Tetrandrine, an activator of autophagy, induces autophagic cell death via PKC-α inhibition and mTOR-dependent mechanisms.

Emerging evidence suggests the therapeutic role of autophagic modulators in cancer therapy. This study aims to identify novel traditional Chinese medicinal herbs as potential anti-tumor agents through autophagic induction, which finally lead to autophagy mediated-cell death in apoptosis-resistant cancer cells. Using bioactivity-guided purification, we identified tetrandrine (Tet) from herbal plant, Radix stephaniae tetrandrae, as an inducer of autophagy. Across a number of cancer cell lines, we found that breast cancer cells treated with tetrandrine show an increase autophagic flux and formation of autophagosomes. In addition, tetrandrine induces cell death in a panel of apoptosis-resistant cell lines that are deficient for caspase 3, caspase 7, caspase 3 and 7, or Bax-Bak respectively. We also showed that tetrandrine-induced cell death is independent of necrotic cell death. Mechanistically, tetrandrine induces autophagy that depends on mTOR inactivation. Furthermore, tetrandrine induces autophagy in a calcium/calmodulin-dependent protein kinase kinase-β (CaMKK-β), 5′ AMP-activated protein kinase (AMPK) independent manner. Finally, by kinase profiling against 300 WT kinases and computational molecular docking analysis, we showed that tetrandrine is a novel PKC-α inhibitor, which lead to autophagic induction through PKC-α inactivation. This study provides detailed insights into the novel cytotoxic mechanism of an anti-tumor compound originated from the herbal plant, which may be useful in promoting autophagy mediated- cell death in cancer cell that is resistant to apoptosis.published_or_final_versio

The current management of acute uncomplicated appendicitis: should there be a change in paradigm? A systematic review of the literatures and analysis of treatment performance

published_or_final_versio

Ginseng extracts restore high-glucose induced vascular dysfunctions by altering triglyceride metabolism and downregulation of atherosclerosis-related genes

2013-2014 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Effects of metformin treatment on radiotherapy efficacy in patients with cancer and diabetes: a systematic review and meta-analysis

Mingyue Rao,1–3 Chenlin Gao,1,2 Man Guo,2 Betty Yuen Kwan Law,1,4 Yong Xu1,2 1Faculty of Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China; 2Department of Endocrinology, 3Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, China; 4State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China Purpose: Metformin is a key pharmaceutical for patients with diabetes mellitus (DM). Metformin also can enhance tumor radiosensitivity in vitro and in vivo. Some retrospective cohort studies have indicated that metformin can improve the efficacy of radiotherapy in patients with cancer and DM. The aim of this systematic review was to evaluate the radiotherapy efficacy of metformin in patients with cancer and DM.Methods: Multiple databases were queried for studies that address the efficacy of metformin in radiotherapy of patients with cancer and DM. Studies were included that involved comparisons of the short-term tumor responses and long-term survival outcomes of these patients who were managed with or without metformin as well as of nondiabetic patients without metformin. The OR and HR with accompanying 95% CI were assessed in a random effects model. The main endpoints were 2-year and 5-year overall survival (2y-OS and 5y-OS, respectively).Results: The database search yielded 17 cohort studies that met the inclusion criteria. The results indicated that the tumor response was higher in patients who also were treated with metformin than in those who were not (OR, 0.48; 95% CI, 0.22–1.07; P=0.07) and nondiabetic (OR, 0.27; 95% CI, 0.07–0.98; P=0.05). Moreover, patients who received metformin had survival benefits compared with patients not treated with metformin (2y-OS: OR, 0.48; 95% CI, 0.29–0.80; P=0.005; 5y-OS: OR, 0.38; 95% CI, 0.25–0.56; P<0.00001). The metformin-related HRs of OS values were not significantly different.Conclusion: Metformin appears to improve the tumor response to radiotherapy in patients with cancer and DM and partly yield survival benefits. Despite the apparent advantages provided by metformin treatment on 2y-OS and 5y-OS, these retrospective data are at risk of bias and should be interpreted with caution. Keywords: metformin, cancer, diabetes mellitus, radiotherapy, surviva

