Inhibitory Factor-1 Research Articles

Crystal structure of N-terminally hexahistidine-tagged Onchocerca volvulus macrophage migration inhibitory factor-1.

Onchocerca volvulus causes blindness, onchocerciasis, skin infections and devastating neurological diseases such as nodding syndrome. New treatments are needed because the currently used drug, ivermectin, is contraindicated in pregnant women and those co-infected with Loa loa. The Seattle Structural Genomics Center for Infectious Disease (SSGCID) produced, crystallized and determined the apo structure of N-terminally hexahistidine-tagged O. volvulus macrophage migration inhibitory factor-1 (His-OvMIF-1). OvMIF-1 is a possible drug target. His-OvMIF-1 has a unique jellyfish-like structure with a prototypical macrophage migration inhibitory factor (MIF) trimer as the `head' and a unique C-terminal `tail'. Deleting the N-terminal tag reveals an OvMIF-1 structure with a larger cavity than that observed in human MIF that can be targeted for drug repurposing and discovery. Removal of the tag will be necessary to determine the actual biological oligomer of OvMIF-1 because size-exclusion chomatographic analysis of His-OvMIF-1 suggests a monomer, while PISA analysis suggests a hexamer stabilized by the unique C-terminal tails.

Clinical study of Wnt inhibitory factor-1 expression and its association with disease severity in non-segmental vitiligo

BackgroundVitiligo is classified as an acquired chronic depigmentation disorder that includes the destruction of epidermal melanocytes. It affects 0.5–1% of the population all over the world. Wnt signaling pathway is vital in melanocytes differentiation and development. WIF-1 is an antagonist of the Wnt signaling pathway; it hinders Wnt from binding its receptors. The present study aims to detect WIF-1 expression in vitiligo skin and if it relates to the disease's severity.ResultsThis case–control study included 70 subjects: 35 vitiligo patients and 35 healthy controls. Skin WIF-1 expression was estimated using quantitative real-time PCR. Assessment of the vitiligo disease activity score and vitiligo area severity index score was determined. WIF-1 expression showed significant elevation in the skin of vitiligo patients compared to the healthy control group.ConclusionOverexpression of WIF-1 may participate in the pathogenesis of vitiligo; hence, it should be a future therapeutic target.

The Toxoplasma gondii homolog of ATPase inhibitory factor 1 is critical for mitochondrial cristae maintenance and stress response.

The production of energy in the form of ATP by the mitochondrial ATP synthase must be tightly controlled. One well-conserved form of regulation is mediated via ATPase inhibitory factor 1 (IF1), which governs ATP synthase activity and gene expression patterns through a cytoprotective process known as mitohormesis. In apicomplexans, the processes regulating ATP synthase activity are not fully elucidated. Using the model apicomplexan Toxoplasma gondii, we found that knockout and overexpression of TgIF1, the structural homolog of IF1, significantly affected gene expression. Additionally, TgIF1 overexpression resulted in the formation of a stable TgIF1 oligomer that increased the presence of higher order ATP synthase oligomers. We also show that parasites lacking TgIF1 exhibit reduced mitochondrial cristae density, and that while TgIF1 levels do not affect growth in conventional culture conditions, they are crucial for parasite survival under hypoxia. Interestingly, TgIF1 overexpression enhances recovery from oxidative stress, suggesting a mitohormetic function. In summary, while TgIF1 does not appear to play a role in metabolic regulation under conventional growth conditions, our work highlights its importance for adapting to stressors faced by T. gondii and other apicomplexans throughout their intricate life cycles.

An insight into the therapeutic effects of isoliquiritigenin in breast cancer.

