• drug therapy
• inflammation
• obesity
• oxidative stress
• pro-inflammatory
• radiation
• tumor microenvironment

• Animals
• Humans
• Male
• Adipokines/metabolism
• Adipose Tissue/metabolism
• Adipose Tissue/pathology
• Disease Progression
• Obesity/metabolism
• Obesity/pathology
• Obesity/complications
• Oxidative Stress
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/metabolism
• Tumor Microenvironment

• R01CA255618 National Institute of Health
• T32 GM153375 NIGMS NIH HHS
• R01 CA255618 NCI NIH HHS
• S10 OD023447 NIH HHS
• P30CA036727 National Institue of Health
• R01 CA178888 NCI NIH HHS
• P20GM104320 Nebraska Center for the Prevention of Obesity and Diseases

• And myeloid-derived suppressor cells
• Anti-Tumor immunity
• CD8+T cells
• Inflammation
• Natural killer cells
• Obesity

• Obesity/immunology
• Obesity/complications
• Obesity/pathology
• Obesity/metabolism
• Humans
• Inflammation/immunology
• Inflammation/pathology
• Neoplasms/immunology
• Neoplasms/pathology
• Animals
• Adipose Tissue/immunology
• Adipose Tissue/pathology
• Adipose Tissue/metabolism
• Tumor Microenvironment/immunology

• P20 GM103434 NIGMS NIH HHS
• P20 RR016477 NCRR NIH HHS
• U54 GM104942 NIGMS NIH HHS

• adipokines
• breast cancer
• obesity
• pathogenesis
• therapeutic resistance

• R01 CA231925 NCI NIH HHS

• docetaxel
• leptin
• triple-negative breast cancer
• tumor-associated macrophages

• Breeding programs
• Broiler and layer chicken lines
• Differentially expressed genes
• Gene ontology
• RNA-Seq
• Regulatory network
• Transcriptome

• Animals
• Female
• Gene Expression Profiling
• Chickens/genetics
• Computational Biology
• Transcriptome
• Cell Differentiation/genetics

• 158979/2018-4 Brazilian National Council for Scientific and Technological Development (CNPq)
• Finance Code 001 Coordination for the Improvement of Higher Education Personnel (CAPES, Brasília, Brazil)
• Finance Code 001 Coordination for the Improvement of Higher Education Personnel (CAPES, Brasília, Brazil)
• 01.15.02.003.05.00 Brazilian Agricultural Research Corporation - Embrapa
• 2014/08704-0, 2014-2017 São Paulo Research Foundation - FAPESP
• Foundation for Agrarian Studies Luiz de Queiroz (FEALQ)
• Brazilian Agricultural Research Corporation – Embrapa

• cancer
• cardiovascular diseases
• epigenetics
• obesity
• prevention
• therapy
• type 2 diseases

• National Natural Science Foundation of China
• Natural Science Foundation of Hunan Province
• Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province

• STAT3
• chaperone-mediated autophagy
• lipid nanoparticles
• protein degradation
• targeted delivery

• Humans
• Chaperone-Mediated Autophagy
• Autophagy
• Neoplasms/metabolism
• Proteolysis
• HSC70 Heat-Shock Proteins/metabolism
• Peptides/metabolism
• Signal Transduction
• Lysosomes/metabolism

• Obesity
• STAT3-mediated
• body mass index
• cancer
• clinical trials.
• epidemiology
• etiological mechanisms
• leptins

• Male
• Humans
• Leptin/metabolism
• Breast Neoplasms/epidemiology
• Breast Neoplasms/etiology
• Breast Neoplasms/metabolism
• Obesity/metabolism
• Adipokines
• Prostatic Neoplasms/complications
• Testosterone

• Antitumor
• Bioactive compounds
• Breast cancer
• Myrciaria jaboticaba

• bone marrow microenvironment
• cancer
• obesity
• targeted therapy

• Humans
• Bone Marrow/metabolism
• Neoplasms/etiology
• Neoplasms/metabolism
• Obesity/complications
• Obesity/metabolism
• Inflammation/metabolism
• Tumor Microenvironment

