• MASLD
• OEA
• hypercholesterolemia
• obesity
• oleoylethanolamide

• 24-75-00072 Russian Science Foundation

• Adiponectin/metabolism
• Liver Transplantation
• Animals
• Resistin/metabolism
• Rats, Sprague-Dawley
• Rats
• Tissue Donors
• Male
• Fatty Liver/metabolism
• Fatty Liver/pathology
• Brain Death
• Liver/metabolism
• Liver/pathology

• adipokines
• metabolic syndrome
• osteoarthritis

• National Natural Science Foundation of China

• adipocyte
• endoplasmic reticulum stress
• inflammation
• insulin resistance
• lipolysis
• obesity

• National Natural Science Foundation of China

• Adipose-derived stem cells
• HDAC11
• Obesity

• Animals
• Mice
• Adipocytes, Brown/metabolism
• Adipose Tissue, Brown/metabolism
• Adipose Tissue, White
• Diabetes Mellitus, Type 2/metabolism
• Diet, High-Fat
• Epigenesis, Genetic
• Histone Deacetylases/metabolism
• Mice, Inbred C57BL
• Mice, Obese
• Neoplasms/metabolism
• Obesity/metabolism
• Stem Cells/metabolism

• AdipoRs
• adiponectin
• diabetes
• pancreatic islets
• single-cell RNAseq

• ATF2
• Bone marrow mesenchymal stem cells
• Enoxaparin sodium
• Femoral defect regeneration
• Femoral defect repair
• Osteogenic differentiation
• Polymethylmethacrylate bone cement
• miR-335-5p

• Animals
• Rats
• Polymethyl Methacrylate/pharmacology
• Bone Cements/pharmacology
• Core Binding Factor Alpha 1 Subunit
• Osteogenesis/genetics
• Calcinosis
• MicroRNAs

• 226Z7720G Science and Technology Development Fund Projects of Central Government Guiding Local Government
• The projects in Xinjiang Assisted by Hebei
• 2019 Hebei Provincial Government Funded Outstanding Talents Project

• COVID-19
• SARS-CoV-2
• adipocytokines
• adiponectin
• leptin

• Humans
• COVID-19
• Adipokines
• SARS-CoV-2
• Pandemics
• Cytokines
• Inflammation
• Obesity/complications

• D.R. n. 834 del 30/09/2022 Bando Giovani Ricercatori Università della Campania L. Vanvitelli

The global burden of diabetic foot ulcers (DFUs) is a significant public health concern, affecting millions of people worldwide. These wounds cause considerable suffering and have a high economic cost. Therefore, there is a need for effective strategies to prevent and treat DFUs. One promising therapeutic approach is the use of adiponectin, a hormone primarily produced and secreted by adipose tissue. Adiponectin has demonstrated anti-inflammatory and anti-atherogenic properties, and researchers have suggested its potential therapeutic applications in the treatment of DFUs. Studies have indicated that adiponectin can inhibit the production of pro-inflammatory cytokines, increase the production of vascular endothelial growth factor, a key mediator of angiogenesis, and inhibit the activation of the intrinsic apoptotic pathway. Additionally, adiponectin has been found to possess antioxidant properties and impact glucose metabolism, the immune system, extracellular matrix remodeling, and nerve function. The objective of this review is to summarize the current state of research on the potential role of adiponectin in the treatment of DFUs and to identify areas where further research is needed in order to fully understand the effects of adiponectin on DFUs and to establish its safety and efficacy as a treatment for DFUs in the clinical setting. This will provide a deeper understanding of the underlying mechanisms of DFUs that can aid in the development of new and more effective treatment strategies.

