Yolk-Shell Au NPs@Carbon Porous Nanoreactors Derived from ZIF-8: A High-Efficiency Catalyst for Three-Component Coupling Reaction.

A yolk-shell Au NPs@carbon porous nanoreactor with an active gold (Au) core and a porous carbon shell has been fabricated and demonstrates excellent high activity and cyclic stability as a heterogeneous catalyst for the three-component coupling reaction of aldehyde, amine, and alkyne. Remarkably, the unique yolk-shell nanostructure can protect gold nanoparticles (Au NPs) from aggregation, allow for efficient mass transport, and benefit substrate enrichment, giving rise to enhanced activity, stability, and recyclability.

VGLL2 and TEAD1 fusion proteins drive YAP/TAZ-independent transcription and tumorigenesis by engaging p300.

Studies on Hippo pathway regulation of tumorigenesis largely center on YAP and TAZ, the transcriptional co-regulators of TEAD. Here, we present an oncogenic mechanism involving VGLL and TEAD fusions that is Hippo pathway-related but YAP/TAZ-independent. We characterize two recurrent fusions, VGLL2-NCOA2 and TEAD1-NCOA2, recently identified in spindle cell rhabdomyosarcoma. We demonstrate that, in contrast to VGLL2 and TEAD1, the fusion proteins are strong activators of TEAD-dependent transcription, and their function does not require YAP/TAZ. Furthermore, we identify that VGLL2 and TEAD1 fusions engage specific epigenetic regulation by recruiting histone acetyltransferase p300 to control TEAD-mediated transcriptional and epigenetic landscapes. We showed that small molecule p300 inhibition can suppress fusion proteins-induced oncogenic transformation both in vitro and in vivo. Overall, our study reveals a molecular basis for VGLL involvement in cancer and provides a framework for targeting tumors carrying VGLL, TEAD, or NCOA translocations.

Loss of FoxO1 activates an alternate mechanism of mitochondrial quality control for healthy adipose browning.

Browning of white adipose tissue is hallmarked by increased mitochondrial density and metabolic improvements. However, it remains largely unknown how mitochondrial turnover and quality control are regulated during adipose browning. In the present study, we found that mice lacking adipocyte FoxO1, a transcription factor that regulates autophagy, adopted an alternate mechanism of mitophagy to maintain mitochondrial turnover and quality control during adipose browning. Post-developmental deletion of adipocyte FoxO1 (adO1KO) suppressed Bnip3 but activated Fundc1/Drp1/OPA1 cascade, concurrent with up-regulation of Atg7 and CTSL. In addition, mitochondrial biogenesis was stimulated via the Pgc1α/Tfam pathway in adO1KO mice. These changes were associated with enhanced mitochondrial homeostasis and metabolic health (e.g., improved glucose tolerance and insulin sensitivity). By contrast, silencing Fundc1 or Pgc1α reversed the changes induced by silencing FoxO1, which impaired mitochondrial quality control and function. Ablation of Atg7 suppressed mitochondrial turnover and function, causing metabolic disorder (e.g., impaired glucose tolerance and insulin sensitivity), regardless of elevated markers of adipose browning. Consistently, suppression of autophagy via CTSL by high-fat diet was associated with a reversal of adO1KO-induced benefits. Our data reveal a unique role of FoxO1 in coordinating mitophagy receptors (Bnip3 and Fundc1) for a fine-tuned mitochondrial turnover and quality control, underscoring autophagic clearance of mitochondria as a prerequisite for healthy browning of adipose tissue.

The health benefits of dietary short-chain fatty acids in metabolic diseases.

