ALDOB/KAT2A interactions epigenetically modulate TGF-ß expression and T cell functions in hepatocellular carcinogenesis.

BACKGROUND AND AIMS: Cross talk between tumor cells and immune cells enables tumor cells to escape immune surveillance and dictate responses to immunotherapy. Previous studies have identified that downregulation of the glycolytic enzyme fructose-1,6-bisphosphate aldolase B (ALDOB) in tumor cells orchestrated metabolic programming to favor HCC. However, it remains elusive whether and how ALDOB expression in tumor cells affects the tumor microenvironment in HCC. APPROACH AND RESULTS: We found that ALDOB downregulation was negatively correlated with CD8 + T cell infiltration in human HCC tumor tissues but in a state of exhaustion. Similar observations were made in mice with liver-specific ALDOB knockout or in subcutaneous tumor models with ALDOB knockdown. Moreover, ALDOB deficiency in tumor cells upregulates TGF-ß expression, thereby increasing the number of Treg cells and impairing the activity of CD8 + T cells. Consistently, a combination of low ALDOB and high TGF-ß expression exhibited the worst overall survival for patients with HCC. More importantly, the simultaneous blocking of TGF-ß and programmed cell death (PD) 1 with antibodies additively inhibited tumorigenesis induced by ALDOB deficiency in mice. Further mechanistic experiments demonstrated that ALDOB enters the nucleus and interacts with lysine acetyltransferase 2A, leading to inhibition of H3K9 acetylation and thereby suppressing TGFB1 transcription. Consistently, inhibition of lysine acetyltransferase 2A activity by small molecule inhibitors suppressed TGF-ß and HCC. CONCLUSIONS: Our study has revealed a novel mechanism by which a metabolic enzyme in tumor cells epigenetically modulates TGF-ß signaling, thereby enabling cancer cells to evade immune surveillance and affect their response to immunotherapy.

MXene-Mediated Cellulose Conductive Hydrogel with Ultrastretchability and Self-Healing Ability.

Constructing natural polymers such as cellulose, chitin, and chitosan into hydrogels with excellent stretchability and self-healing properties can greatly expand their applications but remains very challenging. Generally, the polysaccharide-based hydrogels have suffered from the trade-off between stiffness of the polysaccharide and stretchability due to the inherent nature. Thus, polysaccharide-based hydrogels (polysaccharides act as the matrix) with self-healing properties and excellent stretchability are scarcely reported. Here, a solvent-assisted strategy was developed to construct MXene-mediated cellulose conductive hydrogels with excellent stretchability (∼5300%) and self-healability. MXene (an emerging two-dimensional nanomaterial) was introduced as emerging noncovalent cross-linking sites between the solvated cellulose chains in a benzyltrimethylammonium hydroxide aqueous solution. The electrostatic interaction between the cellulose chains and terminal functional groups (O, OH, F) of MXene led to cross-linking of the cellulose chains by MXene to form a hydrogel. Due to the excellent properties of the cellulose-MXene conductive hydrogel, the work not only enabled their strong potential in both fields of electronic skins and energy storage but provided fresh ideas for some other stubborn polymers such as chitin to prepare hydrogels with excellent properties.

Conductive, water-retaining and knittable hydrogel fiber from xanthan gum and aniline tetramer modified-polysaccharide for strain and pressure sensors.

Herein, we explored strategies for defoaming and controllable adjustment of spinnable and mechanical properties of polyanion polysaccharide-based hydrogels to fabricate conductive, water-retaining, and knittable hydrogel fibers for next-generation flexible electronics. Xanthan gum (XG) and aniline tetramer modified-polysaccharide (TMAT38) were crosslinked with sodium trimetaphosphate (STMP) and subsequently by Fe3+/Fe2+ ions coordination to prepare conductive and spinnable hydrogels. Polypropylene glycol was introduced as chemical antifoam, and solvent displacement method was adopted to improve mechanical and water-retaining properties. The glycerol-immersed XG5-TMAT38-STMP-Fe3+/CA-PPG hydrogel exhibited conductivity of 3.55×10-3-27.30×10-3 S/cm, storage modulus at linear viscoelastic region of 573 Pa-1717 Pa and self-healing percentage of 100 %-108 %. The 2 h glycerol-immersed hydrogel fibers with good flexibility, moisture retention and freezing tolerance were ready to bend and knit into fabrics. The hydrogel fiber braid possessed better conductivity, reliability and durability than the single hydrogel fiber as strain sensors. The hydrogel fiber fabric perceived tiny vibration triggered by swallowing, speaking and writing with good sensitivity and reproducibility. Furthermore, a three-component model was developed to evaluate response sensitivity and recoverability of the hydrogel fiber fabric-based pressure sensors, which facilitated understanding transient response of polymer-based hydrogel strain and pressure sensors.

