Isoeugenol Inhibits Adipogenesis in 3T3-L1 Preadipocytes with Impaired Mitotic Clonal Expansion.

Isoeugenol (IEG), a natural component of clove oil, possesses antioxidant, anti-inflammatory, and antibacterial properties. However, the effects of IEG on adipogenesis have not yet been elucidated. Here, we showed that IEG blocks adipogenesis in 3T3-L1 cells at an early stage. IEG inhibits lipid accumulation in adipocytes in a concentration-dependent manner and reduces the expression of mature adipocyte-related factors including PPARγ, C/EBPα, and FABP4. IEG treatment at different stages of adipogenesis showed that IEG inhibited adipocyte differentiation by suppressing the early stage, as confirmed by lipid accumulation and adipocyte-related biomarkers. The early stage stimulates growth-arrested preadipocytes to enter mitotic clonal expansion (MCE) and initiates their differentiation into adipocytes by regulating cell cycle-related factors. IEG arrested 3T3-L1 preadipocytes in the G0/G1 phase of the cell cycle and attenuated cell cycle-related factors including cyclinD1, CDK6, CDK2, and cyclinB1 during the MCE stage. Furthermore, IEG suppresses reactive oxygen species (ROS) production during MCE and inhibits ROS-related antioxidant enzymes, including superoxide dismutase1 (SOD1) and catalase. The expression of cell proliferation-related biomarkers, including pAKT and pERK1/2, was attenuated by the IEG treatment of 3T3-L1 preadipocytes. These findings suggest that it is a potential therapeutic agent for the treatment of obesity.

Selenium May Be Involved in Esophageal Squamous Cancer Prevention by Affecting GPx3 and FABP1 Expression: A Case-Control Study Based on Bioinformatic Analysis.

The role of selenium in the developmental process of esophageal cancer (EC) requires further investigation. To explore the relationship between selenium-related factors and EC through bioinformatic analysis, a case-control study was conducted to verify the results. Utilizing the GEPIA and TCGA databases, we delineated the differential expression of glutathione peroxidase 3 (GPx3) in EC and normal tissues, identified differentially expressed genes (DEGs), and a performed visualization analysis. Additionally, 100 pairs of dietary and plasma samples from esophageal precancerous lesions (EPLs) of esophageal squamous cancer (ESCC) cases and healthy controls from Huai'an district, Jiangsu, were screened. The levels of dietary selenium, plasma selenium, and related enzymes were analyzed using inductively coupled plasma mass spectrometry (ICP-MS) or ELISA kits. The results showed lower GPx3 expression in tumor tissues compared to normal tissues. Further analysis revealed that DEGs were mainly involved in the fat digestion and absorption pathway, and the core protein fatty acid binding protein 1 (FABP1) was significantly upregulated and negatively correlated with GPx3 expression. Our case-control study found that selenium itself was not associated with EPLs risk. However, both the decreased concentration of GPx3 and the increase in FABP1 were positively correlated with the EPLs risk (p for trend = 0.035 and 0.046, respectively). The different expressions of GPx3 and FABP1 reflect the potential of selenium for preventing ESCC at the EPLs stage. GPx3 may affect myocardial infarction through FABP1, which remains to be further studied.

The Effects of FABP4 on Cardiovascular Disease in the Aging Population.

PURPOSE OF REVIEW: Fatty acid-binding protein 4 (FABP4) plays a role in lipid metabolism and cardiovascular health. In this paper, we cover FABP4 biology, its implications in atherosclerosis from observational studies, genetic factors affecting FABP4 serum levels, and ongoing drug development to target FABP4 and offer insights into future FABP4 research. RECENT FINDINGS: FABP4 impacts cells through JAK2/STAT2 and c-kit pathways, increasing inflammatory and adhesion-related proteins. In addition, FABP4 induces angiogenesis and vascular smooth muscle cell proliferation and migration. FABP4 is established as a reliable predictive biomarker for cardiovascular disease in specific at-risk groups. Genetic studies robustly link PPARG and FABP4 variants to FABP4 serum levels. Considering the potential effects on atherosclerotic lesion development, drug discovery programs have been initiated in search for potent inhibitors of FABP4. Elevated FABP4 levels indicate an increased cardiovascular risk and is causally related to acceleration of atherosclerotic disease, However, clinical trials for FABP4 inhibition are lacking, possibly due to concerns about available compounds' side effects. Further research on FABP4 genetics and its putative causal role in cardiovascular disease is needed, particularly in aging subgroups.

