Altered metabolic phenotype has been recognized as a hallmark of tumor cells for many years, but this aspect of the cancer phenotype has come into greater focus in recent years. NOS2 (inducible ...nitric oxide synthase of iNOS) has been implicated as a component in many aggressive tumor phenotypes, including melanoma, glioblastoma, and breast cancer. Nitric oxide has been well established as a modulator of cellular bioenergetics pathways, in many ways similar to the alteration of cellular metabolism observed in aggressive tumors. In this review we attempt to bring these concepts together with the general hypothesis that one function of NOS2 and NO in cancer is to modulate metabolic processes to facilitate increased tumor aggression. There are many mechanisms by which NO can modulate tumor metabolism, including direct inhibition of respiration, alterations in mitochondrial mass, oxidative inhibition of bioenergetic enzymes, and the stimulation of secondary signaling pathways. Here we review metabolic alterations in the context of cancer cells and discuss the role of NO as a potential mediator of these changes.
•We discuss metabolic alterations in cancer cells.•We discuss how metabolic alterations can alter cancer aggressiveness.•We summarize the chemical biology of nitric oxide.•We discuss how nitric oxide can alter cancer cell metabolism.•We link the effects of nitric oxide on bioenergetics and metabolism to aggressive cancer growth.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Most studies about the trends of acute myocardial infarction (AMI) were based on the data from Western countries. In recent years, little information is available from Asia since 2010. This study ...assessed the nationwide trends of AMI in Taiwan from 2009 to 2015. Using data from the Taiwan National Health Insurance Research Database, we identified 100,570 adult patients hospitalized for AMI from 2009 to 2015 and examined the temporal trends in the incidence of AMI. Overall, the age- and gender-adjusted incidence of AMI (per 100,000 persons) remained constant from 49.8 in 2009 to 50.7 in 2015. The incidence of AMI increased 30.3% and 29.4% in the young male and female populations (<55 years), whereas in other age groups, the incidence decreased or remained unchanged. The ratio of non-ST-segment elevation MI (NSTEMI) to STEMI incidence increased from 1.93 in 2009 to 2.47 in 2015. In young men (<55 years), a 49.8% increase in NSTEMI was observed. The prevalence of dyslipidemia increased significantly and it was the most common risk factor of AMI in young patients. Despite being increasingly used, percutaneous coronary intervention and secondary preventive medications, including dual antiplatelet therapy, angiotensin converting enzyme inhibitor/angiotensin receptor blocker, β blocker and statin, were less prescribed for NSTEMI compared with STEMI. The in-hospital mortality of STEMI continued to decrease from 2013 to 2015 (8.8% to 7.6%), but not in NSTEMI (13.3% to 13.5%). In conclusion, our study revealed a marked increase of NSTEMI in young Taiwanese male population in recent years. Despite the increased utilization of percutaneous coronary intervention and guideline-recommended medications, the overall in-hospital mortality of NSTEMI remained stagnating in Taiwan.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Fluorescent nanodiamond (FND) has excellent biocompatibility and photostability, making it well suited for long‐term labeling and tracking of cancer and stem cells. To prove the concept, the ...exocytosis of FND particles (size ≈100 nm) from three cell lines—HeLa cervical cancer cells, 3T3‐L1 pre‐adipocytes, and 489‐2.1 multipotent stromal cells—is studied in detail. FND labeling is performed by incubating the cells in a serum‐free medium containing 80 μg mL−1 FND for 4 h. No significant alteration in growth or proliferation of the FND‐labeled cells, including the multipotent stromal cells, is observed for up to 8 days. Flow cytometric analysis, in combination with parallel cell doubling‐time measurements, indicates that there is little (≈15% or less) excretion of the endocytosed FND particles after 6 days of labeling for both HeLa and 489‐2.1 cells, but exocytosis occurs more readily (up to 30%) for 3T3‐L1 preadipocytes. A comparative experiment with FND and the widely used dye, carboxyfluorescein diacetate succinimidyl ester, demonstrates that the nanoparticle platform is a promising alternate probe for long‐term cell labeling and tracking applications.
