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Long noncoding RNAs (lncRNAs) influence the transcription of gene networks in many cell types, but their role in tumor‐associated macrophages (TAMs) is still largely unknown. We found that the lncRNA ADPGK‐AS1 was substantially upregulated in artificially induced M2‐like human macrophages, macrophages exposed to lung cancer cells in vitro, and TAMs from human lung cancer tissue. ADPGK‐AS1 is partly located within mitochondria and binds to the mitochondrial ribosomal protein MRPL35. Overexpression of ADPGK‐AS1 in macrophages upregulates the tricarboxylic acid cycle and promotes mitochondrial fission, suggesting a phenotypic switch toward an M2‐like, tumor‐promoting cytokine release profile. Macrophage‐specific knockdown of ADPGK‐AS1 induces a metabolic and phenotypic switch (as judged by cytokine profile and production of reactive oxygen species) to a pro‐inflammatory tumor‐suppressive M1‐like state, inhibiting lung tumor growth in vitro in tumor cell‐macrophage cocultures, ex vivo in human tumor precision‐cut lung slices, and in vivo in mice. Silencing ADPGK‐AS1 in TAMs may thus offer a novel therapeutic strategy for lung cancer. Synopsis: Whether gene network‐controlling long noncoding RNAs also affect tumor‐associated macrophages (TAMs) is unclear. Here, the lncRNA ADPGK‐AS1 is found to be upregulated in TAMs and to drive a tumor‐promoting M2‐like phenotype associated with lung cancer growth. RNA sequencing of the artificially induced M2‐phenotype of human macrophages shows upregulated lncRNA ADPGK‐AS1 expression.ADPGK‐AS1 is expressed/located in macrophage mitochondria and interacts with the mitochondrial ribosomal protein, MRPL35.MRPL35 is highly expressed in M2‐like TAMs and is associated with poor survival in lung cancer patients.Macrophage overexpression of ADPGK‐AS1 increases mitochondrial number and fission and stimulates the tricarboxylic acid cycle, suggesting an M2‐like phenotype.TAMs with high ADPGK‐AS1 expression promote lung tumor growth, while TAMs with little expression suppress it. [ABSTRACT FROM AUTHOR]

Lung cancer classification and treatment has been revolutionized by improving our understanding of driver mutations and the introduction of tumor microenvironment (TME)-associated immune checkpoint inhibitors. Despite the significant improvement of lung cancer patient survival in response to either oncogene-targeted therapy or anticancer immunotherapy, many patients show initial or acquired resistance to these new therapies. Recent advances in genome sequencing reveal that specific driver mutations favor the development of an immunosuppressive TME phenotype, which may result in unfavorable outcomes in lung cancer patients receiving immunotherapies. Clinical studies with follow-up after immunotherapy, assessing oncogenic driver mutations and the TME immune profile, not only reveal the underlying potential molecular mechanisms in the resistant lung cancer patients but also hold the key to better treatment choices and the future of personalized medicine. In this review, we discuss the crosstalk between cancer cell genomic features and the TME to reveal the impact of genetic alterations on the TME phenotype. We also provide insights into the regulatory role of cellular TME components in defining the genetic landscape of cancer cells during tumor development. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a disease with an inflammatory phenotype with increasing prevalence in the elderly. Expanded population of mutant blood cells carrying somatic mutations is termed clonal hematopoiesis of indeterminate potential (CHIP). The association between CHIP and COPD and its relevant effects on DNA methylation in aging are mainly unknown. Analyzing the deep-targeted amplicon sequencing from 125 COPD patients, we found enhanced incidence of CHIP mutations (~20%) with a predominance of DNMT3A CHIP-mediated hypomethylation of Phospholipase D Family Member 5 (PLD5), which in turn is positively correlated with increased levels of glycerol phosphocholine, pro-inflammatory cytokines, and deteriorating lung function. [ABSTRACT FROM AUTHOR]