Breast cancer ranks as the most widespread malignant condition in women, emerging as a primary contributor to mortality. The primary challenges in cancer treatments involve undesirable side effects. Therefore, exploring natural compounds as additional therapy could provide valuable insights. Isoliquiritigenin (ILN), an isoflavonoid featuring a chalcone moiety primarily sourced from Glycyrrhiza species, has garnered increasing interest in breast cancer research. This review aims to provide a comprehensive understanding of ILN's mechanisms of action in breast cancer, drawing from a range of in vitro and in vivo studies. ILN primarily acts by inhibiting angiogenesis, aromatase, inflammation, and cell proliferation, and preventing invasion and metastasis. Mechanistically, it downregulates miR-374a, phosphoinositide-3-kinase-protein kinase B/Akt, maternal embryonic leucine zipper kinase, vascular endothelial growth factor, and estrogen receptor protein levels, and causes enhancement of Wnt inhibitory factor-1, and Unc-51-like kinase 1 expression to treat breast cancer. ILN emerges as a promising natural option, offering therapeutic advantages with minimal side effects. However, it is important to note that current research on ILN is primarily limited to preclinical models, underscoring the need for further investigation to validate its potential efficacy.

Neuroreceptor Inhibition by Clozapine Triggers Mitohormesis and Metabolic Reprogramming in Human Blood Cells.

The antipsychotic drug clozapine demonstrates superior efficacy in treatment-resistant schizophrenia, but its intracellular mode of action is not completely understood. Here, we analysed the effects of clozapine (2.5-20 µM) on metabolic fluxes, cell respiration, and intracellular ATP in human HL60 cells. Some results were confirmed in leukocytes of clozapine-treated patients. Neuroreceptor inhibition under clozapine reduced Akt activation with decreased glucose uptake, thereby inducing ER stress and the unfolded protein response (UPR). Metabolic profiling by liquid-chromatography/mass-spectrometry revealed downregulation of glycolysis and the pentose phosphate pathway, thereby saving glucose to keep the electron transport chain working. Mitochondrial respiration was dampened by upregulation of the F0F1-ATPase inhibitory factor 1 (IF1) leading to 30-40% lower oxygen consumption in HL60 cells. Blocking IF1 expression by cotreatment with epigallocatechin-3-gallate (EGCG) increased apoptosis of HL60 cells. Upregulation of the mitochondrial citrate carrier shifted excess citrate to the cytosol for use in lipogenesis and for storage as triacylglycerol in lipid droplets (LDs). Accordingly, clozapine-treated HL60 cells and leukocytes from clozapine-treated patients contain more LDs than untreated cells. Since mitochondrial disturbances are described in the pathophysiology of schizophrenia, clozapine-induced mitohormesis is an excellent way to escape energy deficits and improve cell survival.

The ATPase Inhibitory Factor 1 (IF1) Contributes to the Warburg Effect and Is Regulated by Its Phosphorylation in S39 by a Protein Kinase A-like Activity.

The relevant role played by the ATPase Inhibitory Factor 1 (IF1) as a physiological in vivo inhibitor of mitochondrial ATP synthase in cancer and non-cancer cells, and in the mitochondria of different mouse tissues, as assessed in different genetic loss- and gain-of-function models of IF1 has been extensively documented. In this review we summarize our findings and those of others that favor the implication of IF1 in metabolic reprogramming to an enhanced glycolytic phenotype, which is mediated by its binding and inhibition of the ATP synthase. Moreover, we emphasize that IF1 is phosphorylated in vivo in its S39 by the c-AMP-dependent PKA activity of mitochondria to render an inactive inhibitor that is unable to interact with the enzyme, thus triggering the activation of ATP synthase. Overall, we discuss and challenge the results that argue against the role of IF1 as in vivo inhibitor of mitochondrial ATP synthase and stress that IF1 cannot be regarded solely as a pro-oncogenic protein because in some prevalent carcinomas, it prevents metastatic disease.

ApoA-I Protects Pancreatic β-Cells From Cholesterol-Induced Mitochondrial Damage and Restores Their Ability to Secrete Insulin.

