Lysosomal Zn2+ release triggers rapid, mitochondria-mediated, non-apoptotic cell death in metastatic melanoma.

During tumor progression, lysosome function is often maladaptively upregulated to match the high energy demand required for cancer cell hyper-proliferation and invasion. Here, we report that mucolipin TRP channel 1 (TRPML1), a lysosomal Ca2+ and Zn2+ release channel that regulates multiple aspects of lysosome function, is dramatically upregulated in metastatic melanoma cells compared with normal cells. TRPML-specific synthetic agonists (ML-SAs) are sufficient to induce rapid (within hours) lysosomal Zn2+-dependent necrotic cell death in metastatic melanoma cells while completely sparing normal cells. ML-SA-caused mitochondria swelling and dysfunction lead to cellular ATP depletion. While pharmacological inhibition or genetic silencing of TRPML1 in metastatic melanoma cells prevents such cell death, overexpression of TRPML1 in normal cells confers ML-SA vulnerability. In the melanoma mouse models, ML-SAs exhibit potent in vivo efficacy of suppressing tumor progression. Hence, targeting maladaptively upregulated lysosome machinery can selectively eradicate metastatic tumor cells in vitro and in vivo.

Magnetic stimulation accelerating rehabilitation of peripheral nerve injury.

The effect of magnetic stimulation (MS) on sciatic nerve injury was observed. After sciatic nerve was crushed in 40 Sprague Dawley (SD) rats, one randomly selected group (group D) was subjected, from the 4th day post-operatively to 3 min of continuous 70% of maximum output of MS daily for 8 weeks. The other group (group E) served as a control group. The nerve regeneration and motor function recovery were evaluated by walking track analysis (sciatic function index, SFI; toe spreading reflex, TSR), electrophysiological, histological and acetylcholineesterase histochemistry. The SFI in the group D was greater than in the group E with the difference being statistically significant (P < 0.01). TSR reached its peak on the 4th day in the group D and on the 10th day in the group E respectively. The amplitude and velocity of MCAP and NCAP in the group D was greater than in the group E with the difference being statistically significant (P < 0.01), while the latency and duration of MCAP and NCAP in the group D were less than in the group E with the difference being also statistically significant (P < 0.01). Histological examination showed the mean axon count above the lesion for thick myelinated fibers (> 6.5 microns) in the group D was greater than in the control group with the difference being statistically significant (P < 0.01), while the mean axon count below the lesion for thick myelinated fibers was less than that in the group E with the difference being statistically significant (P < 0.01). The mean axon count above the lesion for thin myelinated fibers (2-6.5 microns) in the group D was greater than that in the group E with the difference being statistically significant (P < 0.05), while the mean axon count below the lesion for thin myelinated in the group D was greater than that in the group E with the difference being statistically significant (P < 0.01). Acetylcholine esterase examination showed that the MS could significantly increase the number of the motor neurons. There was no significant difference in the number of the motor neurons between the treatment side and the normal side (P > 0.05). It can be concluded that MS can enhance functional recovery and has a considerable effect in the treatment of the peripheral nerve injury.

A Comparative Study of the Effects of Magnetic Stimulation and Electric Stimulation on Peripheral Nerve Injury in Rat / 华中科技大学学报（医学）（英德文版）

The influence of pulsed magnetic stimulation (MS) on the sciatic nerve injury was investigated. Thirty rats were divided into three groups equally: MS group (A), electric stimulation (ES) group (B) and the control group (C). The MS and ES were applied immediately after the first 10 min of the sciatic nerve crush. Sciatic function index (SFI), toe spreading reflex (TSR), muscular weight and volume were measured after the experiment. The TSR of in the groups A and B occurred at 4th day while in the control group it occurs at 10th day. There was statistically significant difference in SFI between groups A and B (P<0.01). The weight and volume of the gastrocnemius muscle were statistically greater in the groups A and B than in the control group (P<0.01). The effect of MS was similar to that of ES. It was suggested that the application of MS immediately after the nerve injury might have an important clinical value as it can accelerate functional recovery and prevent or minimize muscle atrophy. The technique is easily to operate, non-invasion, painless and permits tolerance of high intensity output to be used.

A Comparative Study of the Effects of Magnetic Stimulation and Electric Stimulation on Peripheral Nerve Injury in Rat / 华中科技大学学报（医学）（英德文版）

The influence of pulsed magnetic stimulation (MS) on the sciatic nerve injury was investigated. Thirty rats were divided into three groups equally: MS group (A), electric stimulation (ES) group (B) and the control group (C). The MS and ES were applied immediately after the first 10 min of the sciatic nerve crush. Sciatic function index (SFI), toe spreading reflex (TSR), muscular weight and volume were measured after the experiment. The TSR of in the groups A and B occurred at 4th day while in the control group it occurs at 10th day. There was statistically significant difference in SFI between groups A and B (P<0.01). The weight and volume of the gastrocnemius muscle were statistically greater in the groups A and B than in the control group (P<0.01). The effect of MS was similar to that of ES. It was suggested that the application of MS immediately after the nerve injury might have an important clinical value as it can accelerate functional recovery and prevent or minimize muscle atrophy. The technique is easily to operate, non-invasion, painless and permits tolerance of high intensity output to be used.