Short-chain fatty acids (SCFAs) are a subset of fatty acids that play crucial roles in maintaining normal physiology and developing metabolic diseases, such as obesity, diabetes, cardiovascular disease, and liver disease. Even though dairy products and vegetable oils are the direct dietary sources of SCFAs, their quantities are highly restricted. SCFAs are produced indirectly through microbial fermentation of fibers. The biological roles of SCFAs in human health and metabolic diseases are mainly due to their receptors, GPR41 and GPR43, FFAR2 and FFAR3. Additionally, it has been demonstrated that SCFAs modulate DNMTs and HDAC activities, inhibit NF-κB-STAT signaling, and regulate G(i/o)ßγ-PLC-PKC-PTEN signaling and PPARγ-UCP2-AMPK autophagic signaling, thus mitigating metabolic diseases. Recent studies have uncovered that SCFAs play crucial roles in epigenetic modifications of DNAs, RNAs, and post-translational modifications of proteins, which are critical regulators of metabolic health and diseases. At the same time, dietary recommendations for the purpose of SCFAs have been proposed. The objective of the review is to summarize the most recent research on the role of dietary SCFAs in metabolic diseases, especially the signal transduction of SCFAs in metabolic diseases and their functional efficacy in different backgrounds and models of metabolic diseases, at the same time, to provide dietary and nutritional recommendations for using SCFAs as food ingredients to prevent metabolic diseases.

The circadian clock protein Cryptochrome 1 is a direct target and feedback regulator of the Hippo pathway.

Circadian clock controls daily behavior and physiology. The activity of various signaling pathways affects clock gene expression. Here, we show that the core circadian clock gene CRY1 is a direct target of the Hippo pathway effector YAP. YAP binds to TEADs and occupies the proximal promoter regions of CRY1, positively regulating its transcription. Interestingly, we further identified that CRY1 acts in a feedback loop to fine-tune Hippo pathway activation by modulating the expression of YAP and MOB1. Indeed, loss of CRY1 results in enhanced YAP activation. Consistently, we found that YAP levels and activity control clock gene expression and oscillation in synchronized cells. Furthermore, in breast cancer cells, CRY1 downregulation causes YAP/TAZ hyperactivation and enhanced DNA damage. Together, our findings provide a direct mechanistic link between the Hippo pathway and the circadian clock, where CRY1 and Hippo components form an orchestrated signaling network that influences cell growth and circadian rhythm.

Green Synthesis of MOF-801(Zr/Ce/Hf) for CO2/N2 and CO2/CH4 Separation.

The purification of natural gas and the removal of carbon dioxide from flue gases are crucial to economize precious resources and effectively relieve a series of environmental problems caused by global warming. Metal-organic framework (MOF) materials have demonstrated remarkable performance and benefits in the area of gas separation; however, obtaining materials with high gas capacity and selectivity simultaneously remains difficult. In addition, harsh synthesis conditions and solvent toxicity have been restricted in large-scale production and industrial application. Therefore, MOF-801(Zr/Ce/Hf) was created based on the green synthesis of the MOF-801 construction unit by altering the kinds of metal salts, and the impact of three metal nodes on the performance of gas adsorption and separation was demonstrated by contrasting the three MOFs. The results showed that MOF-801(Ce) has the best CO2 adsorption capacity (3.3 mmol/g at 298 K), which also was demonstrated with in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) results, CO2/CH4 (ideal adsorbed solution theory (IAST) = 13.28 at 298 K, 1 bar, CO2/CH4 = 1:1, v/v), and the separation performance of CO2/N2 (IAST = 57.46 at 298 K, 1 bar, CO2/N2 = 1:1, v/v) among the group. Green synthesis of MOF-801(Zr/Ce/Hf) is an ideal candidate for flue gas separation and methane purification because of its high regeneration capacity and strong cyclic stability.

FoxO1 regulates adipose transdifferentiation and iron influx by mediating Tgfß1 signaling pathway.