High aerobic glycolysis, as one of the hallmarks of cancer cells, requires nicotinamide adenine dinucleotide (NAD+) as a vital co-factor, to guarantee the flow of glycolysis. Malate dehydrogenase (MDH), as an important enzyme in cancer metabolism, is a source of NAD+ additional to lactate dehydrogenase (LDH). The current study aimed to elucidate the kinetic parameters of MDH in human breast cancer and evaluate its supportive role in the glycolysis pathway. The Michaelis-Menten constant (Km) and maximum velocity (Vmax) of MDH were determined in the crude extracts of human breast tumors and healthy tissue samples, which were obtained directly from the operating theatre. To assess the potential role of MDH in supporting glycolysis, the MDH activity was measured when the LDH activity was inhibited by different concentrations of oxamate, an inhibitor of LDH in breast cancer cell lines. The Km of cancerous MDH (C-MDH) was the same as the healthy MDH, although the Vmax of C-MDH was higher relative to the healthy MDH. Notably, the MDH activity was increased in the MDA-MB-231 cell line, which was treated with the LDH inhibitor (oxamate), but not in the MCF-7 cell line (P<0.05). The higher tendency of C-MDH for NAD+ and malate generation in cancer cells is an effective approach for supporting glycolysis. Increasing MDH activity in the absence of LDH demonstrates the supportive role of MDH in glycolysis. Therefore, decreasing MDH activity and expression in a forward reaction may present as a valid molecular target to abolish its potential effect on tumor metabolism. [ABSTRACT FROM AUTHOR]

• Distinct nature and composition of lung epithelial cells across the respiratory track responsible for the heterogeneity in lung cancer types. • Oncogenic transformation in Ciliated cell leads to CMPT; Basal cell to SCC; Neuroendocrine cell to LCNEC, SCLC; ATII, Club, and BASC cell to ADC. • Comprehensive understanding of the cell of origin in lung cancer will assist in improving therapeutic management of lung cancer. Lung cancer is the leading cause of cancer death for both men and women and accounts for almost 18.4% of all deaths due to cancer worldwide, with the global incidence increasing by approximately 0.5% per year. Lung cancer is regarded as a devastating type of cancer owing to its high prevalence, reduction in the health-related quality of life, frequently delayed diagnosis, low response rate, high toxicity, and resistance to available therapeutic options. The highly heterogeneous nature of this cancer with a proximal-to-distal distribution throughout the respiratory tract dramatically affects its diagnostic and therapeutic management. The diverse composition and plasticity of lung epithelial cells across the respiratory tract are regarded as significant factors underlying lung cancer heterogeneity. Therefore, definitions of the cells of origin for different types of lung cancer are urgently needed to understand lung cancer biology and to achieve early diagnosis and develop cell-targeted therapies. In the present review, we will discuss the current understanding of the cellular and molecular alterations in distinct lung epithelial cells that result in each type of lung cancer. [ABSTRACT FROM AUTHOR]

Objective(s): Various beneficial effects of curcumin have been seen specially as anti-inflammator and antioxidant agent. However, until now no human studies have been done on curcumin's role in control of appetite. So, the present study was done to determine the effect of nanocurcumin on appetite in obese Non-Alcoholic Fatty Liver Disease (NAFLD) patients. Materials and Methods: This study was done in the central hospital of Oil Company, Tehran. According to the eligiblity criteria, 84 NAFLD patients with obesity were enrolled. The patients were devided randomly to 2 equal groups (nanocurcumin and placebo, 80 mg/day with meals, follow-up monthly for 3 months). In addition, lifestyle advises were presented. The general questionnaire, appetite sensations (using visual analogue scales [VAS]), weight and height at the beginning and the end of the study were recorded Results: The mean age and body mass index (BMI) were 41.8(±5.6), 30.67(±2.14) and 42.5(±6.2) yrs and 30.75(±2.35) kg/m² for nanocurcumin and placebo groups respectively. The baseline characteristics and dietary intakes were similar between patients, exception for energy, total fat, saturated fat, monounsaturated fatty acid, vitamins D, B1, B6, and folate (DFE). The appetite significantly reduced according to both unadjusted and adjusted analysis models. Conclusion: This study was the first assess of nanocurcumin's role in control of appetite among obese NAFLD patients. Overall results showed the nanocurcumin supplementation reduced appetite significantly. However, determining the potential role of curcumin in managing of NAFLD- and obesity-related conditions need further study. [ABSTRACT FROM AUTHOR]