The role of lncFABP4 in modulating adipogenic differentiation in buffalo intramuscular preadipocytes.

Intramuscular fat (IMF) is a crucial determinant of meat quality and is influenced by various regulatory factors. Despite the growing recognition of the important role of long noncoding RNAs (lncRNAs) in IMF deposition, the mechanisms underlying buffalo IMF deposition remain poorly understood. In this study, we identified and characterized a lncRNA, lncFABP4, which is transcribed from the antisense strand of fatty acid-binding protein 4 (FABP4). lncFABP4 inhibited cell proliferation in buffalo intramuscular preadipocytes. Moreover, lncFABP4 significantly increased intramuscular preadipocyte differentiation, as indicated by an increase in the expression of the adipogenic markers peroxisome proliferator-activated receptor gamma (PPARG), CCAAT enhancer binding protein alpha (C/EBPα), and FABP4. Mechanistically, lncFABP4 was found to have the potential to regulate downstream gene expression by participating in protein-protein interaction pathways. These findings contribute to further understanding of the intricate mechanisms through which lncRNAs modulate intramuscular adipogenesis in buffaloes.

Fatty Acid Binding Protein 1 is an Independent Prognostic Biomarker for Gallbladder Cancer with Direct Hepatic Invasion.

Background: Direct liver invasion (DI) is a predominant pathway of gallbladder cancer (GBC) metastasis, but the molecular alterations associated with DI remain addressed. This study identified specific genes correlated with DI, which may offer a potential biomarker for the diagnosis and prognosis of advanced GBC. Methods: RNA samples from 3 patients with DI of GBC were used for RNA-seq analysis. Differentially expressed genes and metabolic pathways between primary tumor (T) and DI tissue was used to analyze aberrant gene expressions. Immunohistochemistry (IHC) of fatty acid binding protein 1 (FABP1) in 62 patients with DI was engaged to evaluate its association with clinicopathological characteristics and prognosis. IHC of CD3+ and CD8+ T cells was analyzed for their correlation with FABP1 expression, clinicopathological features and prognosis. Univariate and multivariate Cox hazards regression analyses were performed to identify independent prognostic factors for disease-free survival (DFS) and overall survival (OS). Results: FABP1 mRNA levels were significantly upregulated in DI region compared to T tissue. IHC results showed identical results with elevated FABP1 (p < 0.0001). Expression of FABP1 in DI region was significantly associated with lymph node metastasis (P = 0.028), reduced DFS (P = 0.013) and OS (P = 0.022); in contrast, its expression in T region was not associated with clinicopathological characteristics and prognosis (P > 0.05). The density of CD8+ T cells in DI region with higher FABP1 expression was significantly lower than that with lower FABP1 expression (p = 0.0084). Multivariate analysis unveiled those hepatic metastatic nodules (HR = 3.35, 95%CI: 1.37-8.15, P = 0.008) and FABP1 expression in DI region (HR = 2.01, 95%CI: 1.05-3.88, P = 0.036) were high risk factors for OS, and FABP1(HR = 2.05, 95%CI: 1.04-4.06, P = 0.039) was also a high risk factor for DFS. Conclusions: Elevated expression of FABP1 in DI region serves as a potential prognostic biomarker for advanced GBC with DI.

Single-cell sequencing analysis and multiple machine-learning models revealed the cellular crosstalk of dendritic cells and identified FABP5 and KLRB1 as novel biomarkers for psoriasis.

