Inhibitory effect of taurine on rotator cuff degeneration via mitochondrial protection.

OBJECTIVES: Degenerative rotator cuff tears do not heal spontaneously, necessitating surgical intervention. This makes prevention crucial, but effective prophylactic measures are currently lacking. Oxidative stress has recently been implicated as a cause of degenerative rotator cuff tears, while mitochondrial injury has been reported in the development of age-related rotator cuff degeneration. Taurine, which has antioxidant properties, has been found to be effective in the treatment of various mitochondrial abnormalities. This prompted us to investigate the inhibitory effect of taurine and some other antioxidants against rotator cuff degeneration using tenocytes. METHODS: Hydrogen peroxide (H2O2, 2 mM) was added to tenocytes in medium with 0.8 µM taurine (Group TAU), medium with 100 µM α-tocopherol (Group E), and medium with 150 µM ascorbic acid (Group C), then each medium was cultured for 24 h. Tenocytes supplemented with 2 mM H2O2 alone were similarly cultured for 24 h (Group H2O2). In each group, immunostaining was performed for the oxidative stress marker 8-hydroxy-2'-deoxyguanosine and advanced glycation end products (AGE), which contribute to the development of age-related rotator cuff degeneration. In addition, levels of reactive oxygen species were measured using a cell-based assay kit, and results were compared. Immunostaining was also performed for indices of apoptosis (caspase-9, cleaved caspase-3 and Bcl-2), and Western blotting was used to quantify activation of caspase-9 at an early stage in each group. RESULTS: Oxidative stress and AGE levels were decreased in the E and C groups. Levels of all parameters were reduced in the TAU group. CONCLUSIONS: Taurine showed preventative effects against rotator cuff degeneration. The simple method of administration and paucity of side effects make clinical application easy, and the clear potential as a novel prophylactic strategy against degenerative rotator cuff tear warrants further study.

Benign Tumors of the Spine: Has New Chemotherapy and Interventional Radiology Changed the Treatment Paradigm?

STUDY DESIGN: Clinically based systematic review. OBJECTIVE: To determine the role of (A) medical treatment and (B) interventional radiology as either adjuvant or stand-alone treatment in primary benign bone tumors of the spine. METHODS: A multidisciplinary panel of spine surgeons, radiation oncologists, and medical oncologists elaborated specific focused questions regarding aneurysmal bone cyst, giant cell tumor, and osteoid osteoma. Denosumab, bisphosphonate, interferon, bone marrow aspirate, doxycycline, thermal ablation, and selective arterial embolization were identified as areas of interest for the article. A systematic review was performed through MEDLINE and EMBASE. Recommendations based on the literature review and clinical expertise were issued using the GRADE system. RESULTS: The overall quality of the literature is very low with few multicenter prospective studies. For giant cell tumor, combination with Denosumab identified 14 pertinent articles with four multicenter prospective studies. Nine studies were found on bisphosphonates and six for selective arterial embolization. The search on aneurysmal bone cyst and selective arterial embolization revealed 12 articles. Combination with Denosumab, Doxycycline, and bone marrow aspirate identified four, two, and three relevant articles respectively. Eleven focused articles were selected on the role of thermal ablation in osteoid osteoma. CONCLUSION: Alternative and adjuvant therapy for primary benign bone tumors have emerged. Their ability to complement or replace surgery is now being scrutinized and they may impact significantly the algorithm of treatment of these tumors. Most of the data are still emerging and further research is desirable. Close collaboration between the different specialists managing these pathologies is crucial. LEVEL OF EVIDENCE: N/A.

Structure-activity relationships and the cytotoxic effects of novel diterpenoid alkaloid derivatives against A549 human lung carcinoma cells.

The cytotoxicity of three alkaloids from the roots of Aconitum yesoense var. macroyesoense as well as 36 semi-synthetic C(20)-diterpenoid atisine-type alkaloid derivatives against A549 human lung carcinoma cells was examined. Ten acylated alkaloid derivatives, pseudokobusine 11-veratroate (9), 11-anisoate (12), 6,11-dianisoate (14), 11-p-nitrobenzoate (18), 11,15-di-p-nitrobenzoate (22), 11-cinnamate (25) and 11-m-trifluoromethylbenzoate (27), and kobusine 11-p-trifluoromethylbenzoate (35), 11-m-trifluoromethylbenzoate (36) and 11,15-di-p-nitrobenzoate (39), exhibited cytotoxic activity, and 11,15-dianisoylpseudokobusine (16) was found to be the most potent cytotoxic agent. Their IC(50) values against A549 cells ranged from 1.72 to 5.44 µM. In the occurrence of cytotoxic effects of atisine-type alkaloids, replacement by an acyl group at both C-11 and C-15 resulted in the enhancement of activity of the parent alkaloids compared to that from having hydroxy groups at this position, and the presence of a hydroxy group at the C-6 position was required for the cytotoxic effects. These acylated alkaloid derivatives inhibit cell growth through G1 arrest.