• R01 CA193362 NCI NIH HHS

• RNA sequencing
• early life adversity
• gene expression
• immune system
• signal transduction
• social anxiety disorder
• transcriptome

• Female
• Humans
• Animals
• Mice
• Germ-Line Mutation
• Leptin
• Mammary Glands, Human/pathology
• Phosphatidylinositol 3-Kinases
• BRCA2 Protein
• BRCA1 Protein/genetics
• Breast Neoplasms/pathology
• DNA Damage
• Epithelium/pathology
• Obesity
• Estrogens
• Mutation
• Tumor Microenvironment

• R35 CA197588 NCI NIH HHS
• R01 CA215797 NCI NIH HHS
• T32 GM007739 NIGMS NIH HHS
• F31 CA236306 NCI NIH HHS
• KL2 TR002385 NCATS NIH HHS

• DNA damage
• aneurysm
• cell death
• senescence-associated secretory phenotype
• telocytes
• telomere
• thoracic aorta

• Humans
• Heart Valve Diseases/metabolism
• Senescence-Associated Secretory Phenotype
• Aortic Aneurysm, Thoracic/genetics
• Aortic Aneurysm, Thoracic/complications
• Aortic Valve/metabolism
• Bicuspid Aortic Valve Disease

Leptin is a peptide hormone, mainly known for its role as a mediator of adipose tissue endocrine functions, such as appetite control and energy homeostasis. In addition, leptin signaling is involved in several physiological processes as modulation of innate and adaptive immune responses and regulation of sex hormone levels. When adipose tissue expands, an imbalance of adipokines secretion may occur and increasing leptin levels contribute to promoting a chronic inflammatory state, which is largely acknowledged as a hallmark of cancer. Indeed, upon binding its receptor (LEPR), leptin activates several oncogenic pathways, such as JAK/STAT, MAPK, and PI3K/AKT, and seems to affect cancer immune response by inducing a proinflammatory immune polarization and eventually enhancing T-cell exhaustion. In particular, obesity-associated hyperleptinemia has been related to breast cancer risk development, although the underlying mechanism is yet to be completely clarified and needs to be deemed in light of multiple variables, such as menopausal state and immune response. The aim of this review is to provide an overview of the potential role of leptin as a bridge between obesity and breast cancer and to establish the physio-pathological basis of the linkage between these major health concerns in order to identify appropriate and novel therapeutic strategies to adopt in daily clinical practice.

• Humans
• Female
• Leptin/metabolism
• Breast Neoplasms/metabolism
• Proto-Oncogene Proteins c-akt
• Phosphatidylinositol 3-Kinases
• Obesity/metabolism
• Adipokines/metabolism

• Drug-resistance
• G6PD
• Ovarian cancer
• STAT3
• Taxol

• breast cancer
• estrogen
• inflammation
• neoadjuvant therapy
• obesity
• oncogenic signaling
• preventive measures

• National Natural Science Foundation of China

Bisphenol A (BPA) is primarily used to produce polycarbonate plastics, such as water bottles. Exposure to BPA has been shown to increase the growth of breast cancer cells that depend on estrogen for growth due to its ability to mimic estrogen. More recent studies have suggested that BPA also affects the cellular and non-cellular components that compose tumor microenvironments (TMEs), namely the environment around a tumor, thereby potentially promoting breast cancer growth via altering the TME. The TME plays an essential role in cancer development and promotion. Therefore, it is crucial to understand the effect of BPA on breast TMEs to assess its role in the risk of breast cancer adequately. This review examines the potential effects of BPA on immune cells, fibroblasts, extracellular matrices, and adipocytes to highlight their roles in mediating the carcinogenic effect of BPA, and thereby proposes considerations for the risk assessment of BPA exposure.