• Diabetic foot ulcer
• Adiponectin
• Anti-inflammatory
• Adipose tissue
• Antioxidants
• Wound healing

• antidiabetic drug
• diabetes complications
• insulin resistance
• pathology
• therapeutic target
• β cell dysfunction

• National Natural Science Foundation of China
• West China Hospital, Sichuan University

• Humans
• Microphysiological Systems
• Adipose Tissue
• Obesity/pathology
• Extracellular Matrix/metabolism
• Hydrogels/metabolism
• Inflammation/pathology

• ceRNA network
• dairy cow
• heat stress
• hypothalamic-pituitary-mammary gland axis
• lncRNA

• ER stress
• WAT
• autophagy
• fatty acids
• obesity

• Adipoq
• CRISPR-Cas9
• Upstream open reading frame
• adipocyte
• adiponectin
• eukaryotic initiation factor 2alpha
• integrated stress response
• translation

• Animals
• Mice
• Adiponectin/genetics
• Open Reading Frames
• Adipocytes
• 3T3-L1 Cells
• Biological Transport
• Mammals

• R01 DK124203 NIDDK NIH HHS
• R01 AG067146 NIA NIH HHS
• R01 NS124547 NINDS NIH HHS
• R01 CA198103 NCI NIH HHS
• R01 DK132362 NIDDK NIH HHS
• R01 NS124581 NINDS NIH HHS
• 19POST34380725 American Heart Association-American Stroke Association
• R01 DK113171 NIDDK NIH HHS

Osteoarthritis (OA) is a widespread and most common joint disease which leads to social cost increasing accompany with aging population. Surgery is often the final treatment option. The major progression of OA includes cartilage degradation caused by chondrocytes metabolism imbalance. So, the molecular mechanisms of action in chondrocytes may provide insights into treatment methods for OA. Adiponectin is an adipokine with many biological functions in the cell metabolism. Numerous studies have illustrated that adiponectin has diverse biological effects, such as inhibition of cell apoptosis. It regulates various functions in different organs, including muscle, adipose tissue, brain, and bone, and regulates skeletal homeostasis. However, the relationship between adiponectin and cell death in the progression of OA needs further investigation. We elaborate the structure and function and the effect of adiponectin and state the correlation and intersection between adiponectin, autophagy, inflammation, and OA. From the perspective of oxidative stress, apoptosis, pyroptosis, and autophagy, we discuss the possible association between adiponectin, chondrocyte metabolism, and inflammatory factor efforts in OA. What’s more, we summarize the possible treatment methods, including the use of adiponectin as a drug target, and highlight the potential future mechanistic research. In this review, we summarize the molecular pathways and mechanisms of action of adiponectin in chondrocyte inflammation and death and the pathogenesis of OA. We also review the research on adiponectin as a target for treating OA. These studies provide a novel perspective to explore more effective treatment options considering the complex interrelationship between inflammation and metabolism in OA.

• National Natural Science Foundation of China

Adiponectin (APN) is an adipokine concerned in the regulation of glucose metabolism, insulin sensitivity and fatty acid oxidation. APN plays a critical role in viral infections by regulating the immune response through its anti-inflammatory/pro-inflammatory axis. Reduction of APN may augment the severity of viral infections because APN inhibits immune cells’ response via suppression of inflammatory signaling pathways and stimulation of adenosine monophosphate protein kinase (AMPK). Moreover, APN inhibits the stimulation of nuclear factor kappa B (NF-κB) and regulates the release of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) and interleukins (IL-18, IL-6). In COVID-19, abnormalities of the fatty tissue due to oxidative stress (OS) and hyperinflammation may inhibit the production and release of APN. APN has lung-protective effect and can prevent SARS-CoV-2-induced acute lung injury (ALI) through the amelioration of endoplasmic reticulum (ER) stress, endothelial dysfunction (ED) and stimulation of peroxisome proliferator-activated receptor-alpha (PPAR-α). It has been established that there is a potential correlation between inflammatory signal transduction pathways and APN that contributes to the development of SARS-CoV-2 infections. Deregulation of these molecular pathways affects the expression of APN and vice versa. In addition, the reduction of APN effect in SARS-CoV-2 infection could be a potential cause of the exacerbation of pro-inflammatory effects which are associated with the disease severity. In this context, exploratory, developmental, and extensive prospective studies are necessary.