High cholesterol levels in pancreatic β-cells cause oxidative stress and decrease insulin secretion. β-cells can internalize apo (apolipoprotein) A-I, which increases insulin secretion. This study asks whether internalization of apoA-I improves β-cell insulin secretion by reducing oxidative stress. Ins-1E cells were cholesterol-loaded by incubation with cholesterol-methyl-β-cyclodextrin. Insulin secretion in the presence of 2.8 or 25 mmol/L glucose was quantified by radioimmunoassay. Internalization of fluorescently labeled apoA-I by β-cells was monitored by flow cytometry. The effects of apoA-I internalization on β-cell gene expression were evaluated by RNA sequencing. ApoA-I-binding partners on the β-cell surface were identified by mass spectrometry. Mitochondrial oxidative stress was quantified in β-cells and isolated islets with MitoSOX and confocal microscopy. An F1-ATPase β-subunit on the β-cell surface was identified as the main apoA-I-binding partner. β-cell internalization of apoA-I was time-, concentration-, temperature-, cholesterol-, and F1-ATPase β-subunit-dependent. β-cells with internalized apoA-I (apoA-I+ cells) had higher cholesterol and cell surface F1-ATPase β-subunit levels than β-cells without internalized apoA-I (apoA-I- cells). The internalized apoA-I colocalized with mitochondria and was associated with reduced oxidative stress and increased insulin secretion. The IF1 (ATPase inhibitory factor 1) attenuated apoA-I internalization and increased oxidative stress in Ins-1E β-cells and isolated mouse islets. Differentially expressed genes in apoA-I+ and apoA-I- Ins-1E cells were related to protein synthesis, the unfolded protein response, insulin secretion, and mitochondrial function. These results establish that β-cells are functionally heterogeneous, and apoA-I restores insulin secretion in β-cells with elevated cholesterol levels by improving mitochondrial redox balance.

Irisin protected hemopoietic stem cells and improved outcome of severe bone marrow failure

Acquired aplastic anemia (AA) is a bone marrow failure (BMF) disease, characterized by fatty bone marrow (BM) and BM hypocellularity resulted from auto-immune dysregulated T cells-mediated destruction of BM haemopoietic stem cells (HPSC). The objective of this study was to investigate potential therapeutic effect of irisin, a molecule involved in adipose tissue transition, on AA mouse model. Our results showed that the concentration of irisin in serum was lower in AA patients than in healthy controls, suggesting a role of irisin in the pathogenesis of AA. In the AA mice, irisin administration prolonged the survival rate, prevented or attenuated peripheral pancytopenia, and preserved HPSC in the BM. Moreover, irisin also markedly reduced BM adipogenesis. In vitro results showed that irisin increased both cell proliferation and colony numbers of HPSC. Furthermore, our results demonstrated that irisin upregulated the expression of mitochondrial ATPase Inhibitory Factor 1 (IF1) in HPSC, inhibited the activation of mitochondrial fission protein (DRP1) and enhanced aerobic glycolysis. Taken together, our findings indicate novel roles of irisin in the pathogenesis of AA, and in the protection of HPSC through stimulation of proliferation and regulation of mitochondria function, which provides a proof-of-concept for the application of irisin in AA therapy.

Longitudinal Associations Between ATPase Inhibitory Factor 1, Growth Differentiation Factor-15, and Nutritional Status in Older Adults From the MAPT Study.