BPA, a chemical used in the preparation of polycarbonate plastics, is an endocrine disruptor. Exposure to BPA has been suggested to be a risk factor for breast cancer because of its potential to induce estrogen receptor signaling in breast cancer cells. More recently, it has been recognized that BPA also binds to the G protein-coupled estrogen receptor and other nuclear receptors, in addition to estrogen receptors, and acts on immune cells, adipocytes, and fibroblasts, potentially modulating the TME. The TME significantly impacts the behavior of cancer cells. Therefore, understanding how BPA affects stromal components in breast cancer is imperative to adequately assess the association between exposure to BPA and the risk of breast cancer. This review examines the effects of BPA on stromal components of tumors to highlight their potential role in the carcinogenic effect of BPA. As a result, I propose considerations for the risk assessment of BPA exposure and studies needed to improve understanding of the TME-mediated, breast cancer-promoting effect of BPA.

• adipocytes
• bisphenol A
• breast cancer
• endocrine disruptors
• extracellular matrices
• fibroblasts
• immune cells
• tumor microenvironment

• LncRNAs
• M(6)A methylation
• Paraquat
• Parkinson’s disease
• ROS

• Adenosine/analogs & derivatives
• Adenosine/metabolism
• Animals
• Mice
• Oxidative Stress/genetics
• Paraquat/toxicity
• RNA, Long Noncoding/genetics
• RNA, Long Noncoding/metabolism
• Reactive Oxygen Species/metabolism

In vitro spermatogenesis appears to be a promising approach to restore the fertility of childhood cancer survivors. The rat model has proven to be challenging, since germ cell maturation is arrested in organotypic cultures. Here, we report that, despite a meiotic entry, abnormal synaptonemal complexes were found in spermatocytes, and in vitro matured rat prepubertal testicular tissues displayed an immature phenotype. RNA-sequencing analyses highlighted up to 600 differentially expressed genes between in vitro and in vivo conditions, including genes involved in blood-testis barrier (BTB) formation and steroidogenesis. BTB integrity, the expression of two steroidogenic enzymes, and androgen receptors were indeed altered in vitro. Moreover, most of the top 10 predicted upstream regulators of deregulated genes were involved in inflammatory processes or immune cell recruitment. However, none of the three anti-inflammatory molecules tested in this study promoted meiotic progression. By analysing for the first time in vitro matured rat prepubertal testicular tissues at the molecular level, we uncovered the deregulation of several genes and revealed that defective BTB function, altered steroidogenic pathway, and probably inflammation, could be at the origin of meiotic arrest.

• RNA-sequencing
• blood-testis barrier integrity
• in vitro spermatogenesis
• meiotic arrest
• rat prepubertal testis
• steroidogenesis

The seven mammalian FXYD proteins associate closely with α/β heterodimers of Na⁺/K⁺-ATPase. Most of them protect the β1 subunit against glutathionylation, an oxidative modification that destabilizes the heterodimer and inhibits Na⁺/K⁺-ATPase activity. A specific cysteine (Cys) residue of FXYD proteins is critical for such protection. One of the FXYD proteins, FXYD3, confers treatment resistance when overexpressed in cancer cells. We developed two FXYD3 peptide derivatives. FXYD3-pep CKCK retained the Cys residue that can undergo glutathionylation and that is critical for protecting the β1 subunit against glutathionylation. FXYD3-pep SKSK had all Cys residues mutated to Serine (Ser). The chemotherapeutic doxorubicin induces oxidative stress, and suppression of FXYD3 with siRNA in pancreatic- and breast cancer cells that strongly express FXYD3 increased doxorubicin-induced cytotoxicity. Exposing cells to FXYD3-pep SKSK decreased co-immunoprecipitation of FXYD3 with the α1 Na⁺/K⁺-ATPase subunit. FXYD3-pep SKSK reproduced the increase in doxorubicin-induced cytotoxicity seen after FXYD3 siRNA transfection in pancreatic- and breast cancer cells that overexpressed FXYD3, while FXYD3-pep CKCK boosted the native protein’s protection against doxorubicin. Neither peptide affected doxorubicin’s cytotoxicity on cells with no or low FXYD3 expression. Fluorescently labeled FXYD3-pep SKSK was detected in a perinuclear distribution in the cells overexpressing FXYD3, and plasmalemmal Na⁺/K⁺-ATPase turnover could not be implicated in the increased sensitivity to doxorubicin that FXYD3-pep SKSK caused. FXYD peptide derivatives allow rapid elimination or amplification of native FXYD protein function. Here, their effects implicate the Cys residue that is critical for countering β1 subunit glutathionylation in the augmentation of cytotoxicity with siRNA-induced downregulation of FXYD3.