Lung adenocarcinoma (LUAD) is the most challenging neoplasm to treat in clinical practice. Ankyrin repeat domain 49 protein (ANKRD49) is highly expressed in several carcinomas; however, its pattern of expression and role in LUAD are not known. Tissue microarrays, immunohistochemistry, χ² test, Spearman correlation analysis, Kaplan–Meier, log‐rank test, and Cox's proportional hazard model were used to analyse the clinical cases. The effect of ANKRD49 on the LUAD was investigated using CCK‐8, clonal formation, would healing, transwell assays, and nude mice experiment. Expressions of ANKRD49 and its associated downstream protein molecules were verified by real‐time PCR, Western blot, immunohistochemistry, and/or immunofluorescence analyses. ANKRD49 expression was highly elevated in LUAD. The survival rate and Cox's modelling analysis indicated that there may be an independent prognostic indicator for LUAD patients. We also found that ANKRD49 promoted the invasion and migration in both in in vitro and in vivo assays, through upregulating matrix metalloproteinase (MMP)‐2 and MMP‐9 activities via the P38/ATF‐2 signalling pathway Our findings suggest that ANKRD49 is a latent biomarker for evaluating LUAD prognosis and promotes the metastasis of A549 cells via upregulation of MMP‐2 and MMP‐9 in a P38/ATF‐2 pathway‐dependent manner.

• ANKRD49
• ATF-2
• P38/MAPK
• lung adenocarcinoma
• matrix metalloproteinases

The proline rich mitotic checkpoint control factor (PRCC) is involved in the splicing process of pre-mRNA. This study aims to elucidate PRCC molecular function, regulatory mechanism and diagnostic value in hepatocellular carcinoma (HCC).

The tissue microarray and serum samples from HCC patients were used to investigate the clinical value of PRCC. The biological function and molecular mechanism of PRCC were demonstrated by cell biology, biochemical and animal experiments. The relationship between PRCC and intratumoral heterogeneity (ITH) was analyzed by bioinformatics.

PRCC was highly expressed in HCC tissues and related to the poor prognosis of HCC patients, its contents were elevated in the preoperative sera of HCC patients. PRCC exhibited high application potential as a substitute or adjuvant of alpha-fetoprotein (AFP) for clinical diagnosis of HCC. It had no significant effect on the proliferation of cancer cells, but could inhibit spheroid formation and metastasis of HCC cells in vitro and in vivo. The high ectopic expression of PRCC made cancer cells insensitive to DNA damage, and enhanced the heterogeneity of HCC cells by inhibiting the JNK/ATM/ATR/ATF2 axis. The HCC patients with high PRCC expression had high ITH, which corresponded to a short overall survival in patients.

PRCC has high application potential as a substitute or adjuvant of AFP for clinical diagnosis of HCC. The high ectopic expression of PRCC not only caused HCC cells to resist to cell death induced by DNA damage, but also endowed cancer cells with numerous DNA mutations to become increasingly heterogeneous, finally leading to a poor prognosis in HCC patients. These data suggested PRCC could be a promising therapeutic target in HCC patients.

The online version contains supplementary material available at 10.1186/s13578-021-00699-x.

• DNA damage
• Hepatocellular carcinoma
• JNK signaling pathway
• PRCC
• Prognosis

Collagen XV (Col XV), a basement membrane (BM) component, is highly expressed in adipose tissue, and studies have found that Col XV is related to extracellular matrix (ECM) remodeling involving in adipose tissue fibrosis and inflammation. Furthermore, the ECM is essential for maintaining normal development and tissue function. In this study, we found that Col XV is related to the endoplasmic reticulum stress (ERS) and inflammation of adipose tissue. Moreover, we found that overexpression of Col XV in mice could cause macrophages to infiltrate white adipose tissue (iWAT). At the same time, the expression of the ERS sensor IRE1α (Inositol-Requiring Enzyme-1α) was significantly up-regulated, which intensified the inflammation of adipose tissue and the polarization of M1 macrophages after the overexpression of Col XV in mice. In addition, after overexpression of Col XV, the intracellular Ca²⁺ concentration was significantly increased. Using focal adhesion kinase (FAK) inhibitor PF573228, we found that PF-573228 inhibited the phosphorylation of FAK and reversed the upward trend of Col XV-induced protein expression levels of IRE1α, C/EBP-homologous protein (CHOP), and 78 kDa glucose-regulated protein (GRP78). After treatment with IRE1α inhibitor STF-083010, the results showed that the expression of adipocyte inflammation-related genes interleukin 6 (IL-6) and tumor necrosis factor α (TNFα) significantly were decreased. Our results demonstrate that Col XV induces ER-stress in adipocytes by activating the Integrinβ1/FAK pathway and disrupting the intracellular Ca²⁺ balance. At the same time, Col XV regulates the inflammation induced by ER stress in adipocytes by promoting IRE1α/XBP1 (X-Box binding protein 1) signaling. Our study provides new ideas for solving the problems of adipose tissue metabolism disorders caused by abnormal accumulation of ECM.

