Progress of cellular metabolism in renal cell carcinoma and its tumor microenvironment / 肿瘤研究与临床

Renal cell carcinoma is one of the common tumors in the urinary system. Despite the high incidence of renal cell carcinoma worldwide, progress has been made in cancer control and patients' survival profits from advances in laparoscopic technology and the application of targeted drugs. Recent studies have confirmed that the progression of renal cell carcinoma is related to cellular metabolism in the tumor microenvironment. Therefore, based on the existing surgical treatment and immunotherapy, exploring new metabolic therapies that target the metabolic pathway of tumor cells and interfere with the microenvironment of tumor cells will provide a unique treatment for renal cell carcinoma.

GDF15 negatively regulates chemosensitivity via TGFBR2-AKT pathway-dependent metabolism in esophageal squamous cell carcinoma / 医学前沿

Treating patients with esophageal squamous cell carcinoma (ESCC) is challenging due to the high chemoresistance. Growth differentiation factor 15 (GDF15) is crucial in the development of various types of tumors and negatively related to the prognosis of ESCC patients according to our previous research. In this study, the link between GDF15 and chemotherapy resistance in ESCC was further explored. The relationship between GDF15 and the chemotherapy response was investigated through in vitro and in vivo studies. ESCC patients with high levels of GDF15 expression showed an inferior chemotherapeutic response. GDF15 improved the tolerance of ESCC cell lines to low-dose cisplatin by regulating AKT phosphorylation via TGFBR2. Through an in vivo study, we further validated that the anti-GDF15 antibody improved the tumor inhibition effect of cisplatin. Metabolomics showed that GDF15 could alter cellular metabolism and enhance the expression of UGT1A. AKT and TGFBR2 inhibition resulted in the reversal of the GDF15-induced expression of UGT1A, indicating that TGFBR2-AKT pathway-dependent metabolic pathways were involved in the resistance of ESCC cells to cisplatin. The present investigation suggests that a high level of GDF15 expression leads to ESCC chemoresistance and that GDF15 can be targeted during chemotherapy, resulting in beneficial therapeutic outcomes.

Host metabolism dysregulation and cell tropism identification in human airway and alveolar organoids upon SARS-CoV-2 infection

The coronavirus disease 2019 (COVID-19) pandemic is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is spread primary via respiratory droplets and infects the lungs. Currently widely used cell lines and animals are unable to accurately mimic human physiological conditions because of the abnormal status of cell lines (transformed or cancer cells) and species differences between animals and humans. Organoids are stem cell-derived self-organized three-dimensional culture in vitro and model the physiological conditions of natural organs. Here we showed that SARS-CoV-2 infected and extensively replicated in human embryonic stem cells (hESCs)-derived lung organoids, including airway and alveolar organoids which covered the complete infection and spread route for SARS-CoV-2 within lungs. The infected cells were ciliated, club, and alveolar type 2 (AT2) cells, which were sequentially located from the proximal to the distal airway and terminal alveoli, respectively. Additionally, RNA-seq revealed early cell response to virus infection including an unexpected downregulation of the metabolic processes, especially lipid metabolism, in addition to the well-known upregulation of immune response. Further, Remdesivir and a human neutralizing antibody potently inhibited SARS-CoV-2 replication in lung organoids. Therefore, human lung organoids can serve as a pathophysiological model to investigate the underlying mechanism of SARS-CoV-2 infection and to discover and test therapeutic drugs for COVID-19.

Advances in research on the relationship between changes in cellular metabolism and lung diseases / 中华危重病急救医学

As the place for gas exchange, the lungs are metabolically active, and their energy consumption are essential for regulating common cell functions and maintaining the unique function of lung tissues to synthesize pulmonary surfactants. The metabolic pathways of pulmonary cells mainly include glycolysis, pentose phosphate pathway, and tricarboxylic acid cycle. Recent studies have found that changes in pulmonary cells metabolism are closely related to a variety of lung diseases. Herein, we review the main pathways of pulmonary cells metabolism and the relationship between changes in cell metabolism and the four lung diseases of chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), and pulmonary hypertension (PH), to find new ways to treat lung diseases.

Adenosine monophosphate-activated protein kinase in diabetic nephropathy

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease, and its pathogenesis is complex and has not yet been fully elucidated. Abnormal glucose and lipid metabolism is key to understanding the pathogenesis of DN, which can develop in both type 1 and type 2 diabetes. A hallmark of this disease is the accumulation of glucose and lipids in renal cells, resulting in oxidative and endoplasmic reticulum stress, intracellular hypoxia, and inflammation, eventually leading to glomerulosclerosis and interstitial fibrosis. There is a growing body of evidence demonstrating that dysregulation of 5' adenosine monophosphate-activated protein kinase (AMPK), an enzyme that plays a principal role in cell growth and cellular energy homeostasis, in relevant tissues is a key component of the development of metabolic syndrome and type 2 diabetes mellitus; thus, targeting this enzyme may ameliorate some pathologic features of this disease. AMPK regulates the coordination of anabolic processes, with its activation proven to improve glucose and lipid homeostasis in insulin-resistant animal models, as well as demonstrating mitochondrial biogenesis and antitumor activity. In this review, we discuss new findings regarding the role of AMPK in the pathogenesis of DN and offer suggestions for feasible clinical use and future studies of the role of AMPK activators in this disorder.