Background: Psoriasis is an immune-mediated disorder influenced by environmental factors on a genetic basis. Despite advancements, challenges persist, including the diminishing efficacy of biologics and small-molecule targeted agents, alongside managing recurrence and psoriasis-related comorbidities. Unraveling the underlying pathogenesis and identifying valuable biomarkers remain pivotal for diagnosing and treating psoriasis. Methods: We employed a series of bioinformatics (including single-cell sequencing data analysis and machine learning techniques) and statistical methods to integrate and analyze multi-level data. We observed the cellular changes in psoriatic skin tissues, screened the key genes Fatty acid binding protein 5 (FABP5) and The killer cell lectin-like receptor B1 (KLRB1), evaluated the efficacy of six widely prescribed drugs on psoriasis treatment in modulating the dendritic cell-associated pathway, and assessed their overall efficacy. Finally, RT-qPCR, immunohistochemistry, and immunofluorescence assays were used to validate. Results: The regulatory influence of dendritic cells (DCs) on T cells through the CD70/CD27 signaling pathway may emerge as a significant facet of the inflammatory response in psoriasis. Notably, FABP5 and KLRB1 exhibited up-regulation and co-localization in psoriatic skin tissues and M5-induced HaCaT cells, serving as potential biomarkers influencing psoriasis development. Conclusion: Our study analyzed the impact of DC-T cell crosstalk in psoriasis, elucidated the characterization of two biomarkers, FABP5 and KLRB1, in psoriasis, and highlighted the promise and value of tofacitinib in psoriasis therapy targeting DCs.

Genetic or pharmacologic blockade of mPGES-2 attenuates renal lipotoxicity and diabetic kidney disease by targeting Rev-Erbα/FABP5 signaling.

Diabetic kidney disease (DKD) is one of the most common complications of diabetes, and no specific drugs are clinically available. We have previously demonstrated that inhibiting microsomal prostaglandin E synthase-2 (mPGES-2) alleviated type 2 diabetes by enhancing ß cell function and promoting insulin production. However, the involvement of mPGES-2 in DKD remains unclear. Here, we aimed to analyze the association of enhanced mPGES-2 expression with impaired metabolic homeostasis of renal lipids and subsequent renal damage. Notably, global knockout or pharmacological blockage of mPGES-2 attenuated diabetic podocyte injury and tubulointerstitial fibrosis, thereby ameliorating lipid accumulation and lipotoxicity. These findings were further confirmed in podocyte- or tubule-specific mPGES-2-deficient mice. Mechanistically, mPGES-2 and Rev-Erbα competed for heme binding to regulate fatty acid binding protein 5 expression and lipid metabolism in the diabetic kidney. Our findings suggest a potential strategy for treating DKD via mPGES-2 inhibition.

Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring.

Due to the rise in overnutrition, the incidence of obesity-induced hepatocellular carcinoma (HCC) will continue to escalate; however, our understanding of the obesity to HCC developmental axis is limited. We constructed a single-cell atlas to interrogate the dynamic transcriptomic changes during hepatocarcinogenesis in mice. Here we identify fatty acid binding protein 5 (FABP5) as a driver of obesity-induced HCC. Analysis of transformed cells reveals that FABP5 inhibition and silencing predispose cancer cells to lipid peroxidation and ferroptosis-induced cell death. Pharmacological inhibition and genetic ablation of FABP5 ameliorates the HCC burden in male mice, corresponding to enhanced ferroptosis in the tumour. Moreover, FABP5 inhibition induces a pro-inflammatory tumour microenvironment characterized by tumour-associated macrophages with increased expression of the co-stimulatory molecules CD80 and CD86 and increased CD8+ T cell activation. Our work unravels the dual functional role of FABP5 in diet-induced HCC, inducing the transformation of hepatocytes and an immunosuppressive phenotype of tumour-associated macrophages and illustrates FABP5 inhibition as a potential therapeutic approach.

