Toward Systems-Level Metabolic Analysis in Endocrine Disorders and Cancer

Metabolism is a dynamic network of biochemical reactions that support systemic homeostasis amidst changing nutritional, environmental, and physical activity factors. The circulatory system facilitates metabolite exchange among organs, while the endocrine system finely tunes metabolism through hormone release. Endocrine disorders like obesity, diabetes, and Cushing’s syndrome disrupt this balance, contributing to systemic inflammation and global health burdens. They accompany metabolic changes on multiple levels from molecular interactions to individual organs to the whole body. Understanding how metabolic fluxes relate to endocrine disorders illuminates the underlying dysregulation. Cancer is increasingly considered a systemic disorder because it not only affects cells in localized tumors but also the whole body, especially in metastasis. In tumorigenesis, cancer-specific mutations and nutrient availability in the tumor microenvironment reprogram cellular metabolism to meet increased energy and biosynthesis needs. Cancer cachexia results in metabolic changes to other organs like muscle, adipose tissue, and liver. This review explores the interplay between the endocrine system and systems-level metabolism in health and disease. We highlight metabolic fluxes in conditions like obesity, diabetes, Cushing’s syndrome, and cancers. Recent advances in metabolomics, fluxomics, and systems biology promise new insights into dynamic metabolism, offering potential biomarkers, therapeutic targets, and personalized medicine

Urinary chiro-and myo-inositol levels as a biological marker for type 2 diabetes mellitus

Abstract. Background: The aim of this study was to investigate the role of the urinary chiro-and myo-inositol levels in predicting type 2 diabetes mellitus (T2DM). Subjects and methods: A total of 212 normal controls and 101 type 2 diabetic patients were enrolled this study. The concentrations of urinary chiro-and myo-inositol were measured by high performance liquid chromatography/mass spectrometry. Results: The concentration of urinary chiro-inositol was significantly higher in the diabetic subjects (2.24 ± 5.18 ng/L) than those in the control group (0.38 ± 0.62 ng/L; p < 0.001). The urinary myo-inositol level of the diabetic subjects (36.95 ± 37.77 ng/L) was also significantly higher than that of the controls (8.17 ± 13.29 ng/L; p < 0.001). The urinary chiro-inositol multiplied by myo-inositol level of the diabetic subjects (148.10 ± 544.91) was significantly higher than in the controls (5.12 ± 24.15; p < 0.001). The area under the receiver operating characteristic curve for the urinary chiro-inositol multiplied by myo-inositol level to predict T2DM was 0.840 (confidence interval 0.789-0.891, p < 0.001). The cut-off value for the urinary chiro-inositol multiplied by myo-inositol level to predict T2DM was 2.20 (sensitivity 81.3%, specificity 70.3%). Conclusions: The urinary chiro-and myo-inositol concentrations were increased in the type 2 diabetic patients and the urinary chiro-times the myo-inositol was considered to be a sufficient marker in predicting T2DM

Inhibition of mTORC1 through ATF4-induced REDD1 and Sestrin2 expression by Metformin

Background Although the major anticancer effect of metformin involves AMPK-dependent or AMPK-independent mTORC1 inhibition, the mechanisms of action are still not fully understood. Methods To investigate the molecular mechanisms underlying the effect of metformin on the mTORC1 inhibition, MTT assay, RT-PCR, and western blot analysis were performed. Results Metformin induced the expression of ATF4, REDD1, and Sestrin2 concomitant with its inhibition of mTORC1 activity. Treatment with REDD1 or Sestrin2 siRNA reversed the mTORC1 inhibition induced by metformin, indicating that REDD1 and Sestrin2 are important for the inhibition of mTORC1 triggered by metformin treatment. Moreover, REDD1- and Sestrin2-mediated mTORC1 inhibition in response to metformin was independent of AMPK activation. Additionally, lapatinib enhances cell sensitivity to metformin, and knockdown of REDD1 and Sestrin2 decreased cell sensitivity to metformin and lapatinib. Conclusions ATF4-induced REDD1 and Sestrin2 expression in response to metformin plays an important role in mTORC1 inhibition independent of AMPK activation, and this signalling pathway could have therapeutic value.This research was supported by grants from the Korea Institute of Radiological and Medical Sciences (KIRAMS), funded by the Ministry of Science and ICT (MSIT), Republic of Korea (Nos. 50336–2021; 50531–2021; and 50544–2021)

6-Azauridine Induces Autophagy-Mediated Cell Death via a p53- and AMPK-Dependent Pathway

6-Azauridine (6-AZA), a pyrimidine nucleoside analogue, is known to exhibit both antitumor and antiviral activities. Although 6-AZA was discovered more than 60 years ago, the cellular effects of this compound are yet to be elucidated. Here, we report that 6-AZA regulates autophagy-mediated cell death in various human cancer cells, where 6-AZA treatment activates autophagic flux through the activation of lysosomal function. Furthermore, 6-AZA exhibited cytotoxicity in all cancer cells studied, although the mechanisms of action were diverse. In H460 cells, 6-AZA treatment induced apoptosis, and the extent of the latter could be reduced by treatment with chloroquine (CQ), a lysosomal inhibitor. However, 6-AZA treatment resulted in cell cycle arrest in H1299 cells, which could not be reversed by CQ. The cytotoxicity associated with 6-AZA treatment could be linearly correlated to the degree of autophagy-mediated cell death. In addition, we demonstrated that the cytotoxic effect of 6-AZA was dependent on AMPK and p53. These results collectively indicate that autophagy-mediated cell death triggered by 6-AZA contributes to its antitumor effect