Adipose plasticity is critical for metabolic homeostasis. Adipocyte transdifferentiation plays an important role in adipose plasticity, but the molecular mechanism of transdifferentiation remains incompletely understood. Here we show that the transcription factor FoxO1 regulates adipose transdifferentiation by mediating Tgfß1 signaling pathway. Tgfß1 treatment induced whitening phenotype in beige adipocytes, reducing UCP1 and mitochondrial capacity and enlarging lipid droplets. Deletion of adipose FoxO1 (adO1KO) dampened Tgfß1 signaling by downregulating Tgfbr2 and Smad3 and induced browning of adipose tissue in mice, increasing UCP1 and mitochondrial content and activating metabolic pathways. Silencing FoxO1 also abolished the whitening effect of Tgfß1 on beige adipocytes. The adO1KO mice exhibited a significantly higher energy expenditure, lower fat mass, and smaller adipocytes than the control mice. The browning phenotype in adO1KO mice was associated with an increased iron content in adipose tissue, concurrent with upregulation of proteins that facilitate iron uptake (DMT1 and TfR1) and iron import into mitochondria (Mfrn1). Analysis of hepatic and serum iron along with hepatic iron-regulatory proteins (ferritin and ferroportin) in the adO1KO mice revealed an adipose tissue-liver crosstalk that meets the increased iron requirement for adipose browning. The FoxO1-Tgfß1 signaling cascade also underlay adipose browning induced by ß3-AR agonist CL316243. Our study provides the first evidence of a FoxO1-Tgfß1 axis in the regulation of adipose browning-whitening transdifferentiation and iron influx, which sheds light on the compromised adipose plasticity in conditions of dysregulated FoxO1 and Tgfß1 signaling.

Palmitoyl acyltransferase ZDHHC7 inhibits androgen receptor and suppresses prostate cancer.

The hormonal transcription factor androgen receptor (AR) is a master regulator of prostate cancer (PCa). Protein palmitoylation, which attaches a palmitate fatty acid to a substrate protein, is mediated by a class of 23 ZDHHC (Zinc-Finger DHHC motif)-family palmitoyltransferases. Although palmitoylation has been shown to modify many proteins and regulate diverse cellular processes, little is known about ZDHHC genes in cancer. Here we examined ZDHHC family gene expression in human tissue panels and identified ZDHHC7 as a PCa-relevant member. RNA-seq analyses of PCa cells with ZDHHC7 de-regulation revealed global alterations in androgen response and cell cycle pathways. Mechanistically, ZDHHC7 inhibits AR gene transcription and therefore reduces AR protein levels and abolishes AR signaling in PCa cells. Accordingly, ZDHHC7 depletion increased the oncogenic properties of PCa cells, whereas restoring ZDHHC7 is sufficient to suppress PCa cell proliferation and invasion in vitro and mitigate xenograft tumor growth in vivo. Lastly, we demonstrated that ZDHHC7 is downregulated in human PCa compared to benign-adjacent tissues, and its loss is associated with worse clinical outcomes. In summary, our study reveals a global role of ZDHHC7 in inhibiting androgen response and suppressing PCa progression and identifies ZDHHC7 loss as a biomarker for aggressive PCa and a target for therapeutic intervention.

Hormonal regulation of metabolism-recent lessons learned from insulin and estrogen.

Hormonal signaling plays key roles in tissue and metabolic homeostasis. Accumulated evidence has revealed a great deal of insulin and estrogen signaling pathways and their interplays in the regulation of mitochondrial, cellular remodeling, and macronutrient metabolism. Insulin signaling regulates nutrient and mitochondrial metabolism by targeting the IRS-PI3K-Akt-FoxOs signaling cascade and PGC1α. Estrogen signaling fine-tunes protein turnover and mitochondrial metabolism through its receptors (ERα, ERß, and GPER). Insulin and estrogen signaling converge on Sirt1, mTOR, and PI3K in the joint regulation of autophagy and mitochondrial metabolism. Dysregulated insulin and estrogen signaling lead to metabolic diseases. This article reviews the up-to-date evidence that depicts the pathways of insulin signaling and estrogen-ER signaling in the regulation of metabolism. In addition, we discuss the cross-talk between estrogen signaling and insulin signaling via Sirt1, mTOR, and PI3K, as well as new therapeutic options such as agonists of GLP1 receptor, GIP receptor, and ß3-AR. Mapping the molecular pathways of insulin signaling, estrogen signaling, and their interplays advances our understanding of metabolism and discovery of new therapeutic options for metabolic disorders.