Metabolomics and Machine Learning Identify Metabolic Differences and Potential Biomarkers for Frequent Versus Infrequent Gout Flares.

OBJECTIVE: The objective of this study was to discover differential metabolites and pathways underlying infrequent gout flares (InGF) and frequent gout flares (FrGF) using metabolomics and to establish a predictive model by machine learning (ML) algorithms. METHODS: Serum samples from a discovery cohort of 163 patients with InGF and 239 patients with FrGF were analyzed by mass spectrometry-based untargeted metabolomics to profile differential metabolites and explore dysregulated metabolic pathways using pathway enrichment analysis and network propagation-based algorithms. ML algorithms were performed to establish a predictive model based on selected metabolites, which was further optimized by a quantitative targeted metabolomics method and validated in an independent validation cohort with 97 participants with InGF and 139 participants with FrGF. RESULTS: A total of 439 differential metabolites between InGF and FrGF groups were identified. Top dysregulated pathways included carbohydrates, amino acids, bile acids, and nucleotide metabolism. Subnetworks with maximum disturbances in the global metabolic networks featured cross-talk between purine metabolism and caffeine metabolism, as well as interactions among pathways involving primary bile acid biosynthesis, taurine and hypotaurine metabolism, alanine, aspartate, and glutamate metabolism, suggesting epigenetic modifications and gut microbiome in metabolic alterations underlying InGF and FrGF. Potential metabolite biomarkers were identified using ML-based multivariable selection and further validated by targeted metabolomics. Area under receiver operating characteristics curve for differentiating InGF and FrGF achieved 0.88 and 0.67 for the discovery and validation cohorts, respectively. CONCLUSION: Systematic metabolic alterations underlie InGF and FrGF, and distinct profiles are associated with differences in gout flare frequencies. Predictive modeling based on selected metabolites from metabolomics can differentiate InGF and FrGF.

Goliath induces inflammation in obese mice by linking fatty acid ß-oxidation to glycolysis.

Obesity is associated with metabolic disorders and chronic inflammation. However, the obesity-associated metabolic contribution to inflammatory induction remains elusive. Here, we show that, compared with lean mice, CD4+ T cells from obese mice exhibit elevated basal levels of fatty acid ß-oxidation (FAO), which promote T cell glycolysis and thus hyperactivation, leading to enhanced induction of inflammation. Mechanistically, the FAO rate-limiting enzyme carnitine palmitoyltransferase 1a (Cpt1a) stabilizes the mitochondrial E3 ubiquitin ligase Goliath, which mediates deubiquitination of calcineurin and thus enhances activation of NF-AT signaling, thereby promoting glycolysis and hyperactivation of CD4+ T cells in obesity. We also report the specific GOLIATH inhibitor DC-Gonib32, which blocks this FAO-glycolysis metabolic axis in CD4+ T cells of obese mice and reduces the induction of inflammation. Overall, these findings establish a role of a Goliath-bridged FAO-glycolysis axis in mediating CD4+ T cell hyperactivation and thus inflammation in obese mice.

Follicular free fatty acid metabolic signatures and their effects on oocyte competence in non-obese PCOS patients.