Efficacy and Optimal Pressure of Continuous Positive Airway Pressure in Intensity-Modulated Radiotherapy for Locally Advanced Lung Cancer

We aimed to determine the optimal pressure of continuous positive airway pressure (CPAP) for radiotherapy (RT) through changes in the dosimetric parameters and lung volume according to pressure. Patients with locally advanced lung cancer, who underwent CPAP during computed tomography (CT) simulation, were included. The air pressure was raised in five steps of 4, 7, 10, 14, and 17 cmH2O and a CT scan was performed at the baseline and at each pressure step, accompanied by contouring and RT planning. Paired t- and Wilcoxon signed rank tests were used to compare the volumetric and dosimetric parameters according to pressure and interpressure. A total of 29 patients were selected, and 158 CT datasets were obtained. The lung volume increased significantly at all pressures (p 2O (p 2O with increasing pressure, and the Dmean and V5 of the heart decreased significantly from 14 cmH2O with increasing pressure. The V50 showed no significant differences at any pressure. We recommend the use of at least 7 cmH2O with 14 cmH2O as the optimal pressure to achieve the effect of heart preservation

Spontaneous sputum conversion and reversion in Mycobacterium abscessus complex lung disease.

BackgroundWe aim to investigate the rate of spontaneous sputum conversion and reversion in patients with Mycobacterium abscessus complex (MABC) lung disease.MethodsAmong 241 patients diagnosed with MABC lung disease between July 2012 and December 2018, 126 patients with persistent sputum positivity for ≥ 6 months without treatment were enrolled at a tertiary referral center in South Korea. Patients were subdivided into two groups, depending on whether or not treatment was initiated within 2 years of diagnosis. The rates of spontaneous sputum culture conversion and reversion was investigated in patients who did not receive treatment within 2 years.ResultsThe mean age of 126 patients was 62.9 years. During a mean follow-up duration of 3.2 years, 33 (26.2%) patients received treatment within 2 years of diagnosis. Among the remaining 93 patients not receiving treatment within 2 years, spontaneous sputum conversion occurred in 24 (25.8%) patients during a mean follow-up duration of 3.7 years after diagnosis. No significant differences were observed in time to conversion between Mycobacterium abscessus and Mycobacterium massiliense lung diseases. The Cox regression analysis showed that malignancy as a comorbid disease and the lower number of lobes involved were independent predictors of spontaneous sputum conversion. After spontaneous sputum conversion, reversion occurred in 27.8% patients at a median of 18.2 months after conversion.ConclusionsAmong patients with MABC lung disease who did not receive treatment for at least 2 years after diagnosis, approximately one-fourth experienced spontaneous conversion. However, not a few patients experienced reversion after spontaneous conversion

Tea Polyphenols EGCG and Theaflavin Inhibit the Activity of SARS-CoV-2 3CL-Protease In Vitro

COVID-19, a global pandemic, has caused over 750,000 deaths worldwide as of August 2020. A vaccine or remedy for SARS-CoV-2, the virus responsible for COVID-19, is necessary to slow down the spread and lethality of COVID-19. However, there is currently no effective treatment available against SARS-CoV-2. In this report, we demonstrated that EGCG and theaflavin, the main active ingredients of green tea and black tea, respectively, are potentially effective to inhibit SARS-CoV-2 activity. Coronaviruses require the 3CL-protease for the cleavage of its polyprotein to make individual proteins functional. EGCG and theaflavin showed inhibitory activity against the SARS-CoV-2 3CL-protease in a dose-dependent manner, and the half inhibitory concentration (IC50) was 7.58 μg/ml for EGCG and 8.44 μg/ml for theaflavin. In addition, we did not observe any cytotoxicity for either EGCG or theaflavin at the concentrations tested up to 40 μg/ml in HEK293T cells. These results suggest that upon further study, EGCG and theaflavin can be potentially useful to treat COVID-19

Anti-Inflammatory and Neuroprotective Mechanisms of GTS-21, an α7 Nicotinic Acetylcholine Receptor Agonist, in Neuroinflammation and Parkinson’s Disease Mouse Models

Neuroinflammation is crucial in the progression of neurodegenerative diseases. Thus, controlling neuroinflammation has been proposed as an important therapeutic strategy for neurodegenerative disease. In the present study, we examined the anti-inflammatory and neuroprotective effects of GTS-21, a selective α7 nicotinic acetylcholine receptor (α7 nAChR) agonist, in neuroinflammation and Parkinson’s disease (PD) mouse models. GTS-21 inhibited the expression of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and primary microglia. Further research revealed that GTS-21 has anti-inflammatory properties by inhibiting PI3K/Akt, NF-κB, and upregulating AMPK, Nrf2, CREB, and PPARγ signals. The effects of GTS-21 on these pro-/anti-inflammatory signaling molecules were reversed by treatment with an α7 nAChR antagonist, suggesting that the anti-inflammatory effects of GTS-21 are mediated through α7 nAChR activation. The anti-inflammatory and neuroprotective properties of GTS-21 were then confirmed in LPS-induced systemic inflammation and MPTP-induced PD model mice. In LPS-injected mouse brains, GTS-21 reduced microglial activation and production of proinflammatory markers. Furthermore, in the brains of MPTP-injected mice, GTS-21 restored locomotor activity and dopaminergic neuronal cell death while inhibiting microglial activation and pro-inflammatory gene expression. These findings suggest that GTS-21 has therapeutic potential in neuroinflammatory and neurodegenerative diseases such as PD