Assessing the Activity of Transcription Factor FoxO1.

The transcription factor FoxO1 (forkhead box O1) regulates genes that are involved in development, metabolism, cellular innovation, longevity, and stress responses. Assessment of FoxO1 activity is therefore critical to understand the regulatory network of this transcription factor. FoxO1 transactivation activity relies on its ability to bind to the promoters of target genes, which is controlled by posttranslational modifications (e.g., dephosphorylation or phosphorylation) that may promote nuclear translocation or exclusion of FoxO1. In this chapter we describe the protocols for FoxO1 activity assessment using Western blotting analysis of the posttranslational modification of FoxO1 in whole cell lysates and ELISA of DNA binding activity of FoxO1 in nuclear extracts.

Targeting Transcription Factors in Cancer: From "Undruggable" to "Druggable".

Deregulation of transcription factors is critical to hallmarks of cancer. Genetic mutations, gene fusions, amplifications or deletions, epigenetic alternations, and aberrant post-transcriptional modification of transcription factors are involved in the regulation of various stages of carcinogenesis, including cancer initiation, progression, and metastasis. Thus, targeting the dysfunctional transcription factors may lead to new cancer therapeutic strategies. However, transcription factors are conventionally considered as "undruggable." Here, we summarize the recent progresses in understanding the regulation of transcription factors in cancers and strategies to target transcription factors and co-factors for preclinical and clinical drug development, particularly focusing on c-Myc, YAP/TAZ, and ß-catenin due to their significance and interplays in cancer.

Pharmacological blockade of TEAD-YAP reveals its therapeutic limitation in cancer cells.

Targeting TEAD autopalmitoylation has been proposed as a therapeutic approach for YAP-dependent cancers. Here we show that TEAD palmitoylation inhibitor MGH-CP1 and analogues block cancer cell "stemness", organ overgrowth and tumor initiation in vitro and in vivo. MGH-CP1 sensitivity correlates significantly with YAP-dependency in a large panel of cancer cell lines. However, TEAD inhibition or YAP/TAZ knockdown leads to transient inhibition of cell cycle progression without inducing cell death, undermining their potential therapeutic utilities. We further reveal that TEAD inhibition or YAP/TAZ silencing leads to VGLL3-mediated transcriptional activation of SOX4/PI3K/AKT signaling axis, which contributes to cancer cell survival and confers therapeutic resistance to TEAD inhibitors. Consistently, combination of TEAD and AKT inhibitors exhibits strong synergy in inducing cancer cell death. Our work characterizes the therapeutic opportunities and limitations of TEAD palmitoylation inhibitors in cancers, and uncovers an intrinsic molecular mechanism, which confers potential therapeutic resistance.

Molecular insights into the multifaceted functions and therapeutic targeting of high mobility group box 1 in metabolic diseases.

HMGB1 is a ubiquitously expressed protein localized in nucleus, cytoplasm, as well as secreted into extracellular space. Nuclear HMGB1 binds to DNAs and RNAs, regulating genomic stability and transcription. Cytoplasmic HMGB1 regulates autophagy through binding to core autophagy regulators. Secreted extracellular HMGB1 functions as a ligand to various receptors (RAGE and TLRs, etc.), regulating multiple signalling pathways, such as MAPK, PI3K and NF-κB signallings. Trafficking and localization of HMGB1 across cellular compartments could be regulated by its posttranslational modifications, which fine-tune its functions in metabolic diseases, inflammation and cancers. The current review examines the up-to-date findings pertaining to the biological functions of HMGB1, with focus on its posttranslational modifications and roles in downstream signalling pathways involved in metabolic diseases. This review also discusses the feasibility of targeting HMGB1 as a potential pharmacological intervention for metabolic diseases.