In Brief: Polycystic ovary syndrome (PCOS) is a common cause of anovulatory infertility in women. This study identified changes in free fatty acids profiles in the follicular fluid that may lead to better diagnosis and management of infertility in PCOS women. Abstract: Polycystic ovary syndrome (PCOS) is a heterogeneous disease characterized by various endocrine/metabolic disorders and impaired reproductive potential. Alterations in oocyte competence are considered potentially causative factors for infertility in PCOS women and analyzing the composition of follicular fluid in these patients may help to identify which changes have the potential to alter oocyte quality. In this study, free fatty acid metabolic signatures in follicular fluid were performed to identify changes that may impact oocyte competence in non-obese PCOS women. Sixty-four non-obese women (32 with PCOS and 32 age- and BMI-matched controls) undergoing in vitro fertilization were recruited. Embryo quality was morphologically assessed. Free fatty acid metabolic profiling in follicular fluid was performed using gas/liquid chromatography-mass spectrometry. Principal component analysis and orthogonal partial least squares-discriminant analysis models were further constructed. Nine free fatty acids and 24 eicosanoids were identified and several eicosanoids synthesized by the cyclooxygenase pathway were significantly elevated in PCOS patients compared to controls. The combination of PGE2, PGF2α, PGJ2, and TXB2 had an area under the curve of 0.867 (0.775-0.960) for PCOS discrimination. Furthermore, follicular fluid levels of PGE2 and PGJ2 were negatively correlated with high-quality embryo rate in PCOS patients (P < 0.05). Metabolomic analysis revealed that follicular fluid lipidomic profiles undergo changes in non-obese PCOS women, which suggests that identifying changes in important metabolic signatures may give us a better understanding of the pathogenesis of PCOS. Furthermore, elevated PGE2 and PGJ2 concentrations may contribute to impaired oocyte competence in non-obese PCOS patients.

Aldehyde dehydrogenase 2 and PARP1 interaction modulates hepatic HDL biogenesis by LXRα-mediated ABCA1 expression.

HDL cholesterol (HDL-C) predicts risk of cardiovascular disease (CVD), but the factors regulating HDL are incompletely understood. Emerging data link CVD risk to decreased HDL-C in 8% of the world population and 40% of East Asians who carry an SNP of aldehyde dehydrogenase 2 (ALDH2) rs671, responsible for alcohol flushing syndrome; however, the underlying mechanisms remain unknown. We found significantly decreased HDL-C with increased hepatosteatosis in ALDH2-KO (AKO), ALDH2/LDLR-double KO (ALKO), and ALDH2 rs671-knock-in (KI) mice after consumption of a Western diet. Metabolomics identified ADP-ribose as the most significantly increased metabolites in the ALKO mouse liver. Moreover, ALDH2 interacted with poly(ADP-ribose) polymerase 1 (PARP1) and attenuated PARP1 nuclear translocation to downregulate poly(ADP-ribosyl)ation of liver X receptor α (LXRα), leading to an upregulation of ATP-binding cassette transporter A1 (ABCA1) and HDL biogenesis. Conversely, AKO or ALKO mice exhibited lower HDL-C with ABCA1 downregulation due to increased nuclear PARP1 and upregulation of LXRα poly(ADP-ribosyl)ation. Consistently, PARP1 inhibition rescued ALDH2 deficiency-induced fatty liver and elevated HDL-C in AKO mice. Interestingly, KI mouse or human liver tissues showed ABCA1 downregulation with increased nuclear PARP1 and LXRα poly(ADP-ribosyl)ation. Our study uncovered a key role of ALDH2 in HDL biogenesis through the LXRα/PARP1/ABCA1 axis, highlighting a potential therapeutic strategy in CVD.

Biodegradable, Super-Strong, and Conductive Cellulose Macrofibers for Fabric-Based Triboelectric Nanogenerator.

Electronic fibers used to fabricate wearable triboelectric nanogenerator (TENG) for harvesting human mechanical energy have been extensively explored. However, little attention is paid to their mutual advantages of environmental friendliness, mechanical properties, and stability. Here, we report a super-strong, biodegradable, and washable cellulose-based conductive macrofibers, which is prepared by wet-stretching and wet-twisting bacterial cellulose hydrogel incorporated with carbon nanotubes and polypyrrole. The cellulose-based conductive macrofibers possess high tensile strength of 449 MPa (able to lift 2 kg weights), good electrical conductivity (~ 5.32 S cm-1), and excellent stability (Tensile strength and conductivity only decrease by 6.7% and 8.1% after immersing in water for 1 day). The degradation experiment demonstrates macrofibers can be degraded within 108 h in the cellulase solution. The designed fabric-based TENG from the cellulose-base conductive macrofibers shows a maximum open-circuit voltage of 170 V, short-circuit current of 0.8 µA, and output power at 352 µW, which is capable of powering the commercial electronics by charging the capacitors. More importantly, the fabric-based TENGs can be attached to the human body and work as self-powered sensors to effectively monitor human motions. This study suggests the potential of biodegradable, super-strong, and washable conductive cellulose-based fiber for designing eco-friendly fabric-based TENG for energy harvesting and biomechanical monitoring.