Head of fish species, an exquisitely complex anatomical system, is important not only for studying fish evolution and development, but also for economic values. Currently, although some studies have been made on fish growth and body shapes, very limited information is available on the molecular mechanism of head development.

In this study, RNA sequencing (RNA–Seq) and small RNA sequencing (sRNA–Seq) technologies were used to conduct integrated analysis for the head of bighead carp at different development stages, including 1, 3, 5, 15 and 30 Dph (days post hatch). By RNA-Seq data, 26 pathways related to growth and bone formation were identified as the main physiological processes during early development. Coupling this to sRNA–Seq data, we picked out six key pathways that may be responsible for head development, namely ECM receptor interaction, TNF signaling pathway, osteoclast differentiation, PI3K–Akt signaling pathway, Neuroactive ligand–receptor interaction and Jak–STAT signaling pathway. Totally, 114 important candidate genes from the six pathways were obtained. Then we found the top 20 key genes according to the degree value by cytohubba, which regulated cell growth, skeletal formation and blood homeostasis, such as pik3ca, pik3r1, egfr, vegfa, igf1 and itga2b. Finally, we also acquired 19 key miRNAs playing multiple roles in the perfection of various tissues in the head (such as brain, eye and mouth) and mineralization of head bone system, such as let–7e, miR–142a–5p, miR–144–3p, miR–23a–3p and miR–223.

Results of this study will be informative for genetic mechanisms of head development and also provide potential candidate targets for the interaction regulation during early growth in bighead carp.

The online version contains supplementary material available at 10.1186/s12864-022-08387-x.

• Head development
• Hypophthalmichthys nobilis
• RNA–Seq
• sRNA–Seq

Intrauterine growth restriction (IUGR) is defined as a fetus that fails to achieve its genetically determined growth potential. The exact molecular mechanisms of placental insufficiency IUGR pathogenesis are a little known. Our goal was to identify key genes and gene co-expression modules related to placental insufficiency IUGR.

We used weighted gene co-expression network analysis (WGCNA) and protein-protein interaction (PPI) network analysis to examine the IUGR dataset GSE114691 from NCBI Gene Expression Omnibus. Core modules and hub nodes of the protein-protein interaction network were identified. A gene network was constructed and genes were classified by WGCNA into different modules. The validation of potential key genes was carried out using additional datasets (GSE12216 and GSE24129).

We identified in GSE114691 539 down regulated genes and 751 up regulated genes in placental tissues characteristic of placental insufficiency IUGR compared with non-IUGR, and defined 76 genes as hub nodes in the protein-protein interaction network. Genes in the key modules of the WGCNA network were most closely associated with placental insufficiency IUGR and significantly enriched in biological process such as cellular metabolic process and macromolecule metabolic process. We identified as key genes TGFB1, LEP, ENG, ITGA5, STAT5A, LYN, GATA3, FPR1, TGFB2, CEBPB, KLF4, FLT1, and PNPLA2. The RNA expression levels of ENG and LEP, as biomarkers, were validated.