Weight and appetite regulation have been associated with the expression and secretion of ATPase inhibitory factor 1 (IF1) and growth differentiation factor-15 (GDF-15), 2 potential biomarkers for age-related mitochondrial dysfunction. The aim was to explore the associations between these biomarkers and nutritional variables in the Multidomain Alzheimer Preventive Trial study. IF1 and GDF-15 plasma levels were quantified at 1-year follow-up. The nutritional status was measured using the Mini Nutritional Assessment (MNA) score variation between baseline and 1- and 2-year visits; appetite loss was extracted from the MNA. Bodyweight was measured every 6 months until the third year and then yearly until the fifth year of follow-up, and weight loss was established if the loss was greater than 5% or 10% within the past 6 or 12 months, respectively. Bidirectional associations of IF1 and GDF-15 levels with malnutrition, appetite, and weight loss were examined. The interactions between individual IF1 and GDF-15 with sex were explored. Four hundred and forty-eight participants had MNA data and 1 045 had weight loss data. All the associations between IF1 levels and the MNA score, appetite loss, and weight loss were nonsignificant. Higher GDF-15 levels were cross-sectionally associated with appetite loss at the first year of follow-up, and the GDF-15 highest quartile was associated with nearly 80% higher risks of weight loss over 4 years. Interactions between IF1 and GDF-15 levels, and between these 2 markers and sex were not significantly associated with the outcomes. GDF-15 plasma levels were related to key malnutrition criteria.

Associations between physical activity levels and ATPase inhibitory factor 1 concentrations in older adults

BackgroundAdenosine triphosphatase inhibitory factor 1 (IF1) is a key protein involved in energy metabolism. IF1 has been linked to various age-related diseases, although its relationship with physical activity (PA) remains unclear. Additionally, the apolipoprotein A-I (apoA-I), a PA-modulated lipoprotein, could play a role in this relationship because it shares a binding site with IF1 on the cell-surface ATP synthase. We examined here the associations between chronic PA and plasma IF1 concentrations among older adults, and we investigated whether apoA-I mediated these associations. MethodsIn the present work, 1096 healthy adults (63.8% females) aged 70 years and over who were involved in the Multidomain Alzheimer Prevention Trial study were included. IF1 plasma concentrations (square root of ng/mL) were measured at the 1-year visit of the Multidomain Alzheimer Prevention Trial, while PA levels (square root of metabolic equivalent task min/week) were assessed using questionnaires administered each year from baseline to the 3-year visit. Multiple linear regressions were performed to investigate the associations between the first-year mean PA levels and IF1 concentrations. Mediation analyses were conducted to examine whether apoA-I mediated these associations. Mixed-effect linear regressions were carried out to investigate whether the 1-year visit IF1 concentrations predicted subsequent changes in PA. ResultsMultiple linear regressions indicated that first-year mean PA levels were positively associated with IF1 concentrations (B = 0.021; SE = 0.010; p = 0.043). Mediation analyses revealed that about 37.7% of this relationship was mediated by apoA-I (Bab = 0.008; SE = 0.004; p = 0.023). Longitudinal investigations demonstrated that higher concentrations of IF1 at the 1-year visit predicted a faster decline in PA levels over the subsequent 2 years (time × IF1: B = –0.148; SE = 0.066; p = 0.025). ConclusionThis study demonstrates that regular PA is associated with plasma IF1 concentrations, and it suggests that apoA-I partly mediates this association. Additionally, this study finds that baseline concentrations of IF1 can predict future changes in PA. However, further research is needed to fully understand the mechanisms underlying these observations.

The Mitochondrial ATP Synthase/IF1 Axis in Cancer Progression: Targets for Therapeutic Intervention.

Cancer poses a significant global health problem with profound personal and economic implications on National Health Care Systems. The reprograming of metabolism is a major trait of the cancer phenotype with a clear potential for developing effective therapeutic strategies to combat the disease. Herein, we summarize the relevant role that the mitochondrial ATP synthase and its physiological inhibitor, ATPase Inhibitory Factor 1 (IF1), play in metabolic reprogramming to an enhanced glycolytic phenotype. We stress that the interplay in the ATP synthase/IF1 axis has additional functional roles in signaling mitohormetic programs, pro-oncogenic or anti-metastatic phenotypes depending on the cell type. Moreover, the same axis also participates in cell death resistance of cancer cells by restrained mitochondrial permeability transition pore opening. We emphasize the relevance of the different post-transcriptional mechanisms that regulate the specific expression and activity of ATP synthase/IF1, to stimulate further investigations in the field because of their potential as future targets to treat cancer. In addition, we review recent findings stressing that mitochondria metabolism is the primary altered target in lung adenocarcinomas and that the ATP synthase/IF1 axis of OXPHOS is included in the most significant signature of metastatic disease. Finally, we stress that targeting mitochondrial OXPHOS in pre-clinical mouse models affords a most effective therapeutic strategy in cancer treatment.

