Neuronal loss of TRPM8 leads to obesity and glucose intolerance in male mice.

OBJECTIVE: Mice with global deletion of the transient receptor potential channel melastatin family member 8 (TRPM8) are obese, and treatment of diet-induced obese (DIO) mice with TRPM8 agonists decrease body weight. Whether TRPM8 signaling regulates energy metabolism via central or peripheral effects is unknow. Here we assessed the metabolic phenotype of mice with either Nestin Cre-mediated neuronal loss of TRPM8, or with deletion of TRPM8 in Advillin Cre positive sensory neurons of the peripheral nervous system (PNS). METHODS: Nestin Cre- and Advillin Cre-Trpm8 knock-out (KO) mice were metabolically phenotyped under chronic exposure to either chow or high-fat diet (HFD), followed by assessment of energy and glucose metabolism. RESULTS: At room temperature, chow-fed neuronal Trpm8 KO are obese and show decreased energy expenditure when acutely treated with the TRPM8 selective agonist icilin. But body weight of neuronal Trpm8 KO mice is indistinguishable from wildtype controls at thermoneutrality, or when mice are chronically exposed to HFD-feeding. In contrast to previous studies, we show that the TRPM8 agonist icilin has no direct effect on brown adipocytes, but that icilin stimulates energy expenditure, at least in part, via neuronal TRPM8 signaling. We further show that lack of TRPM8 in sensory neurons of the PNS does not lead to a metabolically relevant phenotype. CONCLUSIONS: Our data indicate that obesity in TRPM8-deficient mice is centrally mediated and likely originates from alterations in energy expenditure and/or thermal conductance, but does not depend on TRPM8 signaling in brown adipocytes or sensory neurons of the PVN.

Perspectives on metal induced crystallization of a-Si and a-Ge thin films.

In recent times, the metal induced crystallization (MIC) process in amorphous semiconductors (a-Si and a-Ge) has been extensively investigated by many researchers due to potential applications of crystalline semiconductors in high-density data storage devices, flat panel displays, and high performance solar cells. In this context, we have presented a review on different schemes of MIC in metal/a-Si and metal/a-Ge bilayer films (with stacking change) on various substrates under different annealing conditions. The parameters, which limit crystallization of a-Si and a-Ge have been analyzed and discussed extensively keeping in mind their applications in solar cells and flat panel displays. The MIC of a-Si and a-Ge films under ion beam irradiation has also been discussed in detail. At the end, some suggestions to overcome the limitations of the MIC process in producing better crystalline semiconductors have been proposed. We believe that this review article will inspire readers to perform a thorough investigation on various aspects of MIC for further development of high efficiency solar cells and high quality flat panel displays.

An assessment on crystallization phenomena of Si in Al/a-Si thin films via thermal annealing and ion irradiation.

In the present study, crystallization of amorphous-Si (a-Si) in Al/a-Si bilayer thin films under thermal annealing and ion irradiation has been investigated for future solar energy materials applications. In particular, the effect of thickness ratio (e.g. in Al : a-Si, the ratio of the Al and a-Si layer thickness) and temperature during irradiation on crystallization of the Si films has been explored for the first time. Two sets of samples with thickness ratio 1 : 1 (set-A: 50 nm Al/50 nm a-Si) and thickness ratio 1 : 3 (set-B: 50 nm Al/150 nm a-Si) have been prepared on thermally oxidized Si-substrates. In one experiment, thermal annealing of the as-prepared sample (of both the sets) has been done at different temperatures of 100 °C, 200 °C, 300 °C, 400 °C, and 500 °C. Significant crystallization was found to initiate at 200 °C with the help of thermal annealing, which increased further by increasing the temperature. In another experiment, ion irradiation on both sets of samples has been carried out at 100 °C and 200 °C using 100 MeV Ni7+ ions with fluences of 1 × 1012 ions per cm2, 5 × 1012 ions per cm2, 1 × 1013 ions per cm2, and 5 × 1013 ions per cm2. Significant crystallization of Si was observed at a remarkably low temperature of 100 °C under ion irradiation. The samples irradiated at 100 °C show better crystallization than the samples irradiated at 200 °C. The maximum crystallization of a-Si has been observed at a fluence of 1 × 1012 ions per cm2, which was found to decrease with increasing ion fluence at both temperatures (i.e. 100 °C & 200 °C). The crystallization of a-Si is found to be better for set-B samples as compared to set-A samples at all the fluences and irradiation temperatures. The present work is aimed at developing the understanding of the crystallization process, which may have significant advantages for designing crystalline layers at lower temperature using appropriate masks for irradiation at the desired location. The detailed mechanisms behind all the above observations are discussed in this paper.