A holistic gene expression profile of placental insufficiency IUGR has been generated and the key genes ENG and LEP has potential to serve as circulating diagnosis biomarkers and therapeutic targets for placental insufficiency IUGR.

The online version contains supplementary material available at 10.1186/s12884-022-04399-3.

• Endometrial cancer
• antagonist
• cancer agent
• gynecological cancer
• hydrophobic interaction
• molecular docking

• Drugs, Chinese Herbal/chemistry
• Drugs, Chinese Herbal/pharmacology
• Endometrial Neoplasms/drug therapy
• Female
• Humans
• Medicine, Chinese Traditional
• Molecular Docking Simulation
• Network Pharmacology
• Resveratrol/pharmacology

Breast cancer is the second most common cancer in women worldwide. The risk of developing breast cancer depends on various mechanisms, such as age, heredity, reproductive factors, physical inactivity, and obesity. Obesity increases the risk of breast cancer and worsens outcomes for breast cancer patients. The rate of obesity is increasing worldwide, stressing the need for awareness of the association between obesity and breast cancer. In this review, we outline the biomarkers—including cellular and soluble factors—in the breast, associated with obesity, that affect the risk of breast cancer and breast cancer prognosis. Through these biomarkers, we aim to better identify patients with obesity with a higher risk of breast cancer and an inferior prognosis.

Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer develops in an adipose-rich environment. During obesity, changes in the local environment in the breast occur which are associated with breast cancer. A shift towards a pro-inflammatory state is seen, resulting in altered levels of cytokines and immune cells. Levels of adipokines, such as leptin, adiponectin, and resistin, are changed. Aromatase activity rises, resulting in higher levels of potent estrogen in the breast. Lastly, remodeling of the extracellular matrix takes place. In this review, we address the current knowledge on the changes in the breast adipose tissue in obesity associated with breast cancer initiation and progression. We aim to identify obesity-associated biomarkers in the breast involved in the interplay between obesity and breast cancer. Hereby, we can improve identification of women with obesity with an increased risk of breast cancer and an impaired prognosis. Studies investigating mammary adipocytes and breast adipose tissue in women with obesity versus women without obesity are, however, sparse and further research is needed.

• biomarker
• breast cancer
• initiation
• microenvironment
• obesity
• overweight
• progression

Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of various cells, including breast cancer cells and immune cells. Increasing evidence points to an interaction between the tumor microenvironment, tumor cells, and the immune system. Leptin plays an important role in breast cancer tumorigenesis and may be implicated in activation of the immune system. While breast cancer cannot be considered an immunogenic cancer, the triple-negative subtype is an exception. Specific immune cells - tumor infiltrating lymphocytes - are involved in the immune response and act as predictive and prognostic factors in certain breast cancer subtypes. The aim of this article is to review the interaction between adipose tissue, through the expression of leptin and its receptor, and the adaptive immune system in breast cancer.

• adaptive immunity
• breast cancer
• leptin
• leptin receptor
• tumor-infiltrating lymphocytes (TILs)

• immunohistochemistry
• leptin
• methylation
• ovarian cancer
• prognosis
• survival
• tissue microarray

MicroRNAs (miRNAs) regulate osteogenic differentiation and influence osteoporosis (OP). The aim of this study was to determine the potential role of miR-874-3p in OP. The expression levels of miR-874-3p and leptin (LEP) in the femoral neck trabeculae of 35 patients with or without OP were measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The effects of miR-874-3p or LEP on the cell proliferation and alkaline phosphatase (ALP), runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), and osterix (OSX) levels were observed by upregulating miR-874-3p in human bone marrow mesenchymal stem cells (hBMSCs). Additionally, calcium deposition levels were evaluated using alizarin red staining (ARS). Molecular mechanisms of miR-874-3p and LEP underlying the osteogenic differentiation of hBMSCs were also evaluated using bioinformatics analysis, luciferase reporter assays, and RNA pull-down assays. The miR-874-3p levels were significantly lower in the femoral neck trabeculae of patients with OP than those of the control group, while the opposite was observed regarding the levels of LEP. Expression levels of miR-874-3p in hBMSCs were upregulated during osteogenic differentiation, while those of LEP were downregulated. Moreover, miR-874-3p upregulation promoted ALP, RUNX2, OCN, and OSX mRNA expression, cell proliferation, and calcium deposition in hBMSCs. LEP was found to be a target gene of miR-874-3p. Overexpression of LEP inhibited the expression of osteoblast markers and reversed the effect of osteogenic differentiation induced by the upregulation of miR-874-3p. In conclusion, miR-874-3p promoted the proliferation and differentiation of hBMSCs by downregulating the expression of LEP, thus inhibiting OP.