Fructose-1,6-Bisphosphate Aldolase B Depletion Promotes Hepatocellular Carcinogenesis Through Activating Insulin Receptor Signaling and Lipogenesis.

BACKGROUND AND AIMS: Insulin receptor (IR) transduces cell surface signal through phosphoinositide 3-kinase (PI3K)-AKT pathways or translocates to the nucleus and binds to the promoters to regulate genes associated with insulin actions, including de novo lipogenesis (DNL). Chronic activation of IR signaling drives malignant transformation, but the underlying mechanisms remain poorly defined. Down-regulation of fructose-1,6-bisphosphate aldolase (ALDO) B in hepatocellular carcinoma (HCC) is correlated with poor prognosis. We aim to study whether and how ALDOB is involved in IR signaling in HCC. APPROACH AND RESULTS: Global or liver-specific ALDOB knockout (L-ALDOB-/- ) mice were used in N-diethylnitrosamine (DEN)-induced HCC models, whereas restoration of ALDOB expression was achieved in L-ALDOB-/- mice by adeno-associated virus (AAV). 13 C6 -glucose was employed in metabolic flux analysis to track the de novo fatty acid synthesis from glucose, and nontargeted lipidomics and targeted fatty acid analysis using mass spectrometry were performed. We found that ALDOB physically interacts with IR and attenuates IR signaling through down-regulating PI3K-AKT pathways and suppressing IR nuclear translocation. ALDOB depletion or disruption of IR/ALDOB interaction in ALDOB mutants promotes DNL and tumorigenesis, which is significantly attenuated with ALDOB restoration in L-ALDOB-/- mice. Notably, attenuated IR/ALDOB interaction in ALDOB-R46A mutant exhibits more significant tumorigenesis than releasing ALDOB/AKT interaction in ALDOB-R43A, whereas knockdown IR sufficiently diminishes tumor-promoting effects in both mutants. Furthermore, inhibiting phosphorylated AKT or fatty acid synthase significantly attenuates HCC in L-ALDOB-/- mice. Consistently, ALDOB down-regulation is correlated with up-regulation of IR signaling and DNL in human HCC tumor tissues. CONCLUSIONS: Our study reports a mechanism by which loss of ALDOB activates IR signaling primarily through releasing IR/ALDOB interaction to promote DNL and HCC, highlighting a potential therapeutic strategy in HCC.

Loss of STAT5A promotes glucose metabolism and tumor growth through miRNA-23a-AKT signaling in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Here, we identified that increased miR-23a expression in HCC tissues was associated with worse survival. More importantly, we found that STAT5A was a target of miR-23a, whose levels significantly decreased in tumor tissues. Stable expression of STAT5A in Huh7 cells suppressed glucose metabolism and tumor growth. Finally, this study showed that increased miR-23a negatively regulated STAT5A, which further activated AKT signaling to enable rapid metabolism for accelerated tumor growth in HCC. Taken together, our results demonstrated that the miR-23a-STAT5A-AKT signaling pathway is critical to alter glucose metabolism in HCC and may offer new opportunities for effective therapy.

Loss of hepatic aldolase B activates Akt and promotes hepatocellular carcinogenesis by destabilizing the Aldob/Akt/PP2A protein complex.

Loss of hepatic fructose-1, 6-bisphosphate aldolase B (Aldob) leads to a paradoxical up-regulation of glucose metabolism to favor hepatocellular carcinogenesis (HCC), but the upstream signaling events remain poorly defined. Akt is highly activated in HCC, and targeting Akt is being explored as a potential therapy for HCC. Herein, we demonstrate that Aldob suppresses Akt activity and tumor growth through a protein complex containing Aldob, Akt, and protein phosphatase 2A (PP2A), leading to inhibition of cell viability, cell cycle progression, glucose uptake, and metabolism. Interestingly, Aldob directly interacts with phosphorylated Akt (p-Akt) and promotes the recruitment of PP2A to dephosphorylate p-Akt, and this scaffolding effect of Aldob is independent of its enzymatic activity. Loss of Aldob or disruption of Aldob/Akt interaction in Aldob R304A mutant restores Akt activity and tumor-promoting effects. Consistently, Aldob and p-Akt expression are inversely correlated in human HCC tissues, and Aldob down-regulation coupled with p-Akt up-regulation predicts a poor prognosis for HCC. We have further discovered that Akt inhibition or a specific small-molecule activator of PP2A (SMAP) efficiently attenuates HCC tumorigenesis in xenograft mouse models. Our work reveals a novel nonenzymatic role of Aldob in negative regulation of Akt activation, suggesting that directly inhibiting Akt activity or through reactivating PP2A may be a potential therapeutic approach for HCC treatment.