• Col XV
• ERS
• FAK
• adipose tissue
• inflammation

It has been more than three decades since peroxisome proliferator-activated receptors (PPARs) were first discovered. Many investigations have revealed the central regulators of PPARs in lipid and glucose homeostasis in response to different nutrient conditions. PPARs have attracted much attention due to their ability to improve metabolic syndromes, and they have also been proposed as classical drug targets for the treatment of hyperlipidemia and type 2 diabetes (T2D) mellitus. In parallel, adipose tissue is known to play a unique role in the pathogenesis of insulin resistance and metabolic syndromes due to its ability to “safely” store lipids and secrete cytokines that regulate whole-body metabolism. Adipose tissue relies on a complex and subtle network of transcription factors to maintain its normal physiological function, by coordinating various molecular events, among which PPARs play distinctive and indispensable roles in adipocyte differentiation, lipid metabolism, adipokine secretion, and insulin sensitivity. In this review, we discuss the characteristics of PPARs with special emphasis on the roles of the different isotypes in adipocyte biology.

• PPAR
• adipose tissue
• browning
• lipid metabolism

• Adipocytes
• Apoptosis
• FTO
• UPRmt
• m6A

• ER stress
• Obesity
• adipose tissue
• autophagy
• inflammation
• microRNA

Atherosclerotic plaque vulnerability and rupture increase the risk of acute coronary syndromes. Advanced lesion macrophage apoptosis plays important role in the rupture of atherosclerotic plaque, and endoplasmic reticulum stress (ERS) has been proved to be a key mechanism of macrophage apoptosis. Intermedin (IMD) is a regulator of ERS. Here, we investigated whether IMD enhances atherosclerotic plaque stability by inhibiting ERS-CHOP-mediated apoptosis and subsequent inflammasome in macrophages. We studied the effects of IMD on features of plaque vulnerability in hyperlipemia apolipoprotein E-deficient (ApoE^−/−) mice. Six-week IMD_1-53 infusion significantly reduced atherosclerotic lesion size. Of note, IMD_1-53 lowered lesion macrophage content and necrotic core size and increased fibrous cap thickness and vascular smooth muscle cells (VSMCs) content thus reducing overall plaque vulnerability. Immunohistochemical analysis indicated that IMD_1-53 administration prevented ERS activation in aortic lesions of ApoE^−/− mice, which was further confirmed in oxidized low-density lipoproteins (ox-LDL) induced macrophages. Similar to IMD, taurine (Tau), a non-selective ERS inhibitor significantly reduced atherosclerotic lesion size and plaque vulnerability. Moreover, C/EBP-homologous protein (CHOP), a pro-apoptosis transcription factor involved in ERS, was significantly increased in advanced lesion macrophages, and deficiency of CHOP stabilized atherosclerotic plaques in AopE^−/− mice. IMD_1-53 decreased CHOP level and apoptosis in vivo and in macrophages treated with ox-LDL. In addition, IMD_1-53 infusion ameliorated NLRP3 inflammasome and subsequent proinflammatory cytokines in vivo and in vitro. IMD may attenuate the progression of atherosclerotic lesions and plaque vulnerability by inhibiting ERS-CHOP-mediated macrophage apoptosis, and subsequent NLRP3 triggered inflammation. The inhibitory effect of IMD on ERS-induced macrophages apoptosis was probably mediated by blocking CHOP activation.

