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Esophageal squamous cell carcinoma (ESCC) is a common subtype of esophageal cancer with high incidence. Surgery remains the main strategy for treatment of ESCC at early stage. However, the treatment outcome is unsatisfactory. Therefore, finding new therapeutics is of great importance. In the present study, we measured the level of NEDD4L, an ubiquitin protein ligase, in clinical samples and investigated the effects of NEDD4L on cell viability, cell cycle progression, and glutamine metabolism in TE14 cells determined by CCK-8 assay, flow cytometry and biochemical analysis, respectively. The results show that NEDD4L is significantly decreased in ESCC specimens, and its decreased expression is associated with a poor clinical outcome. Overexpression of NEDD4L significantly inhibits cell viability, cell cycle progression, and glutamine metabolism in TE14 cells. Mechanistic study indicates that NEDD4L regulates tumor progression through ubiquitination of c-Myc and modulation of glutamine metabolism. NEDD4L inhibits cell viability, cell cycle progression, and glutamine metabolism in ESCC by ubiquitination of c-Myc to decrease the expressions of GLS1 and SLC1A5. Our findings highlight the importance of NEDD4L/c-Myc signaling in ESCC.

The increased proliferation of vascular smooth muscle cells (VSMCs) contributes to the pathogenesis of vascular diseases. The intermediate conductance calcium‐activated potassium (IKCa) channel plays a critical role in VSMC proliferation by raising the intracellular calcium concentration ([Ca2+]i), but the underlying mechanism is still not unclear. Here we investigated the cooperation between IKCa and transient receptor potential canonical 1 (TRPC1) channels in mediating extracellular Ca2+ entry, which in turn activates downstream Ca2+ signalling in the regulation of VSMC proliferation using serum‐induced cell proliferation model. Serum‐induced cell proliferation was accompanied with up‐regulation of IKCa expression and an increase in [Ca2+]i. Serum‐induced cell proliferation and increase in [Ca2+]i were suppressed by IKCa inhibition with TRAM‐34 or IKCa knockdown. Serum‐induced cell proliferation was strongly reduced by the removal of extracellular Ca2+ with EGTA or intracellular Ca2+ with BAPTA‐AM and, additionally, by TRPC1 knockdown. Moreover, the increase in [Ca2+]i induced by serum or by IKCa activation with 1‐EBIO was attenuated by TRPC1 knockdown. Finally, serum induced ERK1/2 activation, which was attenuated by treatment with TRAM‐34 or BAPTA‐AM, as well as TRPC1 knockdown. Consistently, serum‐induced cell proliferation was suppressed by ERK1/2 inhibition with PD98059. Taken together, these results suggest that the IKCa and TRPC1 channels cooperate in mediating Ca2+ influx that activates the ERK1/2 pathway to promote cell proliferation, thus providing new mechanistic insights into VSMC proliferation. [ABSTRACT FROM AUTHOR]

Mechanical stimulation is an important factor regulating mesenchymal stem cell (MSC) functions such as proliferation. The Ca2+‐activated K+ channel, KCa3.1, is critically engaged in MSC proliferation but its role in mechanical regulation of MSC proliferation remains unknown. Here, we examined the KCa3.1 channel expression and its role in rat bone marrow‐derived MSC (BMSC) proliferation in response to mechanical stretch. Application of mechanical stretch stimulated BMSC proliferation via promoting cell cycle progression. Such mechanical stimulation up‐regulated the KCa3.1 channel expression and pharmacological or genetic inhibition of the KCa3.1 channel strongly suppressed stretch‐induced increase in cell proliferation and cell cycle progression. These results support that the KCa3.1 channel plays an important role in transducing mechanical forces to MSC proliferation. Our finding provides new mechanistic insights into how mechanical stimuli regulate MSC proliferation and also a viable bioengineering approach to improve MSC proliferation. [ABSTRACT FROM AUTHOR]

• Assembled sensor with hierarchically porous structure is engineered by locking the 3D crumpled conformation of GO nanosheets. • This sensor exhibits unparalleled ultrahigh-pressure response, exceptional sensitivities, and remarkable cycling stability. • The excellent performance empowers the sensor for real-time monitoring of pressure vessel operation and human activities. Based on microstructure engineering, graphene oxide (GO)-based piezoresistive pressure sensors have attracted increasing attention due to its amazing sensitivities, but the point-to-point contact mechanism among nanosheets compromises their high-pressure monitoring capabilities. Inspired by the multiple conformations of GO nanosheets, we utilize π-π conjugated interlayer interactions to lock the 3D crumpled conformation of nanosheets, resulting in controllable assembly into a flexible graphene membrane with hierarchically porous structures (PGM). These designed structures include microscale pores formed by the loose stacking of 3D crumpled nanosheets and nanoscale pores supported by densely packed crumples, reaching up to 100 nm in height. The PGM flexible sensor exhibits an unprecedented ultrahigh-pressure response of up to 2000 kPa, with high sensitivities of 1.1 and 0.7 kPa−1 in the pressure ranges of 1–600 kPa and 600–2000 kPa, respectively, and demonstrates over 10,000 cycles of high-pressure stability. Moreover, the PGM flexible sensors enable real-time monitoring of pressure vessel inflation/deflation processes and human activities such as finger, elbow, and knee bending, as well as walking, running, and jumping. This hierarchically porous structure provides a promising avenue for ultra-wide-range and ultra-high-pressure sensing devices, with potential applications in structural health monitoring, personal healthcare, and medical diagnostics. [ABSTRACT FROM AUTHOR]

To investigate the effect of tanshinone IIA sulfonate sodium combined with α-Lipoic acid on fasting blood sugar (FPG), 2h postprandial blood glucose (2hPG), total cholesterol (TG), triacylglycerol (TC) and therapeutic effect in patients with diabetes peripheral neuropathy (DPN). The control group (n=52) was treated with tanshinone IIA sodium sulfonate alone. The study group was treated with α-Lipoic acid and tanshinone IIA sodium sulfonate. The changes in blood glucose, blood lipid levels, oxidative stress indicators and the improvement of nerve function conduction of both two groups were compared. After treatment, study group's FPG, 2hPG, TG and TC were found to be lower than the control group (P<0.05). The levels of Super oxide dismutase (SOD) and nitric oxide (NO) in the study group were higher than those in the control group. The study group had lower Malondialdehyde (MDA) (P<0.05). The study group had higher nerve motor conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) (P<0.05). Tanshinone IIA sulfonate sodium combined with α-Lipoic acid can improve DPN patients' blood glucose and lipid levels, alleviate the oxidative stress reaction of the body, promote the recovery of nerve conduction function and enhance the therapeutic effect.