The emerging role of fatty acid binding protein 7 (FABP7) in cancers.

Fatty acid binding protein 7 (FABP7) is an intracellular protein involved in the uptake, transportation, metabolism, and storage of fatty acids (FAs). FABP7 is upregulated up to 20-fold in multiple cancers, usually correlated with poor prognosis. FABP7 silencing or pharmacological inhibition suggest FABP7 promotes cell growth, migration, invasion, colony and spheroid formation/increased size, lipid uptake, and lipid droplet formation. Xenograft studies show that suppression of FABP7 inhibits tumour formation and tumour growth, and improves host survival. The molecular mechanisms involve promotion of FA uptake, lipid droplets, signalling [focal adhesion kinase (FAK), proto-oncogene tyrosine-protein kinase Src (Src), mitogen-activated protein kinase kinase/p-extracellular signal-regulated kinase (MEK/ERK), and Wnt/ß-catenin], hypoxia-inducible factor 1-alpha (Hif1α), vascular endothelial growth factor A/prolyl 4-hydroxylase subunit alpha-1 (VEGFA/P4HA1), snail family zinc finger 1 (Snail1), and twist-related protein 1 (Twist1). The oncogenic capacity of FABP7 makes it a promising pharmacological target for future cancer treatments.

Fatty acid-binding proteins 3, 7, and 8 bind cholesterol and facilitate its egress from lysosomes.

Cholesterol from low-density lipoprotein (LDL) can be transported to many organelle membranes by non-vesicular mechanisms involving sterol transfer proteins (STPs). Fatty acid-binding protein (FABP) 7 was identified in our previous study searching for new regulators of intracellular cholesterol trafficking. Whether FABP7 is a bona fide STP remains unknown. Here, we found that FABP7 deficiency resulted in the accumulation of LDL-derived cholesterol in lysosomes and reduced cholesterol levels on the plasma membrane. A crystal structure of human FABP7 protein in complex with cholesterol was resolved at 2.7 Å resolution. In vitro, FABP7 efficiently transported the cholesterol analog dehydroergosterol between the liposomes. Further, the silencing of FABP3 and 8, which belong to the same family as FABP7, caused robust cholesterol accumulation in lysosomes. These two FABP proteins could transport dehydroergosterol in vitro as well. Collectively, our results suggest that FABP3, 7, and 8 are a new class of STPs mediating cholesterol egress from lysosomes.

[Elucidation of the pathology of mental disorders focusing on polyunsaturated fatty acids and FABPs].

Polyunsaturated fatty acids (PUFAs) are essential for brain development and function, and an imbalance of brain PUFAs is linked to mental disorders like autism and schizophrenia. However, the cellular and molecular mechanisms underlying the effects of PUFAs on the brain remain largely unknown. Since they are insoluble in water, specific transporters like fatty acid binding proteins (FABPs), are required for transport and function of PUFAs within cells. We focused on the relationship between FABP-mediated homeostasis of brain PUFAs and neural plasticity. We found that FABP3, with a high affinity for n-6 PUFAs, is predominantly expressed in the GABAergic inhibitory interneurons of the anterior cingulate cortex (ACC) in the adult mouse brain. FABP3 knockout (KO) mice show increased GABA synthesis and inhibitory synaptic transmission in the ACC. We also found that FABP7 controls lipid raft function in astrocytes, and astrocytes lacking FABP7 exhibit changes in response to external stimuli. Furthermore, in FABP7 KO mice, dendritic protrusion formation in pyramidal neurons becomes abnormal, and we have reported a decrease in spine density and excitatory synaptic transmission. Here, we introduced recent advances in the understanding of the functions of PUFAs and FABPs in the brain, focusing especially on FABP3 and FABP7, in relation to human mental disorders.

Integrated multi-omic analysis identifies fatty acid binding protein 4 as a biomarker and therapeutic target of ischemia-reperfusion injury in steatotic liver transplantation.