Self-healing hyaluronic acid hydrogels based on dynamic Schiff base linkages as biomaterials.

Natural hydrogels are widely investigated for biomedical applications because of their structures similar to extracellular matrix of native tissues, possessing excellent biocompatibility and biodegradability. However, they are often susceptible to mechanical disruption. In this study, self-healing hyaluronic acid (HA) hydrogels are fabricated through a facile dynamic covalent Schiff base reaction. Dialdehyde-modified HA (AHA) precursor was synthesized, and then the AHA/cystamine dihydrochloride (AHA/Cys) hydrogels were formed by blending AHA and Cys at acidic pH levels. By varying Cys to AHA ratio, the hydrogel morphology, swelling and kinetics of gelation could be controlled. Gelation occurred fast, which was predominantly attributed to Schiff base reaction between the dialdehyde groups on AHA and amimo groups on Cys. The hydrogel exhibited improved mechanical properties with increase in Cys content. Furthermore, due to dynamic imine bonds, this hydrogel demonstrated excellent self-healing ability based on the stress after mechanical disruption. Also, it was found to be pH-responsive and injectable. Taken together, this kind of hyaluronic acid hydrogel can provide promising future for various biomedical applications in drug delivery, bioprinting, smart robots and tissue regeneration.

Polyphenolic Proanthocyanidin-B2 suppresses proliferation of liver cancer cells and hepatocellular carcinogenesis through directly binding and inhibiting AKT activity.

The well-documented anticarcinogenic properties of natural polyphenolic proanthocyanidins (OPC) have been primarily attributed to their antioxidant and anti-inflammatory potency. Emerging evidence suggests that OPC may target canonical oncogenic pathways, including PI3K/AKT; however, the underlying mechanism and therapeutic potential remain elusive. Here we identify that proanthocyanidin B2 (OPC-B2) directly binds and inhibits AKT activity and downstream signalling, thereby suppressing tumour cell proliferation and metabolism in vitro and in a xenograft and diethyl-nitrosamine (DEN)-induced hepatocellular carcinoma (HCC) mouse models. We further find that OPC-B2 binds to the catalytic and regulatory PH domains to lock the protein in a closed conformation, similar to the well-studied AKT allosteric inhibitor MK-2206. Molecular docking and dynamic simulation suggest that Lys297 and Arg86 are critical sites of OPC-B2 binding; mutation of Lys297 or Arg86 to alanine completely abolishes the antitumor effects of OPC-B2 but not MK-2206. Together, our study reveals that OPC-B2 is a novel allosteric AKT inhibitor with potent anti-tumour efficacy beyond its antioxidant and anti-inflammatory properties.

Dopamine-Modified Hyaluronic Acid Hydrogel Adhesives with Fast-Forming and High Tissue Adhesion.

Commercial or clinical tissue adhesives are currently limited due to their weak bonding strength on wet biological tissue surface, low biological compatibility, and slow adhesion formation. Although catechol-modified hyaluronic acid (HA) adhesives are developed, they suffer from limitations: insufficient adhesiveness and overfast degradation, attributed to low substitution of catechol groups. In this study, we demonstrate a simple and efficient strategy to prepare mussel-inspired HA hydrogel adhesives with improved degree of substitution of catechol groups. Because of the significantly increased grafting ratio of catechol groups, dopamine-conjugated dialdehyde-HA (DAHA) hydrogels exhibit excellent tissue adhesion performance (i.e., adhesive strength of 90.0 ± 6.7 kPa), which are significantly higher than those found in dopamine-conjugated HA hydrogels (∼10 kPa), photo-cross-linkable HA hydrogels (∼13 kPa), or commercially available fibrin glues (2-40 kPa). At the same time, their maximum adhesion energy is 384.6 ± 26.0 J m-2, which also is 40-400-fold, 2-40-fold, and ∼8-fold higher than those of the mussel-based adhesive, cyanoacrylate, and fibrin glues, respectively. Moreover, the hydrogels can gel rapidly within 60 s and have a tunable degradation suitable for tissue regeneration. Together with their cytocompatibility and good cell adhesion, they are promising materials as new biological adhesives.