• ER stress
• Inherited lipodystrophies
• Muscle dysfunctions

• ER stress
• diabetes
• eNOS
• endothelial dysfunction
• icariin

• AMP-Activated Protein Kinases/metabolism
• Animals
• Diabetes Mellitus, Experimental/physiopathology
• Diabetes Mellitus, Type 1/physiopathology
• Endoplasmic Reticulum Stress/drug effects
• Endothelium, Vascular/drug effects
• Endothelium, Vascular/physiopathology
• Flavonoids/pharmacology
• Human Umbilical Vein Endothelial Cells/drug effects
• Human Umbilical Vein Endothelial Cells/metabolism
• Humans
• PPAR alpha/metabolism
• Rats, Sprague-Dawley
• Signal Transduction/drug effects
• Sirtuin 1/metabolism
• Rats

Successful attenuation of endoplasmic reticulum (ER) stress signaling has a beneficial outcome in in vitro embryonal improvement. We evaluated the effect of adiponectin during in vitro culture in porcine embryos derived from parthenogenetic activation and somatic cell nuclear transfer (SCNT). We found that 15 and 30 μg/mL adiponectin treatment significantly improved cleavage rates, blastocyst formation rates, and total cell number (TCN) of blastocysts derived from parthenogenetic activation and reduced the expression levels of XBP1. In SCNT embryos, the cleavage rate, blastocyst formation rate, and TCN of blastocysts were significantly improved by 15 μg/mL adiponectin treatment compared to the control. In addition, the 15 μg/mL adiponectin treatment reduced the levels of XBP1 expression and ER stress-related genes, increased expression levels of pluripotency-related genes, and decreased apoptosis-related gene expression. Comprehensively, treatment with 15 μg/mL adiponectin enhanced the in vitro developmental capacity of early-stage SCNT porcine embryos by reducing ER stress and apoptosis.

The main factor of embryonic demise is endoplasmic reticulum (ER) stress. Successful attenuation of ER stress results in an improvement in embryo development. We studied the impact of adiponectin in the in vitro culture (IVC) of porcine embryos derived from parthenogenetic activation and somatic cell nuclear transfer (SCNT). The first experiment revealed that 15 and 30 μg/mL adiponectin treatments improved cleavage, blastocyst rates, and total cell number (TCN) of parthenogenetic embryos and reduced the expression of XBP1 compared to the 5 μg/mL adiponectin treatment and control groups (p < 0.05). The second experiment showed that cleavage rate, blastocyst formation rate, and TCN of blastocysts were improved in the 15 μg/mL adiponectin treatment group compared with the control group, with significantly reduced XBP1 expression in ≥4-cell stage SCNT embryos and blastocysts (p < 0.05). Treatment with 15 μg/mL adiponectin significantly improved the expression of XBP1 and reduced the expression of ER stress-related genes (uXBP1, sXBP1, PTPN1, and ATF4), increased the expression levels of pluripotency-related genes (Nanog and SOX2), and decreased apoptosis-related gene expression (Caspase-3). These results suggest that 15 μg/mL adiponectin enhanced the in vitro developmental capacity of early-stage SCNT porcine embryos by reducing ER stress and apoptosis.

• adiponectin
• endoplasmic reticulum stress
• in vitro culture
• parthenogenetic activation
• pig
• somatic cell nuclear transfer

• Aldo-keto reductase 1B7(Akr1b7)
• Endoplasmic reticulum stress
• Exosomes
• Fatty liver
• Inflammation
• Lipidomics
• Metabolic disorder
• Nonalcoholic steatohepatitis(NASH)
• Obesity
• Proteomics

• Adipocytes
• Aldehyde Reductase
• Aldo-Keto Reductases
• Animals
• Choline Deficiency
• Chromatography, Liquid
• Disease Models, Animal
• Exosomes
• Liver
• Male
• Methionine
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease/etiology
• Tandem Mass Spectrometry

• adipocyte
• adipogenic differentiation
• adipose-derived stem cells
• angiogenesis
• apoptosis
• fat transplantation

• Adipocytes/metabolism
• Adipose Tissue/transplantation
• Animals
• Humans
• Mice
• Stem Cell Transplantation/methods
• Stem Cells/metabolism