Fluorescent nanodiamond (FND) emits far‐red photoluminescence from built‐in nitrogen‐vacancy centers. The particles of 100 nm in size are readily taken up by cells with low exocytosis. This characteristic, together with the high biocompatibility and excellent photostability of this nanomaterial, makes FND a promising candidate for long‐term labeling and tracking of cancer and stem cells.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Impaired white adipose tissue (WAT) function has been recognized as a critical early event in obesity‐driven disorders, but high buoyancy, fragility, and heterogeneity of primary adipocytes have ...largely prevented their use in drug discovery efforts highlighting the need for human stem cell‐based approaches. Here, human stem cells are utilized to derive metabolically functional 3D adipose tissue (iADIPO) in a microphysiological system (MPS). Surprisingly, previously reported WAT differentiation approaches create insulin resistant WAT ill‐suited for type‐2 diabetes mellitus drug discovery. Using three independent insulin sensitivity assays, i.e., glucose and fatty acid uptake and suppression of lipolysis, as the functional readouts new differentiation conditions yielding hormonally responsive iADIPO are derived. Through concomitant optimization of an iADIPO‐MPS, it is abled to obtain WAT with more unilocular and significantly larger (≈40%) lipid droplets compared to iADIPO in 2D culture, increased insulin responsiveness of glucose uptake (≈2–3 fold), fatty acid uptake (≈3–6 fold), and ≈40% suppressing of stimulated lipolysis giving a dynamic range that is competent to current in vivo and ex vivo models, allowing to identify both insulin sensitizers and desensitizers.
This study uses human stem cells to derive metabolically functional 3D adipose tissue in a microphysiological system. Through concomitant optimization, the adipose system shows mostly unilocular and significantly larger lipid droplets, increased insulin responsiveness of glucose uptake, fatty acid uptake, and suppressing of stimulated lipolysis compared to 2D culture, providing a good dynamic range to identify insulin sensitizers and desensitizers.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
ABSTRACT
Ciliopathies represent a disease class characterized by a broad range of phenotypes including polycystic kidneys and skeletal anomalies. Ciliopathic skeletal phenotypes are among the most ...common and most difficult to treat due to a poor understanding of the pathological mechanisms leading to disease. Using an avian model (talpid2) for a human ciliopathy with both kidney and skeletal anomalies (orofaciodigital syndrome 14), we identified disruptions in the FGF23–PTH axis that resulted in reduced calcium uptake in the developing mandible and subsequent micrognathia. Although pharmacological intervention with the U.S. Food and Drug Administration (FDA)-approved pan-FGFR inhibitor AZD4547 alone rescued expression of the FGF target SPRY2, it did not significantly rescue micrognathia. In contrast, treatment with a cocktail of AZD4547 and teriparatide acetate, a PTH agonist and FDA-approved treatment for osteoporosis, resulted in molecular, cellular and phenotypic rescue of ciliopathic micrognathia in talpid2 mutants. Together, these data provide novel insight into pathological molecular mechanisms associated with ciliopathic skeletal phenotypes and a potential therapeutic strategy for a pleiotropic disease class with limited to no treatment options.
Recent studies have highlighted the fact that cancer cells have an altered metabolic phenotype, and this metabolic reprogramming is required to drive the biosynthesis pathways necessary for rapid ...replication and proliferation. Specifically, the importance of citric acid cycle-generated intermediates in the regulation of cancer cell proliferation has been recently appreciated. One function of MCTs (monocarboxylate transporters) is to transport the citric acid cycle substrate pyruvate across the plasma membrane and into mitochondria, and inhibition of MCTs has been proposed as a therapeutic strategy to target metabolic pathways in cancer. In the present paper, we examined the effect of different metabolic substrates (glucose and pyruvate) on mitochondrial function and proliferation in breast cancer cells. We demonstrated that cancer cells proliferate more rapidly in the presence of exogenous pyruvate when compared with lactate. Pyruvate supplementation fuelled mitochondrial oxygen consumption and the reserve respiratory capacity, and this increase in mitochondrial function correlated with proliferative potential. In addition, inhibition of cellular pyruvate uptake using the MCT inhibitor α-cyano-4-hydroxycinnamic acid impaired mitochondrial respiration and decreased cell growth. These data demonstrate the importance of mitochondrial metabolism in proliferative responses and highlight a novel mechanism of action for MCT inhibitors through suppression of pyruvate-fuelled mitochondrial respiration.