Yeast ß-D-glucan exerts antitumour activity in liver cancer through impairing autophagy and lysosomal function, promoting reactive oxygen species production and apoptosis.

Autophagy is an evolutionarily conserved catabolic process that recycles proteins and organelles in a lysosome-dependent manner and is induced as an alternative source of energy and metabolites in response to diverse stresses. Inhibition of autophagy has emerged as an appealing therapeutic strategy in cancer. However, it remains to be explored whether autophagy inhibition is a viable approach for the treatment of hepatocellular carcinoma (HCC). Here, we identify that water-soluble yeast ß-D-glucan (WSG) is a novel autophagy inhibitor and exerts significant antitumour efficacy on the inhibition of HCC cells proliferation and metabolism as well as the tumour growth in vivo. We further reveal that WSG inhibits autophagic degradation by increasing lysosomal pH and inhibiting lysosome cathepsins (cathepsin B and cathepsin D) activities, which results in the accumulation of damaged mitochondria and reactive oxygen species (ROS) production. Furthermore, WSG sensitizes HCC cells to apoptosis via the activation of caspase 8 and the transfer of truncated BID (tBID) into mitochondria under nutrient deprivation condition. Of note, administration of WSG as a single agent achieves a significant antitumour effect in xenograft mouse model and DEN/CCl4 (diethylnitrosamine/carbon tetrachloride)-induced primary HCC model without apparent toxicity. Our studies reveal, for the first time, that WSG is a novel autophagy inhibitor with significant antitumour efficacy as a single agent, which has great potential in clinical application for liver cancer therapy.

Preparation of [Amine-Terminated Generation 5 Poly(amidoamine)]-graft-Poly(lactic-co-glycolic acid) Electrospun Nanofibrous Mats for Scaffold-Mediated Gene Transfection.

Combining biomaterial scaffolds with gene cargos for gene therapy is promising for tissue engineering. Herein, we developed a gene delivery platform through surface grafting of amine-terminated generation 5 poly(amidoamine) (PAMAM) dendrimers (G5·NH2) with biodegradable electrospun poly(lactic-co-glycolic acid) (PLGA) nanofibers by combining layer-by-layer (LbL) electrostatic assembly technology with dendrimer chemistry. PLGA nanofibers were precoated with positively charged poly(diallydimethylammoium chloride) and poly(acrylic acid) through electrostatic interaction and then subsequently cross-linked with G5·NH2 dendrimer covalently through 1-ethyl-3-[3-(dimethylamino)propyl] carbodiimide hydrochloride chemistry. The successful grafting of G5·NH2 dendrimer on PLGA nanofibers was confirmed by X-ray photoelectron spectroscopy. Scanning electron microscopy studies show that smooth, uniform morphology of nanofibers does not significantly change after grafting of G5·NH2 dendrimers except for a slight increase in the fiber diameter, whereas atomic force microscopy images at a high-resolution scale indicated a slightly rough surface for PLGA nanofibers after grafting with G5·NH2 dendrimer. Additionally, PLGA nanofibrous scaffolds became hydrophilic after grafting with G5·NH2 dendrimers. Biological investigation showed that the developed G5·NH2-g-PLGA nanofibrous scaffolds not only allowed for the attachment and proliferation of NIH 3T3 cells but also were capable of complexing pDNA and delivering pDNA/dendrimer complex for solid state gene transfection in situ. The functionalization of PLGA nanofibers with dendrimers may find diverse applications in the area of tissue engineering, gene therapy, and drug delivery.

Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and pentose phosphate pathways.

Metabolic reprogramming is a core hallmark of cancer but it remains poorly defined in hepatocellular carcinogenesis (HCC). Here we show that hepatic aldolase B (Aldob) suppresses HCC by directly binding and inhibiting the rate-limiting enzyme in the pentose phosphate pathway, glucose-6-phosphate dehydrogenase (G6PD). A stage-dependent decrease of Aldob and increase of G6PD in human tumors are correlated with poor prognosis for patients with HCC. Global or liver-specific Aldob knockout promotes tumorigenesis in mice through enhancing G6PD activity and pentose phosphate pathway metabolism, whereas pharmacological inhibition or genetic knockdown of G6PD suppresses HCC. Consistently, restoration of Aldob in Aldob knockout mice attenuates tumorigenesis. We further demonstrate that Aldob potentiates p53-mediated inhibition of G6PD in an Aldob-G6PD-p53 complex. This scaffolding effect is independent of Aldob enzymatic activity. Together, our study reveals a new mode of metabolic reprogramming in HCC due to the loss of Aldob, suggesting a potential therapeutic strategy for HCC treatment.