Effects of Shenling Baizhu powder on intestinal microflora metabolites and liver mitochondrial energy metabolism in nonalcoholic fatty liver mice.

Non-alcoholic fatty liver disease (NAFLD) is characterised by the excessive accumulation of triglycerides in the liver. Shenling Baizhu powder (SLBZP) is formulated from various natural medicinal plants that protect the liver and are used to treat intestinal diseases. SLBZP improves the symptoms of NAFLD. However, its mechanism of action remains unclear. Herein, we investigated the ameliorative effect of SLBZP on model mice with high-fat-diet (HFD)-induced NAFLD. Additionally, we evaluated the impact of SLBZP on the intestinal flora and its metabolites and mitochondrial energy metabolism in NAFLD. We used HFD to establish a mouse model of NAFLD. Different drug interventions were administered. We measured serum biochemical indices. Liver sections were visualised with hematoxylin-eosin and oil red O staining. 16S rDNA amplicon sequencing technology was used to analyse the diversity and abundance of the intestinal flora. Short-chain fatty acids (SCFAs) in the intestinal contents were detected using GC-MS. Liver tissue was sampled to detect mitochondrial membrane functional indices. Western blotting was used to determine the levels of mitochondrial pathway-related proteins, namely, uncoupling protein 2 (UCP2), adenosine monophosphate-activated protein kinase (AMPK) and inhibitory factor 1 (IF1) of F1Fo ATP synthesis/hydrolase, in the liver. The spleen-invigorating classic recipe of SLBZP reduced liver lipid deposition in mice with HFD-induced NAFLD. Additionally, SCFAs produced by intestinal flora metabolism regulated the UCP2/AMPK/IF1 signalling pathway involved in liver mitochondrial energy metabolism to improve the liver mitochondrial membrane permeability, respiratory state and oxidative phosphorylation efficiency of mice with NAFLD. Finally, SLBZP increased the liver ATP level. Our results suggest that the therapeutic effect of SLBZP on NAFLD is related to the regulation of hepatic mitochondrial energy metabolism by intestinal flora and its metabolites and is possibly associated with the UCP2/AMPK/IF1 signalling pathway.

IF1 ablation prevents ATP synthase oligomerization, enhances mitochondrial ATP turnover and promotes an adenosine-mediated pro-inflammatory phenotype

ATPase Inhibitory Factor 1 (IF1) regulates the activity of mitochondrial ATP synthase. The expression of IF1 in differentiated human and mouse cells is highly variable. In intestinal cells, the overexpression of IF1 protects against colon inflammation. Herein, we have developed a conditional IF1-knockout mouse model in intestinal epithelium to investigate the role of IF1 in mitochondrial function and tissue homeostasis. The results show that IF1-ablated mice have increased ATP synthase/hydrolase activities, leading to profound mitochondrial dysfunction and a pro-inflammatory phenotype that impairs the permeability of the intestinal barrier compromising mouse survival upon inflammation. Deletion of IF1 prevents the formation of oligomeric assemblies of ATP synthase and alters cristae structure and the electron transport chain. Moreover, lack of IF1 promotes an intramitochondrial Ca2+ overload in vivo, minimizing the threshold to Ca2+-induced permeability transition (mPT). Removal of IF1 in cell lines also prevents the formation of oligomeric assemblies of ATP synthase, minimizing the threshold to Ca2+-induced mPT. Metabolomic analyses of mice serum and colon tissue highlight that IF1 ablation promotes the activation of de novo purine and salvage pathways. Mechanistically, lack of IF1 in cell lines increases ATP synthase/hydrolase activities and installs futile ATP hydrolysis in mitochondria, resulting in the activation of purine metabolism and in the accumulation of adenosine, both in culture medium and in mice serum. Adenosine, through ADORA2B receptors, promotes an autoimmune phenotype in mice, stressing the role of the IF1/ATP synthase axis in tissue immune responses. Overall, the results highlight that IF1 is required for ATP synthase oligomerization and that it acts as a brake to prevent ATP hydrolysis under in vivo phosphorylating conditions in intestinal cells.

