L-AP Alleviates Liver Injury in Septic Mice by Inhibiting Macrophage Activation via Suppressing NF-κB and NLRP3 Inflammasome/Caspase-1 Signal Pathways.

Liver injury and progressive liver failure are severe life-threatening complications in sepsis, further worsening the disease and leading to death. Macrophages and their mediated inflammatory cytokine storm are critical regulators in the occurrence and progression of liver injury in sepsis, for which effective treatments are still lacking. l-Ascorbic acid 6-palmitate (L-AP), a food additive, can inhibit neuroinflammation by modulating the phenotype of the microglia, but its pharmacological action in septic liver damage has not been fully explored. We aimed to investigate L-AP's antisepticemia action and the possible pharmacological mechanisms in attenuating septic liver damage by modulating macrophage function. We observed that L-AP treatment significantly increased survival in cecal ligation and puncture-induced WT mice and attenuated hepatic inflammatory injury, including the histopathology of the liver tissues, hepatocyte apoptosis, and the liver enzyme levels in plasma, which were comparable to NLRP3-deficiency in septic mice. L-AP supplementation significantly attenuated the excessive inflammatory response in hepatic tissues of septic mice in vivo and in cultured macrophages challenged by both LPS and ATP in vitro, by reducing the levels of NLRP3, pro-IL-1ß, and pro-IL-18 mRNA expression, as well as the levels of proteins for p-I-κB-α, p-NF-κB-p65, NLRP3, cleaved-caspase-1, IL-1ß, and IL-18. Additionally, it impaired the inflammasome ASC spot activation and reduced the inflammatory factor contents, including IL-1ß and IL-18 in plasma/cultured superannuants. It also prevented the infiltration/migration of macrophages and their M1-like inflammatory polarization while improving their M2-like polarization. Overall, our findings revealed that L-AP protected against sepsis by reducing macrophage activation and inflammatory cytokine production by suppressing their activation in NF-κB and NLRP3 inflammasome signal pathways in septic liver.

Fabrication of caffeoylquinic acid-loaded burdock polysaccharide nanoparticles and their antioxidant activity in hydrogen peroxide-damaged HepaRG cells.

Herein, burdock polysaccharide (BP) and modified burdock polysaccharide (MBP) were prepared, followed by the fabrication of chlorogenic acid (CA)-BP, CA-MBP, isochlorogenic acid A (ICA)-BP, and ICA-MBP nanoparticles. Afterward, the structural characteristics, physical stability, digestive characteristics, and antioxidant activity of hydrogen peroxide (H2O2)-damaged HepaRG cells were evaluated. The result indicated that the loading capacities of CA in BP-CA and MBP-CA were 0.14 and 0.53 µg/mg, respectively. Conversely, the loading capacities of ICA in BP-ICA and MBP-ICA were 0.36 and 0.60 µg/mg, respectively. Four complex nanoparticles exhibited excellent physical stability under different pH values, temperatures, and ionic concentrations, especially MBP-CA and MBP-ICA. Moreover, four complex nanoparticles could protect caffeoylquinic acid from being released in gastric fluid. All six samples exhibited high antioxidant activity in H2O2-induced HepaRG cells, especially BP and MBP-CA. These findings indicated that caffeoylquinic acid-polysaccharide complexes were successfully prepared and highlighted the potential of polysaccharides as natural carriers for hydrophobic bioactive molecules.

Physicochemical, Structural, and Functional Properties of Fructans from Single-Clove Garlic and Multiclove Garlic: A Comparison.