Background: The relationship between dietary components and nonalcoholic fatty liver disease (NAFLD) needs to be further investigated. The potential health benefits of cardamom have been found in some studies. Cardamom showed beneficial effect on hepatomegaly, dyslipidemia, and fasting hyperglycemia in animals. However, some adverse effects of cardamom have been reported in animals. No previous human study had been conducted on the effects of cardamom in NAFLD. This study aims to determine the effects of green cardamom (Elettaria cardamomum) supplementation on blood glucose indices, lipids, inflammatory profiles, and liver function, especially by examining irisin, paraxonase-1 (PON1) and sirtuin-1 (Sirt1) in obese patients with NAFLD.Methods: This trial is to be conducted at the polyclinic of the National Iranian Oil Company (NIOC) Central Hospital, Tehran. Eighty obese patients with NAFLD will be selected according to the eligibility criteria. The NAFLD diagnosis method is ultrasonography. Patients will be randomly divided into two groups by a random-number table (cardamom and placebo groups, two 500-mg capsules, three times/day, taken with meals for 3 months, follow-up monthly). General characteristics, dietary intakes (at the beginning, middle, and end), and physical activity (at the beginning and end) will be assessed using a general, 24-h food recall, and short-form International Physical Activity Questionnaires (IPAQ), respectively. Lifestyle advice will be presented to both groups identically. At the beginning and the end, anthropometrics (weight, height, and waist circumference), blood pressure, extent of fatty liver, and blood biomarkers, including serum glucose indices (fasting blood sugar (FBS)) and insulin (FBI), homeostasis model assessment-insulin resistance (HOMA-IR), Quantitative Insulin Sensitivity Check Index (QUICKI)), lipids (triglyceride (TG), low-density lipoprotein-cholesterol (LDL-c), high-density lipoprotein-cholesterol (HDL-c), total cholesterol (TC)), inflammatory markers (highly sensitive C-reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)), liver enzymes (alanine transaminase (ALT), aspartate transaminase (AST)), irisin, PON1, and Sirt1, will be determined.Discussion: This trial would be the first to assess the effects of green cardamom on several blood factors, including glucose indices, lipids, inflammatory markers, liver enzymes, irisin, PON1, and Sirt1, and blood pressure and anthropometry in obese patients with NAFLD. Further study of cardamom's potential in improving NAFLD is suggested.Trial Registration: Iranian Registry of Clinical Trials (IRCT), ID number: IRCT2015121317254N4 . Registered on 27 December 2015. [ABSTRACT FROM AUTHOR]

Introduction: Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease worldwide. Flavonoids, a group of natural compounds, have garnered a great deal of attention in the management of NAFLD because of their profitable effects on glucose and lipid metabolism, inflammation, and oxidative stress which are the pivotal pathophysiological pathways in NAFLD. Naringenin is a citrus-derived flavonoid with a broad spectrum of potential biological effects including anti-inflammatory and antioxidant properties, which may exert protective effects against NAFLD. The present clinical trial aims to examine the efficacy of naringenin supplementation on plasma adiponectin and neurogulin-4 (NRG-4) concentrations, metabolic parameters, and liver function indices in overweight/obese patients with NAFLD.Methods and Analysis: This is a double-blind, randomized, placebo-controlled clinical study that will investigate the impacts of naringenin supplementation in overweight/obese patients with NAFLD. Liver ultrasonography will be applied to diagnose NAFLD. Forty-four eligible overweight/obese subjects with NAFLD will be selected and randomly assigned to receive naringenin capsules or identical placebo (each capsule contains 100 mg of naringenin or cellulose), twice daily for 4 weeks. Participants will be asked to remain on their usual diet and physical activity. Safety of naringenin supplementation was confirmed by the study pharmacist. The primary outcome of this study is changes in adiponectin circulating levels. The secondary outcomes include changes in NRG-4 levels, liver function indices, metabolic parameters, body weight, body mass index (BMI), waist circumference (WC), blood pressure, and hematological parameters. Statistical analysis will be conducted using the SPSS software (version 25), and P value less than 0.05 will be regarded as statistically significant.Discussion: We hypothesize that naringenin administration may be useful for treating NAFLD by modulating energy balance, glucose and lipid metabolism, oxidative stress, and inflammation through different mechanisms. The current trial will exhibit the effects of naringenin, whether negative or positive, on NAFLD status.Ethical Aspects: The current trial received approval from the Medical Ethics Committee of Tehran University of Medical Sciences, Tehran, Iran (IR.TUMS.MEDICNE.REC.1399.439).Trial Registration: Iranian Registry of Clinical Trials IRCT201311250155336N12 . Registered on 6 June 2020. [ABSTRACT FROM AUTHOR]