Comparison of self-gripping semi-absorbable mesh (PROGRIP) with polypropylene mesh in open inguinal hernia repair: a randomized study

Oral Presentation 4: Open Inguinal Hernia RepairThe 6th International Congress of the Asia-Pacific Hernia Society (APHS 2010), Seoul, Korea, 14-16 October 2010

Development of Serum Lactate Level-Based Nomograms for Predicting Diabetic Kidney Disease in Type 2 Diabetes Mellitus Patients

Chunxia Jiang,1– 4,&ast; Xiumei Ma,1– 4,&ast; Jiao Chen,2– 5,&ast; Yan Zeng,1– 4 Man Guo,2– 4 Xiaozhen Tan,2– 4 Yuping Wang,1,6 Peng Wang,1 Pijun Yan,2– 4 Yi Lei,1– 4 Yang Long,2– 4 Betty Yuen Kwan Law,1 Yong Xu1– 4 1Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, People’s Republic of China; 2Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 4Sichuan Clinical Research Center for Nephropathy, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 5Department of Endocrinology, The Third’s Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, Sichuan, People’s Republic of China; 6Department of Breast, Thyroid and Vascular Surgery, Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou, Sichuan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Betty Yuen Kwan Law, Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macao, 999078, People’s Republic of China, Email [email protected] Yong Xu, Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Email [email protected]: To establish nomograms integrating serum lactate levels and traditional risk factors for predicting diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients.Patients and methods: A total of 570 T2DM patients and 100 healthy subjects were enrolled. T2DM patients were categorized into normal and high lactate groups. Univariate and multivariate logistic regression analyses were employed to identify independent predictors for DKD. Then, nomograms for predicting DKD were established, and the model performance was evaluated using the area under the receiver operating characteristic curve (AUC), calibration, and decision curve analysis (DCA).Results: T2DM patients exhibited higher lactate levels compared to those in healthy subjects. Glucose, platelet, uric acid, creatinine, and hypertension were independent factors for DKD in T2DM patients with normal lactate levels, while diabetes duration, creatinine, total cholesterol, and hypertension were indicators in high lactate levels group (P< 0.05). The AUC values were 0.834 (95% CI, 0.776 to 0.891) and 0.741 (95% CI, 0.688 to 0.795) for nomograms in both normal lactate and high lactate groups, respectively. The calibration curve demonstrated excellent agreement of fit. Furthermore, the DCA revealed that the threshold probability and highest Net Yield were 17– 99% and 0.36, and 24– 99% and 0.24 for the models in normal lactate and high lactate groups, respectively.Conclusion: The serum lactate level-based nomogram models, combined with traditional risk factors, offer an effective tool for predicting DKD probability in T2DM patients. This approach holds promise for early risk assessment and tailored intervention strategies.Keywords: serum lactate, diabetic kidney disease, nomograms, prediction model, risk factor

Alisol B, a novel inhibitor of the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase pump, induces autophagy, endoplasmic reticulum stress, and apoptosis

Emerging evidence suggests that autophagic modulators have therapeutic potential. This study aims to identify novel autophagic inducers from traditional Chinese medicinal herbs as potential antitumor agents. Using an image-based screen and bioactivity-guided purification, we identified alisol B 23-acetate, alisol A 24-acetate, and alisol B from the rhizome of Alisma orientale as novel inducers of autophagy, with alisol B being the most potent natural product. Across several cancer cell lines, we showed that alisol B-treated cells displayed an increase of autophagic flux and formation of autophagosomes, leading to cell cycle arrest at the G1 phase and cell death. Alisol B induced calcium mobilization from internal stores, leading to autophagy through the activation of the CaMKK-AMPK-mammalian target of rapamycin pathway. Moreover, the disruption of calcium homeostasis induces endoplasmic reticulum stress and unfolded protein responses in alisol B-treated cells, leading to apoptotic cell death. Finally, by computational virtual docking analysis and biochemical assays, we showed that the molecular target of alisol B is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase. This study provides detailed insights into the cytotoxic mechanism of a novel antitumor compound. ©2010 AACR.link_to_OA_fulltex