• China GuangHua Science and Technology Foundation

• Activating transcription factor 2
• Antimicrobial peptides
• Innate immunity
• Macrobrachium nipponense
• Tumor necrosis factor

• Activating Transcription Factor 2/chemistry
• Activating Transcription Factor 2/genetics
• Activating Transcription Factor 2/immunology
• Amino Acid Sequence
• Animals
• Arthropod Proteins/chemistry
• Arthropod Proteins/genetics
• Arthropod Proteins/immunology
• Base Sequence
• Gene Expression Profiling
• Gene Expression Regulation/immunology
• Immunity, Innate/genetics
• Penaeidae/genetics
• Penaeidae/immunology
• Phylogeny
• Protein Isoforms
• Random Allocation
• Sequence Alignment
• Staphylococcus aureus/physiology
• Vibrio parahaemolyticus/physiology

• AMPK
• Adiponectin
• ER stress
• Mitochondrial dysfunction
• Rotenone

• Adipokine
• Inflammasomes
• Inflammation
• Metabolic disorder
• Obesity

• APN
• CgAdipoR
• Crassostrea gigas
• Haemocyte
• Immunomodulation

• Adiponectin/metabolism
• Animals
• Apoptosis
• Cloning, Molecular
• Crassostrea/immunology
• Cytokines/genetics
• Cytokines/metabolism
• Gene Expression Regulation
• HEK293 Cells
• Hemocytes/physiology
• Humans
• Immunity, Innate
• Immunomodulation
• Lipopolysaccharides/immunology
• Poly I-C/immunology
• Receptors, Adiponectin/genetics
• Receptors, Adiponectin/metabolism
• Vibrio/physiology
• Vibrio Infections/immunology

Endoplasmic reticulum (ER) stress has been reported to play a pivotal role in diabetic nephropathy (DN). AdipoRon is a newly developed adiponectin receptor agonist that provides beneficial effects for diabetic mice; however, its underlying mechanism remains to be delineated. Here, we demonstrated increased expression levels of ER stress markers, accompanied by upregulated levels of proinflammatory cytokines and increased expression of collagen I, fibronectin, Bax, and cleaved caspase 3 in the kidneys of db/db mice compared with control mice. Decreased expression of adiponectin receptor 1 (AdipoR1) and phosphorylated 5′AMP-activated kinase (p-AMPK) was also observed in the kidneys of db/db mice. However, these alterations were partially reversed by intragastric gavage with AdipoRon. In vitro, AdipoRon alleviated high-glucose-induced ER stress, oxidative stress, and apoptosis in HK-2 cells, a human tubular cell line. Moreover, AdipoRon restored the expression of AdipoR1 and p-AMPK in HK-2 cells exposed to high-glucose conditions. Additionally, these effects were partially abrogated by pretreatment with AdipoR1 siRNA, but this abrogation was ameliorated by cotreatment with AICAR, an AMPK activator. Furthermore, the effects of AdipoRon were also partially abolished by cotreatment with compound C. Together, these results suggest that AdipoRon exerts favorable effects on diabetes-induced tubular injury in DN by inhibiting ER stress mediated by the AdipoR1/p-AMPK pathway.

Suppressor of cytokine signaling 2 (SOCS2) plays an important role in fat deposition, skeletal muscle, central nervous system development, and mitochondria biogenesis. Nevertheless, the regulatory mechanisms of SOCS2 on mitochondrial fatty acid oxidation (FAO) remain unclear. Leptin could inhibit food intake and increase thermogenesis through leptin receptor (LepR), which was present in the hypothalamus and certain peripheral organs, including adipose tissue. With strong interest, we focused on the connection between leptin and SOCS2 and their effect on FAO in adipocytes. In our study, we found that the mRNA level of SOCS2 and the protein levels of PGC-1α, CPT-1b, FAT, and p-ACC were elevated by leptin in the inguinal adipose tissue of mice. On the contrary, the protein levels of FABP4, FATP1, and FAS were declined. The genes related to fatty acid oxidation such as PGC-1α, NRF-1, TFAM, CPT-1b, AOX1, COX2, and UCP2 were attenuated by SOCS2, but elevated by leptin. Moreover, fatty acid oxidation enzyme MCAD, LCAD, and Cyt C levels were reduced in response to SOCS2. These reductions correspond well with the reduced release of free fatty acid and the reduction of mitochondrial complexes I and III by SOCS2. Furthermore, JAK2/AMPK pathway-specific inhibitors could block the mitochondrial FAO; hence, this pathway was implied to have a potential impact on FAO. Together, these studies suggested that SOCS2 had a negative effect on mitochondrial fatty acid oxidation, and the LepR/JAK2/AMPK pathway played a crucial role in this process.

