Increasing evidence suggests that tumor cells exhibit extreme plasticity in migration modes in order to adapt to microenvironments. However, the underlying mechanism for governing the migration mode switching is still unclear. Here, we revealed that epithelial tumor cells could develop a stable directional mode driven by hyperactivated ERK activity. This highly activated and dynamically changing ERK activity, called pERK transition, is crucial for inducing the switch from pauses state to directional movement and is also necessary for maintaining epithelial tumor cells in the directional mode. PERK transition integrated pERK surf, the dynamic and localized ERK activity at the leading edge. The sequential activation of RhoA and Rac1 by pERK transition played critical roles in generation of pERK surf activity through a movement feedback mechanism. PERK transition activity converted the orderly collective migration into the disordered dispersal movement, enhanced the invasiveness of epithelial tumor cells, and promoted their metastasis in immune-deficient mice. These findings revealed that the exquisite spatiotemporal organization of ERK activity orchestrates migration and invasion of tumor cells and provide evidence for the mechanism underlying migration mode switching in epithelial tumor cells.
Abstract Background: Cases of human monensin toxicosis are rare. Symptoms such as rhabdomyolysis and severe respiratory failure may occur after exposure to monensin. Case presentation: A 44-year-old male worker in a pharmaceutical factory complained of generalized muscle pain, muscular weakness, and dark brown colored urine. His creatine kinase (CK) value was as high as 69881IU/L. Aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) was significantly increased, suggesting a high possibility of rhabdomyolysis. During the hospitalization, the patient developed severe respiratory failure and was relieved after receiving bilevel positive airway pressure (BiPAP) ventilation and a large amount of fluids, methylprednisolone, sodium bicarbonate, and other treatments. His muscle biopsy showed that enzymatic activities of cytochrome C oxidase (COX) and succinate dehydrogenase（SDH）were partially absent. After treatment with hormones, urine alkalization, nutritional therapy of mitochondria, and fully rehydration, the patient's symptoms were relieved. Conclusions : Early attention and intervention are needed for rhabdomyolysis and severe respiratory failure caused by monensin.
Best known as the powerhouse of the cell, mitochondria play a crucial role in obesity and associated cardiovascular diseases. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial scaffold protein that regulates mitochondria function by promoting protein kinase A (PKA)-mediated phosphorylation of Dynamin-related protein 1 at Ser637 through recruitment of PKA to the outer mitochondrial membrane. However, the role of mitochondrial AKAP1 in the regulation of blood pressure and the development of hypertension is not known. Here, we used mice harboring the Akap1 gene deletion to investigate the importance of AKAP1 in obesity- and angiotensin II (Ang II)-induced hypertension. AKAP1 −/− mice and wild type (WT) littermates were maintained on a high fat high sucrose diet (HFHSD) for 12 weeks starting from 4 weeks of age. Interestingly, AKAP1 −/− mice fed HFHSD displayed significantly attenuated weight gain compared to control mice fed HFHSD (male: 39.5 ± 1.7 vs 47.3 ± 2.3 g, and female: 29.7 ± 1.3 vs 32.5 ± 1.5 g, p<0.05 for both). This was associated with decreased fat mass in AKAP1 −/− mice-fed HFHSD (male:16.2 ± 0.9 g and female: 8.7 ± 1.1 g) compared to controls (male: 21.2 ± 1.7 g and female: 13.9 ± 1.6 g, p<0.05 for both). Transmission electron microscope analysis of neuronal mitochondrial in the accurate nucleus of the hypothalamus showed that AKAP1 −/− mice fed HFHSD have remarkably reduced mitochondria size (0.14 ± 0.05 vs 0.20 ± 0.07 μm 2 , p<0.05) and mitochondria length (0.57 ± 0.10 vs 0.50 ± 0.10 μm, p<0.05) relative to controls. Next, using the radio-telemetry system, we found that blood pressure was lower in AKAP1 −/− male mice fed HFHSD compared to WT mice fed HFHSD (systolic: 118.2 ± 3.2 mmHg vs 126.7 ± 4.3 mmHg, p = 0.05, n= 5WT and 6 AKAP1 −/− ). Furthermore, infusion of Ang II (600ng/kg/min for 14 days) via osmotic minipumps in normal chow-fed male mice tended to evoke less increase in mean blood pressure in AKAP1 −/− mice compared to WT controls (35.2 ± 3.5 vs 45.7 ± 10.1 mmHg, n=3). Taken together, our findings point to the importance of mitochondrial AKAP1 for the development of hypertension induced by obesity and Ang II. Veterans Affairs NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
OBJECTIVE To study the effect of Supplemented Taoren Chengqi decoction (STCD) on the secretion of insulin and proliferation of NIT-1. METHOD The effect of STCD and the serum of rat after orally administrating of STCD on the secretion of insulin and proliferation of NIT-1 were studied. The proliferation of NIT-1 was measured by 3H-TdR incorporation and cell counting methods, while the secretion of insulin was measured from the cultured medium by the ultra sensitive rat insulin ELISIA kit. RESULT Both the STCD and the serum of rat after orally administrating of STCD significantly could increased the secretion of insulin and proliferation of NIT-1. CONCLUSION The treatment of the diabetic patients by STCD might be through with its improvement of secretion of insulin and proliferation on pancreatic beta-cell.