Ciliopathies represent a broad class of disorders that affect multiple organ systems. The craniofacial complex is among those most severely affected when primary cilia are not functional. We ...previously reported that loss of primary cilia on cranial neural crest cells, via a conditional knockout of the intraflagellar transport protein KIF3a, resulted in midfacial widening due to a gain of Hedgehog (HH) activity. Here, we examine the molecular mechanism of how a loss of primary cilia can produce facial phenotypes associated with a gain of HH function. We show that loss of intraflagellar transport proteins (KIF3a or IFT88) caused aberrant GLI processing such that the amount of GLI3FL and GLI2FL was increased, thus skewing the ratio of GLIFL to GLIR in favor of the FL isoform. Genetic addition of GLI3R partially rescued the ciliopathic midfacial widening. Interestingly, despite several previous studies suggesting midfacial development relies heavily on GLI3R activity, the conditional loss of GLI3 alone did not reproduce the ciliopathic phenotype. Only the combined loss of both GLI2 and GLI3 was able to phenocopy the ciliopathic midfacial appearance. Our findings suggest that ciliopathic facial phenotypes are generated via loss of both GLI3R and GLI2R and that this pathology occurs via a de-repression mechanism. Furthermore, these studies suggest a novel role for GLI2R in craniofacial development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: The aim of this study was to determine whether a combined increase of ≥ 10% in left ventricular ejection fraction (LVEF) and decrease in N-terminal pro-B-type natriuretic peptide (NT ...pro-BNP) to ＜ 1000 pg/mL after treatment with sacubitril/valsartan (SAC/VAL) in patients with heart failure with reduced ejection fraction (HFrEF) translated to better treatment outcomes in a real-world Taiwanese population. Methods: This is a single-center, prospective, non-randomized, observational study. Consecutive patients with HFrEF were treated with SAC/VAL and followed up for at least 12 months. The primary endpoint was a change in LVEF and reduction in NT pro-BNP at 12 months. The secondary outcomes were death and heart failure (HF) rehospitalization. Results: A total of 105 patients were analyzed after 12 months of SAC/VAL treatment. The mean age was 66.0 ± 11.6 years, and the mean LVEF and NT pro-BNP were 33.6 ± 6.7% and 4462.7± 5851.7 pg/mL respectively. The mean LVEF significantly increased to 50.5 ± 10.3% (p ＜ 0.001), while NT pro-BNP decreased to 1270.3 ± 2368.2 pg/mL (p = 0.001) at 12 months, with the greatest changes occurring in the first 3 months of treatment (p ＜ 0.001). Five patients died and 12were rehospitalized for HF. None of the patients in the responder group died compared to 5 deaths in the non-responder group (p = 0.039). Combined ≥ 10% LVEF increase and NT pro-BNP of ＜ 1000 pg/mL was an independent predictor of death and HF rehospitalization (p = 0.019). Conclusions: SAC/VAL treatment resulted in significant improvements in LVEF, reduced NT pro-BNP level, death and HF hospitalization. Taken separately, an NT pro-BNP level of ＜ 1000 pg/mL was a better predictor than ≥ 10% LVEF increase. Combining both variables predicted fewer deaths and HF rehospitalizations. Even with failure to reach the target dose, SAC/VAL still had significantly beneficial treatment outcomes in Taiwanese patients.
Primary cilia are nearly ubiquitous, cellular projections that function to transduce molecular signals during development. Loss of functional primary cilia has a particularly profound effect on the ...developing craniofacial complex, causing several anomalies including craniosynostosis, micrognathia, midfacial dysplasia, cleft lip/palate and oral/dental defects. Development of the craniofacial complex is an intricate process that requires interactions between several different tissues including neural crest cells, neuroectoderm and surface ectoderm. To understand the tissue-specific requirements for primary cilia during craniofacial development we conditionally deleted three separate intraflagellar transport genes, Kif3a, Ift88 and Ttc21b with three distinct drivers, Wnt1-Cre, Crect and AP2-Cre which drive recombination in neural crest, surface ectoderm alone, and neural crest, surface ectoderm and neuroectoderm, respectively. We found that tissue-specific conditional loss of ciliary genes with different functions produces profoundly different facial phenotypes. Furthermore, analysis of basic cellular behaviors in these mutants suggests that loss of primary cilia in a distinct tissue has unique effects on development of adjacent tissues. Together, these data suggest specific spatiotemporal roles for intraflagellar transport genes and the primary cilium during craniofacial development.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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