BACKGROUND AND AIMS: Due to a lack of donor grafts, steatotic livers are used more often for liver transplantation (LT). However, steatotic donor livers are more sensitive to ischemia-reperfusion (IR) injury and have a worse prognosis after LT. Efforts to optimize steatotic liver grafts by identifying injury targets and interventions have become a hot issue. METHODS: Mouse LT models were established, and 4D label-free proteome sequencing was performed for four groups: normal control (NC) SHAM, high-fat (HF) SHAM, NC LT, and HF LT to screen molecular targets for aggravating liver injury in steatotic LT. Expression detection of molecular targets was performed based on liver specimens from 110 donors to verify its impact on the overall survival of recipients. Pharmacological intervention using small-molecule inhibitors on an injury-related target was used to evaluate the therapeutic effect. Transcriptomics and metabolomics were performed to explore the regulatory network and further integrated bioinformatics analysis and multiplex immunofluorescence were adopted to assess the regulation of pathways and organelles. RESULTS: HF LT group represented worse liver function compared with NC LT group, including more apoptotic hepatocytes (P < 0.01) and higher serum transaminase (P < 0.05). Proteomic results revealed that the mitochondrial membrane, endocytosis, and oxidative phosphorylation pathways were upregulated in HF LT group. Fatty acid binding protein 4 (FABP4) was identified as a hypoxia-inducible protein (fold change > 2 and P < 0.05) that sensitized mice to IR injury in steatotic LT. The overall survival of recipients using liver grafts with high expression of FABP4 was significantly worse than low expression of FABP4 (68.5 vs. 87.3%, P < 0.05). Adoption of FABP4 inhibitor could protect the steatotic liver from IR injury during transplantation, including reducing hepatocyte apoptosis, reducing serum transaminase (P < 0.05), and alleviating oxidative stress damage (P < 0.01). According to integrated transcriptomics and metabolomics analysis, cAMP signaling pathway was enriched following FABP4 inhibitor use. The activation of cAMP signaling pathway was validated. Microscopy and immunofluorescence staining results suggested that FABP4 inhibitors could regulate mitochondrial membrane homeostasis in steatotic LT. CONCLUSIONS: FABP4 was identified as a hypoxia-inducible protein that sensitized steatotic liver grafts to IR injury. The FABP4 inhibitor, BMS-309403, could activate of cAMP signaling pathway thereby modulating mitochondrial membrane homeostasis, reducing oxidative stress injury in steatotic donors.

NKX2-1-AS1 promotes the lymphangiogenesis of lung adenocarcinoma through regulation of ERG-mediated FABP4.

Lymphatic metastasis is a common metastasis of lung adenocarcinoma (LUAD). The current study illustrated the action of lncRNA NKX2-1-AS1 in lymphangiogenesis in LUAD and the underlying mechanisms. Clinical tissue samples were collected for determining NKX2-1-AS1 expression. Then, H441 and H661 cells were selected to perform gain- and loss-of-function assays for dissecting the roles of NKX2-1-AS1 in LUAD cell proliferation and migration. Besides, H441 and H661 cell supernatant was harvested to stimulate HLECs for assessing tube formation ability. Interaction among NKX2-1-AS1, ERG, and fatty acid binding protein 4 (FABP4) was validated through luciferase and RIP assays. NKX2-1-AS1 was highly-expressed in LUAD tissues. Silencing NKX2-1-AS1 suppressed H441 and H661 cell proliferation and migration, reduced expression levels of lymphangiogenesis-related factors (LYVE-1, VEGF-C, VEGFR3, VEGF-A, VEGFR2, and CCR7), and inhibited HLEC tube formation. Interaction validation demonstrated that NKX2-1-AS1 regulated FABP4 transcription by binding to ERG. Overexpression of FABP4 could effectively block the inhibition role of NKX2-1-AS1 silencing in lymphangiogenesis in H441 and H661 cells. This study provided evidence that NKX2-1-AS1 regulated FABP4 transcription by binding to ERG to facilitate the proliferation and migration of LUAD cells and tube formation of HLECs, thus participating in lymphangiogenesis.