This article reviews the scientific reasons that support the intriguing vision of pulmonary hypertension (PH) as a disease with a cancer-like nature and to understand whether this point of view may have fruitful consequences for the overall management of PH. This review compares cancer and PH in view of Hanahan and Weinberg's principles (i.e., hallmarks of cancer) with an emphasis on hyperproliferative, metabolic, and immune/inflammatory aspects of the disease. In addition, this review provides a perspective on the role of transcription factors and chromatin and epigenetic aberrations, besides genetics, as "common driving mechanisms" of PH hallmarks and the foreseeable use of transcription factor/epigenome targeting as multitarget approach against the hallmarks of PH. Thus, recognition of the widespread applicability and analogy of these concepts will increasingly affect the development of new means of PH treatment. [ABSTRACT FROM AUTHOR]

Background: Since lifestyle changes are main therapies for non-alcoholic fatty liver disease (NAFLD), changing dietary components (nutritional or bioactive) may play a parallel important role. Few studies have assessed the effects of curcumin on NAFLD (mainly antioxidant and anti-inflammatory effects). We aimed to determine the effects of nano-curcumin (NC) on overweight/obese NAFLD patients by assessing glucose, lipids, inflammation, insulin resistance, and liver function indices, especially through nesfatin. Methods: This double-blind, randomized, placebo-controlled clinical trial was conducted in the Oil Company Central Hospital, Tehran. 84 overweight/obese patients with NAFLD diagnosed using ultrasonography were recruited according to the eligibility criteria (age 25–50 yrs., body mass index [BMI] 25–35 kg/m2). The patients were randomly divided into two equal NC (n = 42) and placebo (n = 42) groups. Interventions were two 40 mg capsules/day after meals for 3 months. Lifestyle changes were advised. A general questionnaire, a 24-h food recall (at the beginning, middle and end), and the short-form international physical activity questionnaire (at the beginning and end) were completed. Also, blood pressure, fatty liver degree, anthropometrics, fasting blood sugar (FBS) and insulin (FBI), glycated hemoglobin (HbA1c), homeostasis model assessment-insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), tumor necrosis factor-alpha (TNF-α), high sensitive c-reactive protein (hs-CRP), interleukin-6 (IL-6), liver transaminases, and nesfatin were determined at the beginning and end. Results: NC compared with placebo significantly increased HDL, QUICKI, and nesfatin and decreased fatty liver degree, liver transaminases, waist circumference (WC), FBS, FBI, HbA1c, TG, TC, LDL, HOMA-IR, TNF-α, hs-CRP, and IL-6 (P < 0.05). The mean changes in weight, BMI, body composition (BC), and blood pressure were not significant (P > 0.05). After adjustment for confounders, the changes were similar to the unadjusted model. Conclusion: NC supplementation in overweight/obese NAFLD patients improved glucose indices, lipids, inflammation, WC, nesfatin, liver transaminases, and fatty liver degree. Accordingly, the proposed mechanism for ameliorating NAFLD with NC was approved by the increased serum nesfatin and likely consequent improvements in inflammation, lipids, and glucose profile. Further trials of nano-curcumin's effects are suggested. Trial registration: Iranian Registry of Clinical Trials, IRCT2016071915536N3. Registered 2016-08-02. [ABSTRACT FROM AUTHOR]