This study aimed to compare the structural features and functional properties of polysaccharides from single-clove garlic (SGPs) and multiclove garlic (MGPs) and to establish their structure-function relationships. Both SGPs and MGPs were identified as fructans consisting mainly of →1)-ß-d-Fruf (2→ and →6)-ß-d-Fruf (2→ residues but differed in average molecular weights (6.76 and 5.40 kDa, respectively). They shared similar thermodynamic properties, X-ray diffraction patterns, and high gastrointestinal digestive stability. These two purified fructans could dose-dependently scavenge free radicals, reduce oxidized metals, and effectively alleviate metronidazole-induced oxidative stress and CuSO4-induced inflammation in zebrafish via inhibiting the overexpression of inflammation-related proteins and cytokines. SGPs showed lower free radical scavenging activity in vitro than MGPs but higher antioxidant and anti-inflammatory activities in vivo. Taken together, the molecular weight was the main structural difference between the two garlic fructans of different varieties, which is a potential reason for their differences in biological activities.

NLRP6 deficiency inhibits neuroinflammation and ameliorates brain injury in ischemic stroke by blocking NLRs inflammasomes activation through proteasomal degradation of pro-caspase-1.

Innate inflammation is crucial for ischemic stroke development. NLRP6, a nucleotide-binding and oligomerization domain-like receptors (NLRs) family member, regulates innate inflammation. Whether NLRP6 regulates neurological damage and neuroinflammation during ischemic stroke remains unclear. We report that NLRP6 is abundantly expressed in microglia and significantly upregulated in the ischemic brain. The brain injury severity was alleviated in NLRP6-deficient mice after ischemic stroke, as evidenced by reduced cerebral infarct volume, decreased neurological deficit scores, improved histopathological morphological changes, ameliorated neuronal denaturation, and relief of sensorimotor dysfunction. In the co-culture OGD/R model, NLRP6 deficiency prevented neuronal death and attenuated microglial cell injury. NLRP6 deficiency blocked several NLRs inflammasomes' activation and abrogated inflammasome-related cytokine production by decreasing the expression of the common effector pro-caspase-1. NLRP6 deficiency reduced pro-caspase-1's protein level by inducing proteasomal degradation. These findings confirm the neuroprotective role of NLRP6 deficiency in ischemic stroke and its underlying regulation mechanism in neuroinflammation and provide a potential therapeutic target for ischemic stroke.

Two rearranged acylphloroglucinols with moderate neuroprotective effects from Hypericum ascyron Linn.

Phytochemical studies on the leaves and twigs of Hypericum ascyron Linn. led to the isolation of two previously undescribed rearranged polycyclic polyprenylated acylphloroglucinols (PPAP) with a 4,5-seco-3(2H)-furanone skeleton, named hyperascone A and B (1-2). Additionally, a known PPAP tomoeone A (3) and two known xanthones 1,3,5 -trihydroxy-6-O-prenylxanthone (4) and 3,7-dihydroxy-1,6-dimethoxyxanthone (5) were also isolated. The structures of the compounds were determined by the analysis of their spectroscopic data including HRMS, NMR and ECD. All of the five isolated compounds exhibited neuroprotective effects against MPP+ and microglia activation induced damage of SH-SY5Y cells.

Cepharanthine analogs mining and genomes of Stephania accelerate anti-coronavirus drug discovery.

Cepharanthine is a secondary metabolite isolated from Stephania. It has been reported that it has anti-conronaviruses activities including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Here, we assemble three Stephania genomes (S. japonica, S. yunnanensis, and S. cepharantha), propose the cepharanthine biosynthetic pathway, and assess the antiviral potential of compounds involved in the pathway. Among the three genomes, S. japonica has a near telomere-to-telomere assembly with one remaining gap, and S. cepharantha and S. yunnanensis have chromosome-level assemblies. Following by biosynthetic gene mining and metabolomics analysis, we identify seven cepharanthine analogs that have broad-spectrum anti-coronavirus activities, including SARS-CoV-2, Guangxi pangolin-CoV (GX_P2V), swine acute diarrhoea syndrome coronavirus (SADS-CoV), and porcine epidemic diarrhea virus (PEDV). We also show that two other genera, Nelumbo and Thalictrum, can produce cepharanthine analogs, and thus have the potential for antiviral compound discovery. Results generated from this study could accelerate broad-spectrum anti-coronavirus drug discovery.