Abbreviations : miRNAs: microRNAs; OP: osteoporosis; hBMSCs: human Bone Marrow Mesenchymal stem cells; LEP: leptin; DEGs: differentially expressed genes

• LEP
• Osteoblast differentiation
• hBMSCs
• miR-874-3p
• osteoporosis

A hormonal imbalance may disrupt the rigorously monitored cellular microenvironment by hampering the natural homeostatic mechanisms. The most common example of such hormonal glitch could be seen in obesity where the uprise in adipokine levels is in virtue of the expanding bulk of adipose tissue. Such aberrant endocrine signaling disrupts the regulation of cellular fate, rendering the cells to live in a tumor supportive microenvironment. Previously, it was believed that the adipokines support cancer proliferation and metastasis with no direct involvement in neoplastic transformations and tumorigenesis. However, the recent studies have reported discrete mechanisms that establish the direct involvement of adipokine signaling in tumorigenesis. Moreover, the individual adipokine profile of the patients has never been considered in the prognosis and staging of the disease. Hence, the present manuscript has focused on the reported extensive mechanisms that culminate the basis of poor prognosis and diminished survival rate in obese cancer patients.

• adipokines
• cell cycle
• leptin signaling
• mesenchymal transition
• obesity derived cancers

Telocytes (TCs), a novel interstitial cell entity promoting tissue regeneration, have been described in various tissues. Their role in inter‐cellular signalling and tissue remodelling has been reported in almost all human tissues. This study hypothesizes that TC also contributes to tissue remodelling and regeneration of the human thoracic aorta (HTA). The understanding of tissue homeostasis and regenerative potential of the HTA is of high clinical interest as it plays a crucial role in pathogenesis from aortic dilatation to lethal dissection. Therefore, we obtained twenty‐five aortic specimens of heart donors during transplantation. The presence of TCs was detected in different layers of aortic tissue and characterized by immunofluorescence and transmission electron microscopy. Further, we cultivated and isolated TCs in highly differentiated form identified by positive staining for CD34 and c‐kit. Aortic‐derived TC was characterized by the expression of PDGFR‐α, PDGFR‐β, CD29/integrin β‐1 and αSMA and the stem cell markers Nanog and KLF‐4. Moreover, TC exosomes were isolated and characterized for soluble angiogenic factors by Western blot. CD34⁺/c‐kit⁺ TCs shed exosomes containing the soluble factors VEGF‐A, KLF‐4 and PDGF‐A. In summary, TC occurs in the aortic wall. Correspondingly, exosomes, derived from aortic TCs, contain vasculogenesis‐relevant proteins. Understanding the regulation of TC‐mediated aortic remodelling may be a crucial step towards designing strategies to promote aortic repair and prevent adverse remodelling.

