Transforming growth factor-β (TGF-β) is a prototypical tumour-suppressor cytokine with cytostatic and pro-apoptotic effects on most target cells; however, mechanisms of its pro-survival/antiapoptotic signalling in certain cell types and contexts remain unclear. In human lung fibroblasts, TGF-β1 is known to induce myofibroblast differentiation in association with the delayed activation of focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Here, we demonstrate that FAK and AKT are independently regulated by early activation of SMAD3 and p38 MAPK, respectively. Pharmacologic or genetic approaches that disrupt SMAD3 signalling block TGF-β1-induced activation of FAK, but not AKT; in contrast, disruption of early p38 MAPK signalling abrogates AKT activation, but does not alter FAK activation. TGF-β1 is able to activate AKT in cells expressing mutant FAK or in cells treated with an RGD-containing peptide that interferes with integrin signalling, inhibits FAK activation and induces anoikis (apoptosis induced by loss of adhesion signalling). TGF-β1 protects myofibroblasts from anoikis, in part, by activation of the PI3K-AKT pathway. Thus, TGF-β1 co-ordinately and independently activates the FAK and AKT protein kinase pathways to confer an anoikis-resistant phenotype to myofibroblasts. Activation of these prosurvival/anti-anoikis pathways in myofibroblasts likely contributes to essential roles of TGF-β1 in tissue fibrosis and tumour-promotion.
Thermogenesis is an important contributor to whole body energy expenditure and metabolic homeostasis. Although circulating factors that promote energy expenditure are known, endocrine molecules that suppress energy expenditure have remained largely elusive. Here we show that Tsukushi (TSK) is a liver-enriched secreted factor that is highly inducible in response to increased energy expenditure. Hepatic Tsk expression and plasma TSK levels are elevated in obesity. TSK deficiency increases sympathetic innervation and norepinephrine release in adipose tissue, leading to enhanced adrenergic signaling and thermogenesis, attenuation of brown fat whitening and protection from diet-induced obesity in mice. Our work reveals TSK as part of a negative feedback mechanism that gates thermogenic energy expenditure and highlights TSK as a potential target for therapeutic intervention in metabolic disease.
Alkylation chemotherapy has been a long-standing treatment protocol for human neoplasia. N-methyl-N ¶-nitro-N-nitrosoguanidine (MNNG) is a direct-acting monofunctional alkylator. Temozolomide is a clinical chemotherapeutic equivalent requiring metabolic breakdown to the alkylating agent. Both chemicals have similar mechanistic efficacy against DNA mismatch repair-proficient tumor cells that lack expression of methylguanine methyltransferase. Clinically relevant concentrations of both agents affect replicating cells only after the first cell cycle. This phenomenon has been attributed to replication fork arrest at unrepaired O 6 -methyldeoxyguanine lesions mispaired with thymine during the first replication cycle. Here, we show, by several different approaches, that MNNG-treated tumor cells do not arrest within the second cell cycle. Instead, the population slowly traverses through mitosis without cytokinesis into a third cell cycle. The peak of both ssDNA and dsDNA breaks occurs at the height of the long mitotic phase. The majority of the population emerges from mitosis as multinucleated cells that subsequently undergo cell death. However, a very small proportion of cells, <1:45,000, survive to form new colonies. Taken together, these results indicate that multinucleation within the third cell cycle, rather than replication fork arrest within the second cell cycle, is the primary trigger for cell death. Importantly, multinucleation and cell death are consistently avoided by a small percentage of the population that continues to divide. This information should prove clinically relevant for the future design of enhanced cancer chemotherapeutics. [Cancer Res 2009;69(15):6307-14]
Heavy metal is released from many industries into water. Before the industrial wastewater is discharged, the contamination level should be reduced to meet the recommended level as prescribed by the local laws of a country. They may be poisonous or cancerous in origin. Their presence does not only damage people, but also animals and vegetation because of their mobility, toxicity, and non-biodegradability into aquatic ecosystems. The review comprehensively discusses the progress made by various adsorbents such as natural materials, synthetic, agricultural, biopolymers, and commercial for extraction of the metal ions such as Ni2+, Cu2+, Pb2+, Cd2+, As2+ and Zn2+ along with their adsorption mechanisms. The adsorption isotherm indicates the relation between the amount adsorbed by the adsorbent and the concentration. The Freundlich isotherm explains the effective physical adsorption of the solute particle from the solution on the adsorbent and Langmuir isotherm gives an idea about the effect of various factors on the adsorption process. The adsorption kinetics data provide valuable insights into the reaction pathways, the mechanism of the sorption reaction, and solute uptake. The pseudo-first-order and pseudo-second-order models were applied to describe the sorption kinetics. The presented information can be used for the development of bio-based water treatment strategies.
BackgroundCurcuminoids of the spice turmeric and their enhanced derivatives have much potential as cancer treatments. They act on a wide variety of biological pathways, including those regulating cell division and circadian rhythms. It is known that circadian clocks can modify cancer therapy effectiveness, according to studies aimed at optimizing treatments based on the circadian cycle. It is therefore important to determine whether treatments with curcumin or similar chemotherapeutic agents are regulated by circadian timing. Similarly, it is important to characterize any effects of curcumin on timing abilities of the circadian clocks within cancer cells.MethodsWe examined the circadian clock’s impact on the timing of cell death and cell division in curcumin-treated C6 rat glioma cells through continuous video microscopy for several days. To evaluate its persistence and distribution in cancer cells, curcumin was localized within cell compartments by imaging its autofluorescence. Finally, HPLC and spectroscopy were used to determine the relative stabilities of the curcumin congeners demethoxycurcumin and bisdemethoxycurcumin that are present in turmeric.ResultsCircadian rhythms in cell death were observed in response to low (5 μM) curcumin, reaching a peak several hours before the peak in rhythmic expression of mPER2 protein, a major circadian clock component. These results revealed a sensitive phase of the circadian cycle that could be effectively targeted in patient therapies based on curcumin or its analogs. Curcumin fluorescence was observed in cell compartments at least 24 h after treatment, and the two congeners displayed greater stability than curcumin in cell culture medium.ConclusionsWe propose a mechanism whereby curcuminoids act in a sustained manner, over several days, despite their tendency to degrade rapidly in blood and other aqueous media. During cancer therapy, curcumin or its analogs should be delivered to tumor cells at the optimal phase for highest efficacy after identifying the circadian phase of the cancer cells. We confirmed the greater stability of the curcumin congeners, suggesting that they may produce sustained toxicity in cancer cells and should be considered for use in patient care.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2789-9) contains supplementary material, which is available to authorized users.
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