Intervention with drug resistance related to metabolism of cancer cells:advances in research / 中国药理学与毒理学杂志

The metabolic properties of cancer cells diverge significantly from those of normal cells. Energy production in cancer cells is abnormally dependent on aerobic glycolysis. In addition,cancer cells have other metabolic characteristics,such as increasing fatty acid synthesis and glutamine metabolism. Emerging evidences show that many key enzymes in dysregulated Warburg-like glucose metabolism,fatty acid synthesis and glutaminolysis are linked to drug resistance in cancer treatment. For example, lactate dehydrogenase A contributes to paclitaxel/trastuzuma resistance in breast cancer, fatty acid synthase is linked to docetaxel/trastuzumab/adriamycin resistance in breast cancer, and glutaminolysis is linked to cisplatin resistance in gastric cancer. Therefore,targeting cellular metabolism may improve the response to cancer therapeutics,and the combination of chemotherapeutic drugs with cellular metabolism inhibitors may overcome drug resistance in cancer therapy. This review discussed the relationship between dysregulated cellular metabolism and chemotherapy resistance, and the way in which targeting of metabolic enzymes can help overcome the resistance to cancer therapy or enhance the efficacy of common therapeutic agents.

Efeito da suplementação de ß-caroteno sintético no DNA e no metabolismo de células hepáticas de ratos recebendo etanol / Effect of synthetic ß-carotene supplementattion in the DNA and metabolism of hepatic cells of rats receiving ethanol

A suplementação de ß-caroteno em fumantes e alcoólatras pode promover efeitos indesejáveis, manifestando a característica pró-oxidante deste carotenóide. Sabendo que o fígado é principal órgão de armazenamento de vitamina A e ß-caroteno, e local de oxidação do etanol, o presente estudo buscou investigar no fígado de ratos, a influência da suplementação de ß-caroteno isolado ou associado ao etanol, sobre o metabolismo celular, danos no DNA, proliferação celular e função da proteína p53. Os ratos receberam dietas líquidas contendo ß-caroteno (24mg/L dieta) com (GAB) ou sem (GBC) a adição de etanol (36 porcento da calorias totais da dieta) e dieta líquida normal (isenta de ß-caroteno e etanol) (GDN), durante seis semanas de período experimental...

ß-carotene, when supplemented in smokers and alcohol drinkers may act as prooxidant, resulting in undesirable effects. The liver is the ß-carotene and vitamin A main storage organ and where ethanol oxidation takes place. This study investigated in rats' liver, the influence of ß-carotene supplementation either alone or associated with ethanol in cellular metabolism, DNA damage, cellular proliferation and p53 protein function. Three groups of 12 rats received liquid diets containing ß-carotene (24mg/L diet) with (BAG) or without (CBG) ethanol (36% of total energy intake). Control animals received liquid diet free of ethanol and ß-carotene (NDG). After 6 weeks the animals were sacrificed for hepatic and plasma concentrations of ß-carotene, retinol, palmitate retinyl, steatosis, GSH and TBARS, DNA damage, PCNA and p53 expression were evaluated in the liver. Differences were significant for hepatic (BAG: 2.49 ± 0.25; CBG: 4.22 ± 0.24; NDG: 2.83 ± 0.21 mg/g) and plasmatic (BAG: 1.42 ± 0.12; CBG: 0.69 ± 0.06; NDG: 2,37 ± 0,28mmol/L) retinol and hepatic palmitate retinyl (BAG: 40.87 ± 3.98; CBG: 83.72 ± 6.00; NDG: 46.33 ± 3.60), steatosis (BAG: 2.30 ± 0.21; CBG: 1.00 ± 0.00; NDG: 1.00 ± 0.00), DNA damage (BAG: 285.90 ± 15.20; CBG: 273.83 ± 13.39; NDG: 138.00 ±4.04 DNA damages/100 hepatocytes) and PCNA expression (BAG: 7.12 ± 1.46; CBG: 1.47 ± 0.27; NDG: 2.04 ± 0.31) among the groups (p<0.05). Hepatic and plasmatic concentrations of ßcarotene, TBARS and GSH were not statistically different. p53 staining was not detected in any group. This suggests that ß-carotene alone or with ethanol association does not influence lipid peroxidation and p53 expression. ß-carotene+ethanol caused metabolic alteration, steatosis, DNA damage and cellular proliferation in hepatocytes. Furthermore, supplementation with ß-carotene alone had genotoxic effects in the liver.