• CD34
• KLF-4
• PDGF-A
• VEGF-A
• adventitia
• exosome
• human thoracic aorta
• telocytes
• transmission electron microscopy

• chemotherapy
• chronic inflammation
• colorectal cancer
• microenvironment
• obesity

• bioinformatics
• breast cancer
• leptin
• obesity

• Female
• Humans
• Middle Aged
• Biomarkers, Tumor/genetics
• Breast Neoplasms/genetics
• Breast Neoplasms/mortality
• Correlation of Data
• Gene Expression Regulation, Neoplastic
• Leptin/genetics
• Prognosis
• Survival Rate

Obese women with hormone receptor-positive breast cancer exhibit poor response to therapy and inferior outcomes. However, the underlying molecular mechanisms by which obesity/hyperleptinemia may reduce the efficacy of hormonal therapy remain elusive. Obese mice with hyperleptinemia exhibit increased tumor progression and respond poorly to tamoxifen compared to non-obese mice. Exogenous leptin abrogates tamoxifen-mediated growth inhibition and potentiates breast tumor growth even in the presence of tamoxifen. Mechanistically, leptin induces nuclear translocation of phosphorylated-ER and increases the expression of ER-responsive genes, while reducing tamoxifen-mediated gene repression by abrogating tamoxifen-induced recruitment of corepressors NCoR, SMRT, and Mi2 and potentiating coactivator binding. Furthermore, in silico analysis revealed that coactivator Med1 potentially associates with 48 (out of 74) obesity-signature genes. Interestingly, leptin upregulates Med1 expression by decreasing miR-205, and increases its functional activation via phosphorylation, which is mediated by activation of Her2 and EGFR. It is important to note that Med1 silencing abrogates the negative effects of leptin on tamoxifen efficacy. In addition, honokiol or adiponectin treatment effectively inhibits leptin-induced Med1 expression and improves tamoxifen efficacy in hyperleptinemic state. These studies uncover the mechanistic insights how obese/hyperleptinemic state may contribute to poor response to tamoxifen implicating leptin-miR205-Med1 and leptin-Her2-EGFR-Med1 axes, and present bioactive compound honokiol and adipocytokine adiponectin as agents that can block leptin’s negative effect on tamoxifen.

• bone marrow stromal cells
• adipocytes
• statin
• prostate cancer
• bone metastasis
• androgen depletion

• Male
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology
• Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
• Animals
• Adiposity/drug effects
• Prostatic Neoplasms, Castration-Resistant/pathology
• Prostatic Neoplasms, Castration-Resistant/drug therapy
• Prostatic Neoplasms, Castration-Resistant/metabolism
• Mice
• Disease Progression
• Bone Marrow/drug effects
• Bone Marrow/pathology
• Bone Marrow/metabolism
• Leptin/metabolism
• Cell Line, Tumor
• Tumor Microenvironment/drug effects
• Adipocytes/drug effects
• Adipocytes/metabolism
• Adipocytes/pathology
• Bone Neoplasms/drug therapy
• Bone Neoplasms/secondary
• Bone Neoplasms/metabolism
• Bone Neoplasms/pathology
• Prostatic Neoplasms/pathology
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/metabolism
• Receptors, Androgen/metabolism
• Receptors, Androgen/genetics
• Mesenchymal Stem Cells/drug effects
• Mesenchymal Stem Cells/metabolism

• P30 CA016672 NCI NIH HHS
• P50 CA140388 NCI NIH HHS
• R01 CA174798 NCI NIH HHS

• adipokines
• adiponectin
• androgen receptor
• androgens
• breast cancer
• leptin
• obesity

The discovery of the archetypal adipocytokine leptin and how it regulates energy homeostasis have represented breakthroughs in our understanding of the endocrine function of the adipose tissue and the biological determinants of human obesity. Investigations on leptin have also been instrumental in identifying physio-pathological connections between metabolic regulation and multiple immunological functions. For example, the description of the promoting activities of leptin on inflammation and cell proliferation have recognized the detrimental effects of leptin in connecting dysmetabolic conditions with cancer and with onset and/or progression of autoimmune disease. Here we review the multiple biological functions and complex framework of operations of leptin, discussing why and how the pleiotropic activities of this adipocytokine still pose major hurdles in the development of effective leptin-based therapeutic opportunities for different clinical conditions.