Mechanisms of autophagic responses to altered nutritional status.

Autophagy is a dynamic process and critical for cellular remodeling and organelle quality control. In response to altered nutritional status (e.g., fasting and feeding), autophagic activity is finely tuned by transcriptional, posttranslational, and epigenetic regulations via various signaling pathways, including energy sensors (e.g., mechanistic target of rapamycin (mTOR)/ AMP-activated protein kinase - Unc-51 Like Autophagy Activating Kinase 1, mTORC1- WD Repeat Domain, Phosphoinositide Interacting 2, mTORC1- transcription factor EB, perilipin 5- Sirtuin 1, and Sirtuin 1-mediated deacetylation of autophagy proteins), fasting or feeding induced hormones (e.g., fibroblast growth factor [FGF21]- protein kinase A - Jumonji domain-containing protein D3, FGF21- downstream regulatory element antagonist modulator - E3 ligase Midline-1- transcription factor EB, FGF19-SHP- lysine-specific demethylase, insulin- insulin receptor substrate - protein kinase B - forkhead box O, glucagon- protein kinase A - cAMP response binding protein), and lysosomal enzymes (e.g., cathepsin B and cathepsin L). In contrast to fasting that induces autophagy and health benefits, nutrient oversupply (overfeeding or feeding on high energy diets) dysregulates autophagy, which has been increasingly observed in animal models of human chronic diseases such as obesity, diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. Studies have revealed multifaceted effects of high energy diets on autophagy, being either an inhibitor or enhancer of autophagy. The conundrum may arise from the variations in methods for autophagy analysis, components of high energy diets and control diets for treatments, treatment durations, and the ages of genetic backgrounds of laboratory animals. In this article, we reviewed the evidence from both human and animal studies, presenting the molecular mechanism of autophagic response to altered nutritional status and discussing the contributing factors of and possible solution to the current conundrum concerning the exact role of high energy diets in autophagic regulation.

Sirt1 coordinates with ERα to regulate autophagy and adiposity.

Sex difference in adiposity has long been recognized but the mechanism remains incompletely understood. Previous studies suggested that adiposity was regulated by autophagy in response to energy status change. Here, we show that the energy sensor Sirt1 mediates sex difference in adiposity by regulating autophagy and adipogenesis in partnership with estrogen receptor α (ERα). Autophagy and adipogenesis were suppressed by Sirt1 activation or overexpression, which was associated with reduced sex difference in adiposity. Mechanistically, Sirt1 deacetylated and activated AKT and STAT3, resulting in suppression of autophagy and adipogenesis via mTOR-ULK1 and p55 cascades. ERα induced Sirt1 expression and inhibited autophagy in adipocytes, while silencing Sirt1 reversed the effects of ERα on autophagy and promoted adipogenesis. Moreover, Sirt1 deacetylated ERα, which constituted a positive feedback loop in the regulation of autophagy and adiposity. Our results revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity.

Insights into auto-S-fatty acylation: targets, druggability, and inhibitors.

Posttranslational S-fatty acylation (or S-palmitoylation) modulates protein localization and functions, and has been implicated in neurological, metabolic, and infectious diseases, and cancers. Auto-S-fatty acylation involves reactive cysteine residues in the proteins which directly react with fatty acyl-CoA through thioester transfer reactions, and is the first step in some palmitoyl acyltransferase (PAT)-mediated catalysis reactions. In addition, many structural proteins, transcription factors and adaptor proteins might possess such "enzyme-like" activities and undergo auto-S-fatty acylation upon fatty acyl-CoA binding. Auto-S-fatty acylated proteins represent a new class of potential drug targets, which often harbor lipid-binding hydrophobic pockets and reactive cysteine residues, providing potential binding sites for covalent and non-covalent modulators. Therefore, targeting auto-S-fatty acylation could be a promising avenue to pharmacologically intervene in important cellular signaling pathways. Here, we summarize the recent progress in understanding the regulation and functions of auto-S-fatty acylation in cell signaling and diseases. We highlight the druggability of auto-S-fatty acylated proteins, including PATs and other proteins, with potential in silico and rationalized drug design approaches. We also highlight structural analysis and examples of currently known small molecules targeting auto-S-fatty acylation, to gain insights into targeting this class of proteins, and to expand the "druggable" proteome.

