enhanced by administration at the time of day when ALDH activity was increased in 4T1 tumor cells. Our findings reveal a new role for the circadian clock within the tumor microenvironment in regulating the circadian dynamics of CSC. These results should enable the development of novel therapeutic strategies for treatment of TNBC with ALDH inhibitors.Significance: This seminal report reveals that circadian dynamics of CSC are regulated by the tumor microenvironment and provides a proof of principle of its implication for chronotherapy in TNBC. Cancer Res; 78(13); 3698-708. ©2018 AACR.

Establishment and validation of a rabbit model for in vivo pharmacodynamic screening of tachykinin NK2 antagonists.

We attempted to establish and validate an in vivo pharmacodynamic (PD) rabbit model to screen tachykinin NK(2) receptor (NK(2)-R) antagonists using pharmacological and pharmacokinetic (PK)/PD analyses. Under urethane anesthesia, changes in intracolonic pressure associated with intravenous (i.v.) administration of a selective NK(2)-R agonist, ßAla(8)-neurokinin A(4-10) (ßA-NKA), was monitored as a PD marker. The analgesic effects of NK(2)-R antagonists were evaluated by monitoring visceromotor response (VMR) to colorectal distension in a rabbit model of visceral hypersensitivity induced by intracolonic treatment of acetic acid. Intravenous administration of ßA-NKA induced transient colonic contractions dose-dependently, which were inhibited by the selective NK(2)-R antagonists in dose- and/or plasma concentration-dependent manners. The correlation between PD inhibition and plasma concentration normalized with the corresponding in vitro binding affinity was relatively high (r(2) = 0.61). Furthermore, the minimum effective doses on the VMR and ID(50) values calculated in the PD model were highly correlated (r(2) = 0.74). In conclusion, we newly established and validated a rabbit model of agonist-induced colonic contractions as a screening tool for NK(2)-R antagonists. In a drug discovery process, this PD model could enhance the therapeutic candidate selection for irritable bowel syndrome, pharmacologically connecting in vitro affinity for NK(2)-R with in vivo therapeutic efficacy.