GSK-J4 is the inhibitor of H3K27me3 demethylase. Recent studies demonstrated that GSK-J4 could affect the proliferation and apoptosis of a variety of cancer cells. However, the effects and underlying mechanisms of GSK-J4 on the proliferation and apoptosis of human acute myeloid leukemia (AML) KG-1a cells have not been explored thoroughly.

The effect of GSK-J4 on cell proliferation was assessed with CCK8, while cell cycle distribution and apoptosis were analyzed using flow cytometry. The proteins related to cell cycle, cell apoptosis, endoplastic reticulum (ER) stress and PKC-α/p-Bcl2 pathway were detected by Western blotting. The expression level of PKC-α mRNA was measured by quantitative real-time PCR.ER stress inhibitor 4-phenyl butyric acid (4-PBA) was used to explore the role of ER stress in GSK-J4 induced cell-cycle arrest and cell apoptosis. The combination effects of Decitabine and GSK-J4 on KG-1a cells proliferation and apoptosis were also evaluated by CCK8, flow cytometry and immunoblot analysis.

GSK-J4 reduced cell viability and arrested cell cycle progression at the S phase by decreasing the expression of CyclinD1 and CyclinA2 and increasing that of P21. Moreover, GSK-J4 enhanced the expression of apoptosis-related proteins (cle-caspase-9 and bax) and inhibited PKC-a/p-Bcl2 pathway to promote cell apoptosis. In addition, ER stress-related proteins (caspase-12, GRP78 and ATF4) were increased markedly after exposure to GSK-J4. The effects of GSK-J4 on cell cycle, apoptosis and PKC-a/p-Bcl2 pathway were attenuated after treatment with ER stress inhibitor. Furthermore, decitabine could significantly inhibit the proliferation and induce the apoptosis of KG-1a cells after combined treatment with GSK-J4.

Taken together, this study provided evidence that ER stress could regulate the process of GSK-J4-induced cell cycle arrest, cell apoptosis and PKC-α/p-bcl2 pathway inhibition and demonstrated a potential combinatory effect of decitabine and GSK-J4 on leukemic cell proliferation and apoptosis.

• Cell apoptosis
• Cell cycle
• Decitabine
• ER stress
• GSK-J4
• KG-1a cells
• PKC-α/p-bcl2 pathway

• adiponectin
• cardiopulmonary resuscitation
• global cerebral ischemia-reperfusion injury
• oxidative stress
• aMP-activated protein kinase

