Dietary Supplements of Shiikuwasha Extract Attenuates Osteoarthritis Progression in Meniscal/ligamentous Injury and Obese Rats.

Osteoarthritis (OA), also called degenerative joint disease, is characterized by joint cartilage loss and is strongly linked to obesity. Medicine to alleviate pain is currently the only treatment. Shiikuwasha extract (SE) has been reported to possess valuable bioactive substances exhibiting anti-inflammatory, antiobesity, and anticancer effects. Research is limited to the use of SE in the treatment of OA and obesity. We performed both anterior cruciate ligament transections and medial meniscectomies to induce OA on Sprague-Dawley rats after 11 weeks of a high fat diet followed by 9 weeks of oral SE administration (300, 600, and 1500 mg/kg). This study showed that SE treatment could reduce weight gain and joint pain. Additionally, SE significantly decreased triglycerides and total cholesterol in plasma of the S1500 group but increased high-density lipoprotein cholesterol in the plasma of the S600 group. Meanwhile, plasma levels of tumor necrosis factor alpha (TNF-α) was significantly reduced in the S1500 groups. Histopathological findings confirmed administration of SE attenuated cartilage degeneration. Immunohistochemistry examination demonstrated that caspase 3 and phospho-Janus kinase 2 (p-JAK2) expression levels on chondrocytes were downregulated by SE treatment. Our findings demonstrate that SE can alleviate OA progression by improving obesity.

Expression of survivin and p53 modulates honokiol-induced apoptosis in colorectal cancer cells.

Honokiol is a small biphenolic compound, which exerts antitumor activities; however, the precise mechanism of honokiol-induced apoptosis in the human colorectal cancer cells remains unclear. Here, we show that survivin and p53 display the opposite role on the regulation of honokiol-induced apoptosis in the human colorectal cancer cells. Honokiol induced the cell death and apoptosis in various colorectal cancer cell lines. Moreover, honokiol elicited the extrinsic death receptor pathway of DR5 and caspase 8 and the intrinsic pathway of caspase 9. The common intrinsic and extrinsic downstream targets of activated caspase 3 and PARP protein cleavage were induced by honokiol. Interestingly, honokiol reduced anti-apoptotic survivin protein and gene expression. Transfection with a green fluorescent protein (GFP)-survivin-expressed vector increased the colorectal cancer cell viability and resisted the honokiol-induced apoptosis. Meantime, honokiol increased total p53 and the phosphorylated p53 proteins at Ser15 and Ser46. The p53-wild type colorectal cancer cells were exhibited greater cytotoxicity, apoptosis and survivin reduction than the p53-null cancer cells after treatment with honokiol. Together, these findings demonstrate that the existence of survivin and p53 can modulate the honokiol-induced apoptosis in the human colorectal cancer cells.

A sorafenib derivative and novel SHP-1 agonist, SC-59, acts synergistically with radiotherapy in hepatocellular carcinoma cells through inhibition of STAT3.

Radiotherapy shows limited benefit as treatment for hepatocellular carcinoma (HCC). In this study, we aimed to overcome the radioresistance of HCC by using a novel sorafenib derivative, SC-59 that targets SHP-1-related signaling. HCC cell lines (SK-Hep1, Hep3B, and Huh7) were treated with sorafenib, SC-59, radiation, sorafenib plus radiation, or SC-59 plus radiation, and then apoptosis, colony formation, signal transduction and the phosphatase activity were analyzed. The synergistic effect of radiotherapy and SC-59 was analyzed using a combination index (CI) approach. In vivo efficacy was determined in a Huh7-bearing subcutaneous model. Mice were treated with radiation (5 Gy, one fraction per day) for 4 days, SC-59 (10mg/kg/day) for 24 days, or a combination. Tumor samples were further analyzed for p-STAT3 and SHP-1 activity. SC-59 displayed a better synergistic effect when used in combination with radiotherapy than sorafenib in HCC cell lines. SC-59 downregulated p-STAT3 and its downstream targets and increased SHP-1 phosphatase activity. Both ectopic STAT3 and inhibition of SHP-1 abolished SC-59-induced radiosensitization. Moreover, SC-59 significantly synergized radiotherapy in a Huh7 xenograft model by targeting SHP-1/STAT3 signaling. The novel sorafenib derivative, SC-59, acting as a SHP-1 agonist, displays a better synergistic effect when used in combination with radiotherapy than sorafenib for the treatment of HCC. Further clinical investigation is warranted.

Epigallocatechin-3-gallate effectively attenuates skeletal muscle atrophy caused by cancer cachexia.

Cachexia, also known as wasting syndrome notably with skeletal muscle atrophy, costs nearly one-third of all cancer deaths in man. (-)-Epigallocatechin-3-gallate (EGCG), the principal polyphenolic component in green tea, is a potent preventive against cachexia as well as cancers. However, how EGCG counteracts cachexia-provoked muscle wasting is unclear. EGCG was demonstrated to be able to retard tumor progression as well as to prevent body weight from loss, because EGCG attenuates skeletal muscle leukocytic infiltration and down-regulates tumor-induced NF-κB and E3-ligases in muscle. In mice, the dosages optimized against cachexia were determined to be 0.2 mg/mouse/day for prevention and to be 0.6 mg/mouse/day for treatment. Anti-cachexia effects were assessed using the LLC tumor model. Mice with the same body weight were divided into groups, including control, tumor bearing, and tumor-bearing but receiving water or EGCG in both prevention and treatment experiments. RT-PCR was used to assess mRNA expressions of NF-κB, MuRF 1, and MAFbx. The intracellular NF-κB, MuRF 1 and MAFbx were determined and quantified by immunofluorescence and Western blotting, respectively. Our results conclude EGCG regulates the expressions of NF-κB as well as downstream mediators, MuRF 1 and MAFbx, so EGCG may be an appropriate agent to be included in ensemble therapeutics of the tumor-induced muscle atrophy.