Mitochondria are best known as the powerhouse of the cell playing a critical role in energy metabolism with important implications in the development of obesity, a major cause of type 2 diabetes and hypertension. A-kinase anchoring protein 1 (AKAP1) is a mitochondrial scaffold protein that promote protein kinase A (PKA)-mediated phosphorylation of Drp1(Ser637) by increasing the local concentration of PKA at the outer mitochondrial membrane. However, the role of AKAP1 in the regulation of body weight, glucose homeostasis and blood pressure is not known. We used AKAP1 deficient mice to understand the physiological significance of this protein. Male and female AKAP1 -/- and AKAP1 +/- mice fed normal chow exhibit normal body weight relative to littermate controls. In contrast, AKAP1 -/- and AKAP1 +/- mice fed high fat high/sucrose diet (HFHSD) display attenuated weight gain compared to controls (male: 39.5 + 1.7 and 42.5 + 1.6 vs 47.3 + 2.3g, and female: 29.7 + 1.3 and 29.2 + 1.8 vs 32.5 + 1.5g). This was associated with significant decreased in fat mass in AKAP1 -/- (male:16.2 + 0.9g and female: 8.7 + 1.1g) and AKAP1 +/- (male:15.0 + 2.5g and female: 9.2 + 1.0g) mice compared to controls (male: 21.2 + 1.7g and female: 13.9 + 1.6g) whereas lean mass was not different between the three groups. Glucose tolerance test revealed that female AKAP1 -/- mice have improved glucose handling, and insulin tolerance test showed that insulin sensitivity is better in male AKAP1 -/- mice than controls. Notably, blood pressure was significantly lower in HFHSD-fed male AKAP1 -/- (systolic: 124.4 + 6 mmHg) and AKAP1 +/- (116.4 + 3 mmHg) mice vs control mice (146.4 + 5 mmHg). These findings demonstrated the importance of AKAP1 in the development of obesity and associated diabetes and hypertension. Our data also point to mitochondria function as a potential therapeutic target for treatment of common obesity and related diseases.