F-ATP synthase inhibitory factor 1 regulates metabolic reprogramming involving its interaction with c-Myc and PGC1α.

F-ATP synthase inhibitory factor 1 (IF1) is an intrinsic inhibitor of F-ATP synthase. It is known that IF1 mediates metabolic phenotypes and cell fate, yet the molecular mechanisms through which IF1 fulfills its physiological functions are not fully understood. Ablation of IF1 favors metabolic switch to oxidative metabolism from glycolysis. c-Myc and PGC1α are critical for metabolic reprogramming. This work identified that IF1 interacted with Thr-58 phosphorylated c-Myc, which might thus mediate the activity of c-Myc and promote glycolysis. The interaction of IF1 with PGC1α inhibited oxidative respiration. c-Myc and PGC1α were localized to mitochondria under mitochondrial stress in an IF1-dependent manner. Furthermore, IF1 was found to be required for the protective effect of hypoxia on c-Myc- and PGC1α-induced cell death. This study suggested that the interactions of IF1 with transcription factors c-Myc and PGC1α might be involved in IF1-regulatory metabolic reprogramming and cell fate.

1684-P: Transgene Integration-Induced Genomic Rearrangement in a Noncoding Region of Chromosome 1 Leads to Spontaneous Obesity and Type 2 Diabetes in Mice

Obesity is a critical risk factor for type 2 diabetes (T2D) and has become a global health issue. We found that a mouse line (C57/B6J) of Floxed-stop over expression of IF1 (ATPase Inhibitory Factor 1) (hereon called FEI) develops spontaneous obesity without induction of transgenic expression. Targeted-Locus-Amplification (TLA) analyses revealed a rearrangement in upstream sequences of the transgene integration site, and a duplication downstream in a non-coding region of chromosome 1. Male and female FEI mice show early dyslipidemia before weight gain at two months, reaching 50-60 grams at 6-8 months. Body composition revealed FEI mice have markedly increased fat mass and modestly increased lean mass, consistent with morphometric findings of substantially increased peripheral fat pads. FEI mice were hyperphagic. When subjected to pair-feeding, they reverted to comparable WT body weight levels, then gained weight again when fed ad libidum. Adult FEI mice maintain comparable physical activity levels to their WT counterparts, but indirect metabolic levels among FEI mice declined. These mice exhibited glucose and insulin tolerance at six weeks of age, as well as hyperglycemia, hyper-insulinemia, and hyper-leptinemia. Histology H&E staining revealed markedly enlarged adipocytes with crown-like structures on visceral white adipose tissue sections, and increased fat deposition in liver sections. RNAseq analyses from subcutaneous white adipose tissues of 5-month-old FEI mice demonstrate upregulation of adipogenic and inflammatory genes. Isolated FEI preadipocytes exhibited increased proliferation but impaired lipid deposition. RT-PCR revealed upregulation of inflammatory genes (IFI202b, TNF-α, and IL6). Together, we show FEI mice are a novel obese mouse model. Preclinical studies using this model may help yield insights into novel pathogenic mechanisms and effective treatments for obesity. Disclosure D.White: None. S.Alahari: None. E.D.Lazartigues: None. Q.Yang: None. J.Wu: None. S.Kang: None. L.Lauterboeck: None. P.Mobasheran: None. F.Paliarin: None. T.Nguyen: None. M.Elgazzaz: None. R.Maiya: None. Funding American Diabetes Association (1-17-IBS-184 to Q.Y.)