The applications and prospects of hydrophobic metal-organic frameworks in catalysis.

In recent years, large numbers of hydrophobic/superhydrophobic metal-organic frameworks (MOFs) have been developed. These hydrophobic MOFs not only retain rich structural variety, highly crystalline frameworks, and uniform micropores, but they also have lower affinity towards water and boosted hydrolytic stability. Until now, there were two main strategies to prepare hydrophobic MOFs, including a one-step method and post-synthesis modification (PSM). PSM was an often-used strategy for preparing hydrophobic MOFs. Hydrophobic MOFs showed unique advantages when used as catalysts for various categories of reactions. Herein, recent research advances relating to hydrophobic MOFs in the catalytic field are presented. The catalytic activities of hydrophobic MOFs and corresponding hydrophilic ones are also compared, and the superiority of hydrophobic MOFs or MOF materials as catalysts in 10 reactions is discussed. Finally, the advantages of hydrophobic MOFs as catalysts or auxiliary materials are summarized and promising future developments of hydrophobic MOFs are highlighted.

Obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland.

BACKGROUND AND OBJECTIVE: Our patient cohort revealed that obesity is strongly associated with steroid-5α reductase type 2 (SRD5A2) promoter methylation and reduced protein expression. The underlying mechanism of prostatic growth in this population is poorly understood. Here we addressed the question of how obesity, inflammation, and steroid hormones affect the development of benign prostatic hyperplasia (BPH). MATERIAL AND METHODS: We used preadipocytes, macrophages, primary human prostatic stromal cells, prostate tissues from high-fat diet-induced obese mice, and 35 prostate specimens that were collected from patients who underwent transurethral resection of the prostate (TURP). RNA was isolated and quantified with RT-PCR. Genome DNA was extracted and SRD5A2 promoter methylation was determined. Sex hormones were determined by high-performance liquid chromatography-tandem mass spectrometry. Protein was extracted and determined by ELISA test. RESULTS: In prostatic tissues with obesity, the levels of inflammatory mediators were elevated. SRD5A2 promoter methylation was promoted, but SRD5A2 expression was inhibited. Inflammatory mediators and saturated fatty acid synergistically regulated aromatase activity. Obesity promoted an androgenic to estrogenic switch in the prostate. CONCLUSIONS: Our findings suggest that obesity-associated inflammation induces androgenic to estrogenic switch in the prostate gland, which may serve as an effective strategy for alternative therapies for management of lower urinary tract symptoms associated with BPH in select individuals.

Autophagy in Adipocyte Differentiation.

Adipose tissue regulates metabolic homeostasis by acting as an endocrine organ and energy reservoir. Adipose tissue development and functional maintenance are dependent on adipocyte differentiation, in which autophagy plays an important role. It has been shown that autophagy deficiency dampens adipocyte differentiation, compromises adipose tissue development, dysregulates adipocytokine secretion, and even causes sudden death in young animals. Therefore, accurate assessment of autophagy in adipocyte is critical for the study of adipose biology or pathology of metabolic diseases. In this chapter, we described the procedure of autophagy analysis during adipocyte differentiation, and discussed the power of steady-state autophagy protein (e.g., beclin 1, LC3, and p62) levels versus autophagy flux to reflect autophagy activity.