Primary cilia possess an array of receptors and signaling from this organelle is critical for neuronal function. BBS1 is an important component of a receptor trafficking complex (BBSome) that facilitates signaling in both primary cilia and plasma membrane. Humans harboring BBS1 mutations develop obesity and type 2 diabetes. Recent studies from our lab and others have shown that BBS1 deletion in hypothalamic neurons lead to obesity and glucose dysregulation. However, the role of hindbrain BBS1 in metabolic control is unknown. We hypothesized that brainstem BBS1 regulates metabolism through primary cilia function. As an initial step towards testing this hypothesis, we deleted BBS1 selectively from hindbrain neurons by crossing Phox2b Cre mice with BBS1 fl/fl mice and assessed metabolic parameters. Cre expression in hindbrain nuclei was validated by crossing these mice on a Cre-dependent tdTomato background. Both male and female Phox2b Cre /BBS1 fl/fl mice fed a chow diet exhibited reduced body weight (P<0.05) during adolescence (5-8 weeks old) but had normal weights in adulthood (9-20 weeks) relative to control littermates. In both sexes, hindbrain BBS1 deletion impaired glucose clearance at 20 weeks of age, independent of insulin sensitivity, as indicated by elevated area under the curve (AUC) in glucose (male AUC 31368±1986 vs. 25497±1834, female AUC 22643±1427 vs. 19304±800, P<0.05), but not insulin (male AUC 11505±905 vs. 10416±680, female AUC 8314±333 vs. 9098±525), tolerance test. Interestingly, male Phox2b Cre /BBS1 fl/fl mice maintained on an obesogenic (high fat-sucrose) diet displayed blunted weight gain during the first 14 weeks of age (P<0.05) which tended to be reduced relative to controls up to 20 weeks of age. Remarkably, NMR-based body composition revealed reduced lean (22.9±0.6 vs. 24.9±0.6 g, P<0.05), but not fat (23.8±1.4 vs. 23.7±1.2 g), mass in diet-induced obese adult Phox2b Cre /BBS1 fl/fl mice. These data suggest that hindbrain BBS1 is important for weight gain during adolescence and glucose handling in both male and female mice. Moreover, these results suggest that brainstem BBS1 negatively regulates weight gain induced by a high fat/sucrose diet. Since BBS1 has functions independent of cilia, we directly tested the role of hindbrain primary cilia on metabolic homeostasis. For this, we assessed how brainstem ablation of cilia through deletion of IFT88 protein (Phox2b Cre /IFT88 fl/fl mice) affect metabolic parameters. Male, but not female, Phox2b Cre /IFT88 fl/fl animals displayed reduced body weight during adolescence (P<0.05). Glucose tolerance test showed normal glucose regulation in adulthood (male AUC 28565±2007 vs. 28762±2321, female AUC 23820±836 vs.22601±175). Collectively, these data show a sex-dependent role for brainstem primary cilia in body weight gain during adolescence. Furthermore, our findings reveal that the critical role of hindbrain BBS1 in glucose homeostasis is independent of its function in primary cilia. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
To determine the ability of radiation to modulate kidney tubule epithelial cell expression of various molecules involved in regulating extracellular matrix accumulation (collagen types I and III, fibronectin, plasminogen activator-inhibitor 1 (PAI-1), TGF-beta and tissue inhibitor of metalloproteinases-2 (TIMP-2)) and degradation (plasminogen activators u-PA or t-PA, MMP-2 and MMP-9).NRK52E rat tubule epithelial cells were placed in serum-free medium 24 h prior to irradiation with single doses of 1.0-10.0 Gy 137Cs gamma-rays. After irradiation, cells were maintained in serum-free medium for up to 48 h.Irradiation of NRK52E cells was associated with significant dose-dependent increases in collagen I (p<0.05) and PAI-1 (p< or =0.002) mRNA. Collagen III mRNA levels also exhibited a dose-dependent increase; however, this increase failed to reach levels that were statistically significant. Fibronectin mRNA levels were unaltered following irradiation. Radiation also led to an isoform-specific alteration in TGF-beta expression; TGF-beta1 mRNA increased, TGF-beta3 mRNA decreased. The amount of TGF-beta protein secreted into the medium was unchanged following irradiation; however, there was a fivefold increase in the relative amount of active TGF-beta. Irradiation was also associated with differential changes in MMP expression: active MMP-2 levels increased, while MMP-9 levels were unaltered; PA secretion into the medium was unchanged following irradiation.Irradiation of rat kidney tubule epithelial cells leads to altered production of various molecules associated with extracellular matrix accumulation and degradation.
Hibifolin, the highest-content bioactive flavonoid of the flowers of Abelmoschus manihot, was incubated with human intestinal bacteria, and four metabolites (1–4) were obtained from the incubated solution by chromatographic methods. The structures of the four metabolites were elucidated as gossypetin 8-O-β-D-4′′-deoxy-Δ 4′′-glucuropyranoside (1), gossypetin (2), quercetin (3), and 8-methoxy-quercetin (4), respectively, on the basis of UV, NMR, and MS data. Metabolite 1 was obtained as a new compound with a specific β-D-4′′-deoxy-Δ 4′′-glucuropyranosyl moiety, which was formed through a unique and novel metabolic pathway that has not been reported previously.
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