Structure-activity relationships between the Aconitum C20-diterpenoid alkaloid derivatives and the growth suppressive activities of Non-Hodgkin's lymphoma Raji cells and human hematopoietic stem/progenitor cells.

The anti-tumor properties of novel derivatives prepared from Aconitum C(20)-diterpenoid alkaloid, which show the least toxicity among the Aconitum alkaloids, were investigated in the Non-Hodgkin's lymphoma cell line Raji cells. Two novel Aconitum C(20)-diterpenoid alkaloid derivatives, 11-m-Trifluorometylbenzoyl (Mb)-pseudokobuisne and 11-Anisoyl (As)-pseudokobusine, showed significant suppressive effects and their 50% inhibitory concentrations were 2.2 µg/ml and 2.4 µg/ml against Raji cells, respectively. Both compounds have the same structure except for a functional group in the C-11 position. One of the active compounds, 11-Mb-pseudokobusine, clearly inhibited the phosphorylation of extracellular signal-regulated kinase, induced enhanced phosphoinositide 3 kinase phosphorylation and led to the subsequent accumulation of G1 and/or sub G1 phase in Raji cells. In addition, no significant suppressive effects on the growth of human CD34(+) hematopoietic stem/progenitor cells (HSPC) were observed by 11-Mb-pseudokobusine which showed a strong suppressive activity on the growth of Raji cells, whereas 11-As-pseudokobusine also a showed significantly suppressive effect on the growth of HSPC. Therefore, the atisine type structure characteristic of C(20)-diterpenoid alkaloids plays a very important role in the pharmacological properties. In particular, the C-11 residues are an important component for the anti-tumor properties and for the lower toxicity to hematopoiesis.

Suppressive effects of novel derivatives prepared from Aconitum alkaloids on tumor growth.

Little information has so far been reported regarding the antiproliferative properties of Aconitum alkaloids against human tumor cells despite of their intense toxicities. In the present study, the antitumor properties and radiation sensitizing effects were investigated by various types of novel derivatives prepared from Aconitum alkaloids. The antitumor properties were investigated against human tumor cell lines, A172, A549, HeLa and Raji, respectively, by a cell growth, a clonogenic assay, cell cycle distribution, cell cycle related molecules and gammaH2AX expression. The novel compounds derived from C(20)-diterupenoid alkaloids showed a significantly suppressive effect in all cell lines. In contrast, natural C(19)-norditerpenoid alkaloids and their derivatives showed either no effect or only a slight effect. One of the compounds also showed radiosensitizing properties on A549 cells. These effects are not related to either the cell cycle distribution, the enhancement of apoptosis or the gammaH2AX expression. Novel derivatives prepared from Aconitum alkaloids, not but natural alkaloids, clearly showed anti-proliferative activity in human tumor cell lines.

Inhibitory effects of diterpenoid alkaloids on the growth of A172 human malignant cells.

The cytotoxicity against A172 human malignant glioma cells was examined for 14 alkaloids from the roots of Aconitum yesoense var. macroyesoense and of Aconitum japonicum and from the seeds of Delphinium elatum as well as for 25 semisynthetic derivatives. The major alkaloid constituents of A. yesoense var. macroyesoense, kobusine (2) and pseudokobusine (3), a minor alkaloid constituent of A. japonicum, aljesaconitine A (5), and six alkaloid derivatives, N-deethyldelcosine (10), N-deethyldelsoline (11), 12-benzoylluciculine (18), 12-anisoylluciculine (19), 6,11-dibenzoylpseudokobusine (28), and 6-veratroylpseudokobusine (29), had only very weak activity. Four acylated alkaloid derivatives, 12-acetylluciculine (23), 11-veratroylpseudokobusine (30), 11-(m-trifluoromethylbenzoyl)pseudokobusine (32), and 11-(m-trifluoromethylbenzoyl)kobusine (39), exhibited more potent activity, while pseudokobusine 11-cinnamoate (31), 11-anisoate (33), and 11-p-nitrobenzoate (34) were found to be the most potent cytotoxic agents.