Circular RNA circFCHO2(hsa_circ_0002490) promotes the proliferation of melanoma by directly binding to DND1.

Circular RNAs (circRNAs) have been documented to play crucial roles in the biology of various cancers. However, their investigation in melanoma is still at an early stage, particularly as a broader mechanism beyond acting as miRNA sponges needs to be explored. We report here that circFCHO2(hsa_circ_0002490), a circRNA encompassing exons 19 and 20 of the FCHO2 gene, exhibited a consistent overexpression in melanoma tissues. Furthermore, elevated circFCHO2 levels demonstrated a positive correlation with the malignant phenotype and poor prognosis among the 158 melanoma patients studied. Besides, we observed that heightened levels of circFCHO2 promoted melanoma cell proliferation, migration, and invasion in vitro, along with contributing to tumor growth in vivo. Furthermore, we found differences in the secondary structure of circFCHO2 compared to most other circular RNA structures. It has fewer miRNA binding sites, while it has more RNA binding protein binding sites. We therefore speculate that circFCHO2 may have a function of interacting with RNA binding proteins. Mechanistically, it was confirmed by fluorescence in situ hybridization (FISH), RNA-pull down, RNA immunoprecipitation (RIP), and western blotting assays that circFCHO2 interacts with dead end protein homolog 1 (DND1) and reverses the inhibition of the PI3K/AKT signaling pathway by binding to DND1. Our findings reveal that circFCHO2 drives melanoma progression by regulating the PI3K/AKT signaling pathway through direct binding to DND1 and may serve as a potential diagnostic biomarker and therapeutic target for the treatment of melanoma.

High levels of fatty acid-binding protein 5 excessively enhances fatty acid synthesis and proliferation of granulosa cells in polycystic ovary syndrome.

BACKGROUND: Polycystic ovary syndrome (PCOS) is one of the most complex endocrine disorders in women of reproductive age. Abnormal proliferation of granulosa cells (GCs) is an important cause of PCOS. This study aimed to explore the role of fatty acid-binding protein 5 (FABP5) in granulosa cell (GC) proliferation in polycystic ovary syndrome (PCOS) patients. METHODS: The FABP5 gene, which is related to lipid metabolism, was identified through data analysis of the gene expression profiles of GSE138518 from the Gene Expression Omnibus (GEO) database. The expression levels of FABP5 were measured by quantitative real-time PCR (qRT‒PCR) and western blotting. Cell proliferation was evaluated with a cell counting kit-8 (CCK-8) assay. Western blotting was used to assess the expression of the proliferation marker PCNA, and immunofluorescence microscopy was used to detect Ki67 expression. Moreover, lipid droplet formation was detected with Nile red staining, and qRT‒PCR was used to analyze fatty acid storage-related gene expression. RESULTS: We found that FABP5 was upregulated in ovarian GCs obtained from PCOS patients and PCOS mice. FABP5 knockdown suppressed lipid droplet formation and proliferation in a human granulosa-like tumor cell line (KGN), whereas FABP5 overexpression significantly enhanced lipid droplet formation and KGN cell proliferation. Moreover, we determined that FABP5 knockdown inhibited PI3K-AKT signaling by suppressing AKT phosphorylation and that FABP5 overexpression activated PI3K-AKT signaling by facilitating AKT phosphorylation. Finally, we used the PI3K-AKT signaling pathway inhibitor LY294002 and found that the facilitation of KGN cell proliferation and lipid droplet formation induced by FABP5 overexpression was inhibited. In contrast, the PI3K-AKT signaling pathway agonist SC79 significantly rescued the suppression of KGN cell proliferation and lipid droplet formation caused by FABP5 knockdown. CONCLUSIONS: FABP5 promotes active fatty acid synthesis and excessive proliferation of GCs by activating PI3K-AKT signaling, suggesting that abnormally high expression of FABP5 in GCs may be a novel biomarker or a research target for PCOS treatment.