Rheological and ion-conductive properties of injectable and self-healing hydrogels based on xanthan gum and silk fibroin.

The hydrogels with injectable and self-healing properties were prepared from xanthan gum (XG) and silk fibroin (SF) by using sodium trimetaphosphate (STMP) as crosslinker. A three-stage model of oscillation-shear-oscillation experiment was designed to mimic injection process and to observe destruction and regeneration of the hydrogels after shear. The XG3-SF-STMP hydrogels immediately recovered to original storage modulus of 80.6%-93.8% on removing shear. The hydrogels were 3D printed into the self-supporting constructions of hydrogel fibers with connected porous structures, and the XG3-SF-STMP hydrogel fibers exhibited smaller width than XG3-STMP. Oscillation rheological behavior indicated that XG3-SF-STMP hydrogels formed rapidly and exhibited more solid-like gel behavior than XG3-STMP. The hydrogel structures were destroyed under a strain (100%) larger than critical strain, but were rebuilt under a small strain (1%) with recovery ratio of 91.36-93.96% within 120 s, suggesting a self-healing property. Introduction of SF particles into XG3-STMP crosslinked networks improved stiffness and retained recoverability. Carboxyl and phosphate groups in the hydrogel networks are beneficial for XG3-SF-STMP hydrogels to absorb enough liquid electrolytes, leading to effective ionic conductivity. The ion-conductive hydrogel with injectable, self-healing, controlled release and non-cytotoxic properties possesses a promising prospect for tissue engineering and drug release application.

Elevated levels of arachidonic acid metabolites in follicular fluid of PCOS patients.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive-age women usually accompanied by lipid metabolic disorders. However, it remains unknown whether arachidonic acid (AA) and its metabolites in follicular fluid (FF) were altered in PCOS patients. This study was intended to measure the levels of AA and its metabolites in the FF of non-obese PCOS patients that underwent in vitro fertilization (IVF) and to explore the possible causes of the alterations. Thirty-nine non-obese women with PCOS and 30 non-obese women without PCOS were enrolled. AA and its metabolites were measured by liquid chromatography-mass spectrometry. The levels of AA metabolites generated via cyclooxygenase-2 (COX-2) pathway and cytochrome P450 epoxygenase pathway but not lipoxygenase (LOX) pathway were significantly higher in the FF of PCOS patients. The metabolites generated via COX-2 pathway were significantly correlated with levels of testosterone and fasting insulin in serum. The in vitro study further demonstrated that insulin but not testosterone could promote the IL-1ß and hCG-induced COX-2 expression and prostaglandin E2 (PGE2) secretion in primary human granulosa cells. In conclusion, there was an elevation in AA metabolites in FF of PCOS patients. Insulin played a pivotal role in the increased AA metabolites generated via COX-2, which could be interpreted as another novel molecular pathophysiological mechanism of PCOS.

Recent development on liquid chromatography-mass spectrometry analysis of oxidized lipids.

Polyunsaturated fatty acids (PUFAs) in the cellular membrane can be oxidized by various enzymes or reactive oxygen species (ROS) to form many oxidized lipids. These metabolites are highly bioactive, participating in a variety of physiological and pathophysiological processes. Mass spectrometry (MS), coupled with Liquid Chromatography, has been increasingly recognized as an indispensable tool for the analysis of oxidized lipids due to its excellent sensitivity and selectivity. We will give an update on the understanding of the molecular mechanisms related to generation of various oxidized lipids and recent progress on the development of LC-MS in the detection of these bioactive lipids derived from fatty acids, cholesterol esters, and phospholipids. The purpose of this review is to provide an overview of the formation mechanisms and technological advances in LC-MS for the study of oxidized lipids in human diseases, and to shed new light on the potential of using oxidized lipids as biomarkers and mechanistic clues of pathogenesis related to lipid metabolism. The key technical problems associated with analysis of oxidized lipids and challenges in the field will also discussed.