Background: Aerobic glycolysis rate is higher in breast cancer tissues than adjacent normal tissues which providethe ATP, lactate and anabolic precursors required for tumourgenesis and metastasis. Lactate dehydrogenase (LDH) is a critical enzyme during aerobic glycolysis as it is typically responsible for the production of lactate and regeneration of NAD+, which allows for the continued functioning of glycolysis even in the absence of oxygen. LDH has been found to be highly expressed in breast tumors. Enzyme kinetic characteristics is related to environmentinvolving the enzyme, and tumor microenvironment has distinct features relative to adjacent normal tissues, thus we hypothesized that LDH should have different kinetic characteristics in breast tumors compared to normal breast tissues. Methods: LDH was partially purifiedfrom human breast tumors and normal tissues, which were obtained directly from operating room. TheMichaelis-Menten constant (Km), maximum velocity (Vmax), activation energy (Ea) and enzyme efficiency in breast tumors and normal tissueswere determined. Results: It was found that tumor LDH affinity in forward reaction was the same as normal LDH but Vmax of cancerous LDH was higher relative to normal LDH. In reverse reaction, affinity of tumor LDH for lactate and NAD+ was lower than normal LDH, also enzyme efficiency for lactate and NAD+ was higher in normal samples. The Ea of reverse reaction was higher in cancerous tissues. Conclusions: It was concluded that thelow LDH affinity for lactate and NAD+ is a valuable tool for preserving lactate by cancer cells. We also conclude that increasing of LDH affinity may be a valid molecular target to abolish lactate dependent tumor growth and kinetic characteristics of LDH could be a novel diagnostic parameter for human breast cancer. [ABSTRACT FROM AUTHOR]

Objective: Although several experimental models have suggested promising pharmacological effects of naringenin in the management of obesity and its related disorders, the effects of naringenin supplementation on cardiovascular disorders as one of the main complications of non-alcoholic fatty liver disease (NAFLD) are yet to be examined in human. Methods: In this double-blind placebocontrolled randomized clinical trial, 44 overweight/obese patients with NAFLD were equally allocated into either naringenin or placebo group for four weeks. Cardiovascular risk factors including atherogenic factors, hematological indices, obesity-related parameters, blood pressure, and heart rate were assessed pre-and post-intervention. Results: AIP value, serum non-HDL-C levels as well as total cholesterol/HDL-C, triglyceride/HDL-C, LDL-C/HDL-C, and non HDLC/HDL-C ratios were significantly reduced in the intervention group, compared to the placebo group post-intervention (P<0.05). Moreover, there was a significant reduction in BMI and visceral fat level in the intervention group when compared with the placebo group (P=0.001 and P=0.039, respectively). Furthermore, naringenin supplementation could marginally reduce systolic blood pressure (P=0.055). Mean corpuscular hemoglobin (MCH) increased significantly in the naringenin group compared to the placebo group at the endpoint (P=0.023). Supplementation with naringenin also resulted in marginally significant increase in mean corpuscular hemoglobin concentration (MCHC) when compared with the placebo group (P=0.050). There were no significant betweengroup differences for other study outcomes, postintervention. Conclusion: In conclusion, these data indicate that naringenin supplementation may be a promising treatment strategy for cardiovascular complications among NAFLD patients. However, further trials are warranted. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is the hepatic component of metabolic syndrome. Despite the beneficial health effects of cardamom on dyslipidemia, hepatomegaly, and fasting hyperglycemia, no previous human study has been conducted on the efficacy of cardamom in NAFLD. The aim of this study was to assess the effects of green cardamom (GC) on serum Sirtuin-1 (Sirt1), inflammatory factors, and liver enzymes in overweight or obese NAFLD patients. Methods: The recruitment of subjects was conducted at the polyclinic of the central hospital of National Iranian Oil Company (NIOC), Tehran. Eighty-seven patients who participated were divided randomly into two groups according to the ultrasonography and eligibility criteria as cardamom (n = 43) or placebo (n = 44). The intervention involves taking two 500 mg capsules three times per day with meals for 3 months. General characteristics, dietary intake and physical activity status, weight and height were determined. In addition, serum Sirt1, tumor necrosis factor-alpha (TNF-α), high sensitive c-reactive protein (hs-CRP), interleukin-6 (IL-6), alanine transaminase (ALT), and aspartate transaminase (AST) were measured. The degree of fatty liver was determined at beginning and end of the study. Results: In comparison with placebo, GC significantly increased Sirt1 and decreased hs-CRP, TNF-α, IL-6, ALT, and the degree of fatty liver (P < 0.05). The differences in weight, BMI, and AST were not significant (P > 0.05). Conclusion: GC supplementation could improve some biomarkers related to fatty liver including inflammation, ALT, and Sirt1 in overweight/obese NAFLD patients. Further trials on cardamom's potential are suggested. Trial registration: Iranian Registry of Clinical Trials, IRCT2015121317254N4. Registered 27/12/2015. [ABSTRACT FROM AUTHOR]