F-ATP Synthase Inhibitory Factor 1 in Regulation of Mitochondria Permeability Transition Pore and Metabolic Reprogramming

Mitochondrial permeability transition pore (PTP) plays an important role in mitochondrial physiology and cell fate. Emerging studies highlight PTP forms from F-ATP synthase, but whether F-ATP synthase inhibitory factor 1 (IF1) regulates the activity of PTP is basically unknown. We have recently demonstrated that IF1 interacts with p53-CyPD complex and promotes opening of the PTP, and IF1 is necessary for the formation of p53-CyPD complex. IF1, a natural inhibitor of F-ATP synthase, acts as a main driver of metabolic switch to a Warburg phenotype. In this Commentary, we intend to discuss that the PTP may act as an alternative mechanism through which IF1 regulates metabolic reprogramming. The PTP participates in physiological Ca2+/ROS homeostasis and cell fate depending on the open state. The PTP-regulatory role of IF1 provides a clue that IF1 participates in metabolic plasticity probably involving modulation of PTP activity.

Plasma Level of ATPase Inhibitory Factor 1 and Intrinsic Capacity in Community-Dwelling Older Adults: Prospective Data From the MAPT Study.

Intrinsic capacity (IC) is a concept related to functionality that reflects healthy aging. ATPase inhibitory factor 1 (IF1) is a multifaceted protein that regulates mitochondrial oxidative phosphorylation (OXPHOS), and may be involved in IC. The objective of this study is to investigate the association between plasma levels of IF1 and IC changes in community-dwelling older adults. Community-dwelling older adults from the Multidomain Alzheimer Preventive Trial (MAPT Study) were enrolled in this study. A composite IC score was calculated based on 4 IC domains: locomotion, psychological dimension, cognition, and vitality (with data available annually over 4 years of follow-up). Secondary analyses were conducted on the sensory domain (with data available only for 1 year of follow-up). Mixed-model linear regression adjusted for confounders was conducted. A total of 1 090 participants with usable IF1 values were included in the study (75.3 ± 4.4 years; 64% females). Compared to the lowest quartile, both the low- and high-intermediate IF1 quartiles were found to be cross-sectionally associated with greater composite IC scores across 4 domains (βlow-intermediate, 1.33; 95% confidence interval [CI] 0.06-2.60 and βhigh-intermediate, 1.78; 95% CI 0.49-3.06). In the secondary analyses, the highest quartile was found to be associated with a slower decline in composite IC scores across 5 domains over 1 year (βhigh 1.60; 95% CI 0.06-3.15). The low- and high-intermediate IF1 quartiles were also found to be cross-sectionally associated with greater locomotion (βlow-intermediate, 2.72; 95% CI 0.36-5.08) and vitality scores (βhigh-intermediate, 1.59; 95% CI 0.06-3.12), respectively. This study is the first to demonstrate that levels of circulating IF1, a mitochondrial-related biomarker, are associated with IC composite scores in both cross-sectional and prospective analyses among community-dwelling older adults. However, further research is needed to confirm these findings and elucidate the potential underlying mechanisms that may explain these associations.

The effect of krill oil on Wnt/β-catenin signaling pathway in acetaminophen-induced acute liver injury in mice