Impaired Hepatic Very Low-Density Lipoprotein Secretion Promotes Tumorigenesis and Is Accelerated with Fabp1 Deletion.

Genetic polymorphisms that impair very low-density lipoprotein (VLDL) secretion are linked to hepatic steatosis, fibrosis, and hepatocellular cancer. Liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) impairs VLDL assembly, promoting hepatic steatosis and fibrosis, which are attenuated in Mttp-LKO X Fabp1-null [Fabp1/Mttp double knockout (DKO)] mice. The current study examined the impact of impaired VLDL secretion in Mttp-LKO mice on hepatocellular cancer incidence and progression in comparison to Fabp1/Mttp DKO mice. Diethylnitrosamine-treated Mttp-LKO mice exhibited steatosis with increased tumor burden compared with flox controls, whereas diethylnitrosamine-treated Fabp1/Mttp DKO mice exhibited a paradoxical increase in tumor burden and >50% mortality by 50 weeks. Serum high-density lipoprotein cholesterol was elevated in both Mttp-LKO and Fabp1/Mttp DKO mice, with increased intratumoral expression of apolipoprotein A1 and apolipoprotein E. Lipidomic surveys revealed progressive enrichment in distinct triglyceride species in livers from Mttp-LKO mice with further enrichment in Fabp1/Mttp DKO mice. RNA sequencing revealed mRNA changes suggesting altered monocarboxylic acid use and increased aerobic glycolysis, whereas hepatocytes from Fabp1/Mttp DKO mice exhibited increased capacity to use glucose and glutamine. These metabolic shifts were accompanied by reduced expression of HNF1 homeobox A (HNF1a), which correlated with tumor burden. Taken together, these findings demonstrate that hepatic tumorigenesis is increased in mice with impaired VLDL secretion and further accelerated via pathways including altered fatty acid compartmentalization and shifts in hepatic energy use.

Transcriptomic Profiling of OSCC Patients in an Indian Subset.

BACKGROUND: Tumor-specific biomarkers are needed for accomplishing antidote in early detection, as well as prognosis and designing therapeutic strategies. Comprehensive transcriptome profiling offers critical insights into the disease and reveal new avenue for drug discovery. METHODS: Total 5 cancerous and histopathological normal tissue pairs of 5 OSCC patients included in the petite study. Transcriptome sequencing was performed using Roche's 454 sequencing platform followed by CLC Genomics Workbench was used to examine gene expression in OC development. RESULTS: A total 2082 genes were differentially expressed across all the five tumor-control pairs collected from the OC patients during the surgery. From these 1092 upregulated and 273 downregulated genes, whereas 717 genes were found to be non-significant. The genes with pvalue <0.05 and log2foldchange > 1 or log2foldchange < -1 were considered for further enrichment analysis. Topfunn was used for gene enrichment analysis to identify gene enrichment pathway analysis found some cancer related pathways such as TNF signaling, p53 signaling pathway, cGMP-PKG signaling pathway, Apelin signaling pathway and IL-17 signaling pathway were strikingly involved in proliferation and apoptosis of tumor cells. The PPI network construction was performed and identified 8 best protein interactions. CONCLUSION: The current study reports molecular biomarkers including INHBA, FJX1, OLR1, CDK2, IGHM, CXCL11, SH2D5 and FABP5 associated with cancer that can led to identify potential therapeutic targets for the better prognosis of the cancer patients. The signature candidate can be translated to clinical practice to increase early diagnostic accuracy.

p21-activated kinase 4 counteracts PKA-dependent lipolysis by phosphorylating FABP4 and HSL.