• adipose tissue
• mitochondria
• obesity

• adiponectin
• endoplasmic reticulum stress
• lung injury
• obesity

• Adiponectin
• Autophagy
• ER stress
• Inflammation

Several biological effects of haem oxygenase (HO)‐1, including anti‐inflammatory, antiapoptotic and antioxidative properties were reported; however, the role of HO‐1 in apoptosis is still unclear. In the presence of stimulation by cobalt protoporphyrin (CoPP), an HO‐1 inducer, apoptotic characteristics were observed, including DNA laddering, hypodiploid cells, and cleavages of caspase (Casp)‐3 and poly(ADP) ribose polymerase (PARP) proteins in human colon carcinoma COLO205, HCT‐15, LOVO and HT‐29 cells in serum‐free (SF) conditions with increased HO‐1, but not heat shock protein 70 (HSP70) or HSP90. The addition of 10% foetal bovine serum (FBS) or 1% bovine serum albumin accordingly inhibited CoPP‐induced apoptosis and HO‐1 protein expression in human colon cancer cells. CoPP‐induced apoptosis of colon cancer cells was prevented by the addition of the pan‐caspase inhibitor, Z‐VAD‐FMK (VAD), and the Casp‐3 inhibitor, Z‐DEVD‐FMK (DEVD). N‐Acetyl cysteine inhibited reactive oxygen species‐generated H₂O₂‐induced cell death with reduced intracellular peroxide production, but did not affect CoPP‐induced apoptosis in human colorectal carcinoma (CRC) cells. Two CoPP analogs, ferric protoporphyrin and tin protoporphyrin, did not affect the viability of human CRC cells or HO‐1 expression by those cells, and knockdown of HO‐1 protein expression by HO‐1 small interfering (si)RNA reversed the cytotoxic effect elicited by CoPP. Furthermore, the carbon monoxide (CO) donor, CORM, but not FeSO₄ or biliverdin, induced DNA ladders, and cleavage of Casp‐3 and PARP proteins in human CRC cells. Increased phosphorylated levels of the endoplasmic reticular (ER) stress proteins, protein kinase R‐like ER kinase (PERK), and eukaryotic initiation factor 2α (eIF2α) by CORM and CoPP were identified, and the addition of the PERK inhibitor, GSK2606414, inhibited CORM‐ and CoPP‐induced apoptosis. Increased GRP78 level and formation of the HO‐1/GRP78 complex were detected in CORM‐ and CoPP‐treated human CRC cells. A pro‐apoptotic role of HO‐1 against the viability of human CRC cells via induction of CO and ER stress was firstly demonstrated herein.

• CoPP
• ER stress
• apoptosis
• haem oxygenase-1
• human colorectal carcinoma cells

• Adipokines
• Endoplasmic reticulum stress
• Lipid and glucose metabolism
• Mercury
• PPARs
• White adipose tissue

• ATF2
• JNK/p38 signaling pathway
• Microglia
• Neuroinflammation
• TRAF6

While controlled thermal changes in subcutaneous tissue have been used to trigger apoptosis of fat cells and have been proven clinically efficacious, another mechanism of electromagnetic stress suggests that fat apoptosis could be achieved by a non‐thermal manner as well. This animal model study investigates the use of a non‐invasive high‐intensity magnetic field device to induce apoptosis in fat cells.

Yorkshire pigs (N = 2) received one treatment (30 minutes) in the abdominal area using a High‐Intensity Focused Electromagnetic (HIFEM) device. Punch biopsy samples of fat tissue and blood samples were collected at the baseline, 1 and 8 hours after the treatment. Biopsy samples were sectioned and evaluated for the levels of an apoptotic index (AI) by the TUNEL method. Statistical significance was examined using the rANOVA and Tukey's test (α 5%). Biopsy samples were also assessed for molecular biomarkers. Blood samples were evaluated to determine changes related to fat and muscle metabolism. Free fatty acids (FFA), triacylglycerol (TG), glycerol and glucose (Glu) were used as the main biomarkers of fat metabolism. Creatinine, creatinine kinase (CK), lactate dehydrogenase (LDH) and interleukin 6 (IL6) served as the main biomarkers to evaluate muscle metabolism.

In treated pigs, a statistically significant increase in the apoptotic index (AI) (P = 1.17E‐4) was observed. A significant difference was found between AI at baseline (AI = 18.75%) and 8‐hours post‐treatment (AI = 35.95%). Serum levels of fat and muscle metabolism indicated trends (FFA −0.32 mmol · l⁻¹, −28.1%; TG −0.24 mmol · l⁻¹, −51.8%; Glycerol −5.68 mg · l⁻¹, −54.8%; CK +67.58 μkat · l⁻¹, +227.8%; LDH +4.9 μkat · l⁻¹,+35.4%) suggesting that both adipose and muscle tissue were affected by HIFEM treatment. No adverse events were noted to skin and surrounding tissue.

Application of a high‐intensity electromagnetic field in a porcine model results in adipocyte apoptosis. The analysis of serum levels suggests that HIFEM treatment influences fat and muscle metabolism. Lasers Surg. Med. 51:47–53, 2019. © 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

• HIFEM
• apoptosis
• fat disruption
• magnetic technology
• non-thermal