• breast cancer
• development
• estrogen
• growth
• obesity

• F31 CA236306 NCI NIH HHS
• R01 CA215797 NCI NIH HHS

Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.

• HCC
• NAFLD/NASH
• adipokines
• adiponectin
• adipose tissue
• leptin
• therapeutic targets

• Adipokines/metabolism
• Adiponectin/metabolism
• Adipose Tissue/metabolism
• Adipose Tissue/pathology
• Amino Acids, Branched-Chain/metabolism
• Animals
• Carcinoma, Hepatocellular/drug therapy
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Hepatocytes/metabolism
• Hepatocytes/pathology
• Humans
• Insulin Resistance/physiology
• Leptin/antagonists & inhibitors
• Leptin/metabolism
• Lipid Metabolism
• Liver/metabolism
• Liver/pathology
• Liver Neoplasms/drug therapy
• Liver Neoplasms/etiology
• Liver Neoplasms/pathology
• Obesity/complications
• Obesity/metabolism

• R01 CA230561 NCI NIH HHS
• 1R01CA230561-01A1 NCI NIH HHS
• R01 CA244993 NCI NIH HHS
• 1R01CA244993-01 NCI NIH HHS
• R01 CA240004 NCI NIH HHS
• 1R01DK107451-01A1 NIDDK NIH HHS
• R01 DK107451 NIDDK NIH HHS
• 1R01CA240004-01 NCI NIH HHS

Unlike other cancers, lung cancer risk is inversely associated with body mass index (BMI) with limited mechanistic understanding. Overweight and obese patients have been consistently found to respond better to therapy and show better survival. The adipose tissue—in addition to storing energy—secretes multiple unique cytokines or adipokines. Our in silico analysis reveals that a novel adipokine, omentin, is significantly and consistently downregulated in lung cancers compared to healthy lung tissue. Omentin was also found to be negatively correlated with important oncogenic transcription factors like ELK4, FOXA1 and FOXC1. Our study warrants further mechanistic studies on the role of omentin in lung cancers.

Lung cancer remains the second-most-common cancer worldwide and is associated with the highest number of cancer-related mortality. While tobacco smoking is the most important risk factor for lung cancer, many other lifestyles and occupational factors significantly contribute. Obesity is a growing global health concern and contributes to ~30% cancer-related mortality, but unlike other lifestyle diseases, lung cancer is negatively associated with obesity. We meta-analyzed multiple case-control studies confirming increased survival and better outcomes in overweight and obese lung cancer patients. Tumor heterogeneity analysis showed significant enrichment of adipocytes and preadipocytes in normal lungs compared to lung cancers. Interestingly, one of the understudied adipokine, omentin, was significantly and consistently lower in lung neoplasms compared to normal lungs. Omentin has been examined in relation to osteoarthritis, inflammatory bowel disease, cardiovascular diseases, diabetes, chronic liver disease, psoriasis and some other cancers. Aberrant expression of omentin has been reported in solid tumors; however, little is known about its role in lung cancer. We found omentin to be consistently downregulated in lung cancers, and it exhibited a negative correlation with important transcription factors FOXA1, EN1, FOXC1 and ELK4. We, therefore, suggest that omentin may serve as a prognostic factor in lung cancer and explain the “obesity paradox” in lung cancer.

• lung cancer
• obesity
• omentin

• associated-pathologies
• obesity
• pharmacotherapy
• polypharmacology

• behavior
• brain
• neuroendocrine
• nuclear receptor corepressor (NCOR)
• steroid receptor coactivator (SRC)

• Animals
• Behavior/physiology
• Brain/metabolism
• Brain/physiology
• Co-Repressor Proteins/metabolism
• Co-Repressor Proteins/physiology
• Humans
• Neurosecretory Systems/physiology
• Nuclear Receptor Coactivators/metabolism
• Nuclear Receptor Coactivators/physiology
• Transcriptional Activation