Adipose tissue lipolysis is mediated by cAMP-protein kinase A (PKA)-dependent intracellular signalling. Here, we show that PKA targets p21-activated kinase 4 (PAK4), leading to its protein degradation. Adipose tissue-specific overexpression of PAK4 in mice attenuates lipolysis and exacerbates diet-induced obesity. Conversely, adipose tissue-specific knockout of Pak4 or the administration of a PAK4 inhibitor in mice ameliorates diet-induced obesity and insulin resistance while enhancing lipolysis. Pak4 knockout also increases energy expenditure and adipose tissue browning activity. Mechanistically, PAK4 directly phosphorylates fatty acid-binding protein 4 (FABP4) at T126 and hormone-sensitive lipase (HSL) at S565, impairing their interaction and thereby inhibiting lipolysis. Levels of PAK4 and the phosphorylation of FABP4-T126 and HSL-S565 are enhanced in the visceral fat of individuals with obesity compared to their lean counterparts. In summary, we have uncovered an important role for FABP4 phosphorylation in regulating adipose tissue lipolysis, and PAK4 inhibition may offer a therapeutic strategy for the treatment of obesity.

Inhibition of FABP5 attenuates inflammatory bowel disease by modulating macrophage alternative activation.

Fatty acid binding protein 5 (FABP5) is an intracellular chaperone of fatty acid molecules that regulates lipid metabolism and cell growth. However, its role in intestinal inflammation remains enigmatic. Through examination of human tissue samples and single-cell data, we observed a significant upregulation of FABP5 within the mucosa of patients afflicted with ulcerative colitis (UC) and Crohn's disease (CD), predominantly localized in intestinal macrophages. Herein, we investigate the regulation of FABP5-IN-1, a FABP5 inhibitor, on various cells of the gut in an inflammatory environment. Our investigations confirmed that FABP5 ameliorates DSS-induced colitis in mice by impeding the differentiation of macrophages into M1 macrophages in vitro and in vivo. Furthermore, following FABP5-IN-1 intervention, we observed a notable restoration of intestinal goblet cells and tuft cells, even under inflammatory conditions. Additionally, FABP5-IN-1 exhibits a protective effect against DSS-induced colitis by promoting the polarization of macrophages towards the M2 phenotype in vivo. In summary, FABP5-IN-1 confers protection against DSS-induced acute colitis through a multifaceted approach, encompassing the reduction of inflammatory macrophage infiltration, macrophage polarization, regulating Th17/Treg cells to play an anti-inflammatory role in IBD. The implications for IBD are underscored by the comprehensive in vivo and in vitro experiments presented in this article, thereby positioning FABP5 as a promising and novel therapeutic target for the treatment of IBD.

Urinary liver-type fatty acid binding protein is a biomarker reflecting renal damage and the ameliorative effect of drugs at an early stage of histone-induced acute kidney injury.

AIM: Circulated histones play a crucial role in the pathogenesis of infectious diseases and severe trauma, and it is one of the potential molecular targets for therapeutics. Recently, we reported that histone is one of the causative agents for urinary L-FABP increase. However, the mechanism is still unclear, especially in severe cases. We further investigated the mechanism of urinary L-FABP increase using a more severe mouse model with histone-induced kidney injury. This study also aims to evaluate the therapeutic responsiveness of urinary L-FABP as a preliminary study. METHODS: Human L-FABP chromosomal transgenic mice were administrated 30 mg/kg histone from a tail vein with a single dose. We also performed a comparative study in LPS administration model. For the evaluation of the therapeutic responsiveness of urinary L-FABP, we used heparin and rolipram. RESULTS: The histological change with cast formation as a characteristic of the models was observed in proximal tubules. Urinary L-FABP levels were significantly elevated and these levels tended to be higher in those with more cast formation. Heparin and rolipram had the ameliorative effect of the cast formation induced by histone and urinary L-FABP levels significantly decreased. CONCLUSION: Histone is one of the causative agents for the increase of urinary L-FABP at an early stage of AKI. In addition, it suggested that urinary L-FABP may be useful as a subclinical AKI marker reflecting kidney damage induced by histone. Furthermore, urinary L-FABP reflected the degree of the damage after the administration of therapeutic agents such as heparin and PDE4 inhibitor.