Abstract Objectives This study investigated the effect of krill oil (KO) on liver damage caused by acetaminophen (APAP). Methods In the present study, the control and APAP groups were given distilled water by gavage for 14 days. In addition, the KO and APAP+KO groups were given 500 mg/kg krill oil by gavage for 14 days. At the end of 14 days, 0.9 % sodium chloride solution (saline solution) administration was applied intraperitoneally to the control and KO groups. Meanwhile, 220 mg/kg acetaminophen was administered to the APAP and APAP+KO groups. While some biochemical parameters in plasma were examined, some oxidative stress parameters in plasma and liver tissue were evaluated. Apoptotic and inflammatory responses of some primer sequences determined by quantitative Real-Time PCR (qPCR) in liver tissue. After histopathological examination of liver tissue, immunohistochemical analysis was performed with Wnt inhibitory factor-1 (Wif-1), beta-catenin (β-Catenin), and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Results The Wif-1 positivity in hepatocytes increased significantly in the APAP group (5.29 ± 0.71) compared to the control (1.14 ± 0.51), and KO (2.14 ± 0.55) groups (p<0.001). The 8-OHdG positivity in hepatocytes increased significantly in the APAP group (19.57 ± 0.58) compared to the control (0.43 ± 0.20), KO (3.57 ± 0.48), and APAP+KO (4.00 ± 2.53) groups (p<0.001). Conclusions As a result, krill oil could be used as a nutritional supplement to protect the liver against acetaminophen-induced liver injury.

An in-silico approach to understand the potential role of Wnt inhibitory factor-1 (WIF-1) in the inhibition of the Wnt signalling pathway

WIF1 (Wnt inhibitory factor 1) is a potent tumour suppressor gene which is epigenetically silenced in numerous malignancies. The associations of WIF1 protein with the Wnt pathway molecules have not been fully explored, despite their involvement in the downregulation of several malignancies. In the present study, a computational approach encompassing the expression, gene ontology analysis and pathway analysis is employed to obtain an insight into the role of the WIF1 protein. Moreover, the interaction of the WIF1 domain with the Wnt pathway molecules was carried out to ascertain the tumour-suppressive role of the domain, along with the determination of their plausible interactions. Initially, the protein-protein interaction network analysis endowed us with the Wnt ligands (such as Wnt1, Wnt3a, Wnt4, Wnt5a, Wnt8a and Wnt9a), along with the Frizzled receptors (Fzd1 and Fzd2) and the low-density lipoprotein complex (Lrp5/6) as the foremost interactors of the protein. Further, the expression analysis of the aforementioned genes and proteins was determined using The Cancer Genome Atlas to comprehend the significance of the signalling molecules in the major cancer subtypes. Moreover, the associations of the aforementioned macromolecular entities with the WIF1 domain were explored using the molecular docking studies, whereas the dynamics and stability of the assemblage were investigated using 100 ns molecular dynamics simulations. Therefore, providing us insights into the plausible roles of WIF1 in inhibiting the Wnt pathways in various malignancies. Communicated by Ramaswamy H. Sarma

Aberrant promoter methylation of Wnt inhibitory factor-1 gene is a potential target for treating psoriasis

Psoriasis is a chronic inflammatory skin disease mediated by immune and complex genetic factors. The wingless-related integration site (Wnt) signaling pathway plays a critical role in psoriasis, but how the Wnt pathway is regulated in psoriatic skin and whether it can be exploited for therapeutic benefits is unclear. By comparing biopsies from healthy and psoriatic skin, we found that Wnt inhibitory factor 1 (WIF1), an inhibitor of Wnt signaling, showed reduced expression at both mRNA and protein levels in psoriatic skin. We then quantified methylation of the WIF1 gene promoter by DNA methylation sequencing and found that the WIF1 promoter region was hypermethylated. We further showed that recombinant WIF1 injection ameliorates the imiquimod (IMQ) mouse model of psoriasis. We also revealed that treatment with the DNA methylation inhibitor, decitabine, inhibited proliferation of immortalized human keratinocytes (HaCaT) in a psoriasis-like inflammatory environment. Finally, we applied decitabine to the IMQ mouse model and demonstrated that treatment of mice with decitabine ameliorates the disease. Therefore, our study reveals that methylation of the WIF1 gene is associated with the pathogenesis of psoriasis, and suggests that pharmacological targeting of DNA methylation is a potential treatment strategy for psoriasis.