CCN5/WISP-2 restores ER-∝ in normal and neoplastic breast cells and sensitizes triple negative breast cancer cells to tamoxifen.

CCN5/WISP-2 is an anti-invasive molecule and prevents breast cancer (BC) progression. However, it is not well understood how CCN5 prevents invasive phenotypes of BC cells. CCN5 protein expression is detected in estrogen receptor-α (ER-α) -positive normal breast epithelial cells as well as BC cells, which are weakly invasive and rarely metastasize depending on the functional status of ER-α. A unique molecular relation between CCN5 and ER-α has been established as the components of the same signaling pathway that coordinate some essential signals associated with the proliferation as well as delaying the disease progression from a non-invasive to invasive phenotypes. Given the importance of this connection, we determined the role of CCN5 in regulation of ER-α in different cellular settings and their functional relationship. In a genetically engineered mouse model, induced expression of CCN5 in the mammary ductal epithelial cells by doxycycline promotes ER-α expression. Similarly, CCN5 regulates ER-α expression and activity in normal and neoplastic breast cells, as documented in various in vitro settings such as mouse mammary gland culture, human mammary epithelial cell and different BC cell cultures in the presence or absence of human recombinant CCN5 (hrCCN5) protein. Mechanistically, at least in the BC cells, CCN5 is sufficient to induce ER-α expression at the transcription level via interacting with integrins-α6ß1 and suppressing Akt followed by activation of FOXO3a. Moreover, in vitro and in vivo functional assays indicate that CCN5 treatment promotes response to tamoxifen in triple-negative BC (TNBC) cells possibly via restoring ER-α. Collectively, these studies implicates that the combination treatments of CCN5 (via activation of CCN5 or hrCCN5 treatment) and tamoxifen as potential therapies for TNBC.

CCN5/WISP-2 promotes growth arrest of triple-negative breast cancer cells through accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation.

The matricellular protein CCN5/WISP-2 represents a promising target in triple-negative breast cancer (TNBC) because treatment or induced activation of CCN5 in TNBC cells promotes cell growth arrest at the G0/G1 phase, reduces cell proliferation and delays tumor growth in the xenograft model. Our studies found that the p27(Kip1) tumor suppressor protein is upregulated and relocalized to the nucleus from cytoplasm by CCN5 in these cells and that these two events (upregulation and relocalization of p27(Kip1)) are critical for CCN5-induced growth inhibition of TNBC cells. In the absence of CCN5, p27(Kip1) resides mostly in the cytoplasm, which is associated with the aggressive nature of cancer cells. Mechanistically, CCN5 inhibits Skp2 expression, which seems to stabilize the p27(Kip1) protein in these cells. On the other hand, CCN5 also recruits FOXO3a to mediate the transcriptional regulation of p27(Kip1). The recruitment of FOXO3a is achieved by the induction of its expression and activity through shifting from cytoplasm to the nucleus. Our data indicate that CCN5 blocks PI3K/AKT signaling to dephosphorylate at S318, S253 and Thr32 in FOXO3a for nuclear relocalization and activation of FOXO3a. Moreover, inhibition of α6ß1 receptors diminishes CCN5 action on p27(Kip1) in TNBC cells. Collectively, these data suggest that CCN5 effectively inhibits TNBC growth through the accumulation and trafficking of p27(Kip1) via Skp2 and FOXO3a regulation, and thus, activation of CCN5 may have the therapeutic potential to kill TNBC.