Cytogenetic and genomic characterization of a novel wheat-tetraploid Thinopyrum elongatum 1BS·1EL translocation line with stripe rust resistance.

Stripe rust, caused by Puccinia striiformis f. sp tritici (Pst), is a destructive wheat disease pathogen. Thinopyrum elongatum is a valuable germplasm including diploid, tetraploid, and decaploid with plenty of biotic and abiotic resistance. In a previous study, we generated a stripe rust resistance wheat-tetraploid Th. elongatum 1E/1D substitution line K17-841-1. To further apply the wild germplasm for wheat breeding, we selected and obtained a new homozygous wheat-tetraploid Th. elongatum translocation line T1BS·1EL using genomic in situ hybridization (GISH), fluorescence in situ hybridization (FISH), oligo-FISH-Painting, and the wheat 55K single nucleotide polymorphisms (SNPs) genotyping array. The T1BS·1EL is highly resistant to stripe rust at the seedling and adult stage. Pedigree and molecular marker analyses revealed that the resistance gene was located on chromosome arm 1EL of tetraploid Th. elongatum, tentatively named Yr1EL. Besides, we developed and validated 32 Simple Sequence Repeats (SSR) markers and two kompititive allele specific PCR (KASP) assays which were specific to tetraploid Th. elongatum chromosome arm 1EL to facilitate marker-assisted selection for alien 1EL stripe rust resistance breeding. This will help us explore and locate the stripe rust resistance gene mapping on the 1E chromosome and deploy it in the wheat breeding program.

Localized biogenic volatile organic compound emission inventory in China: A comprehensive review.

Volatile organic compounds (VOCs) are the precursors of forming ozone (O3) and fine particulate matter (PM2.5). Accurate estimates of biogenic VOC (BVOC) emissions is essential for understanding the formation mechanism of O3 and PM2.5 pollution and precise reduction on anthropogenic emissions and thereby mitigating O3 and PM2.5 pollution. To gain comprehensive knowledge of BVOC emissions and improve the accuracy of their estimation, this study reviewed localized national, regional, and municipal emission estimations in China. From their comparisons, BVOC emission characteristics and deficiencies in the inventory compilation methodology were also investigated. The estimated BVOC emissions in China ranged between 10 and 58.9 Tg yr-1 and 10.9-18.9 Tg C yr-1, with diverse contributions for different BVOC categories. The simulated historical and future BVOC emissions exhibited an increasing trend. The uncertainty of the BVOC estimates was mainly from the applications of incomplete emission models, less localized accurate emission factors, deficient vegetation cover information, and low-resolution meteorological data in the inventory compilation. The regional and municipal BVOC emission inventories mainly focused on the Beijing-Tianjin-Hebei, Pearl River Delta, Sichuan Basin, and Yangtze River Delta regions, as well as the cities therein. For the same area, different studies reported diverse BVOC emissions by a maximum of two orders of magnitude. There is usually a lack of basic data with more detailed investigations and higher precision for estimation of BVOC emissions. By summarizing the measurements on terrestrial and marine BVOC emission fluxes, they are mainly focused on the Guangdong, Zhejiang and Jiangxi provinces, and Yellow Sea, East China Sea, and South China Sea, respectively. Expanding the temporal and spatial scales of observations is encouraged to enhance our understanding on the emissions and improve the emission estimates.

Effects of age and disease duration on the efficacy and safety of iGlarLixi in Asian people with type 2 diabetes: A post hoc analysis of the LixiLan-O-AP and LixiLan-L-CN trials.

AIM: To evaluate the effect of age and disease duration on the efficacy and safety of iGlarLixi versus insulin glargine 100 units/ml (iGlar) or lixisenatide (Lixi) alone in Asian people with type 2 diabetes (T2D) uncontrolled on oral antidiabetic drugs (LixiLan-O-AP) or basal insulin ± oral antidiabetic drugs (LixiLan-L-CN). MATERIALS AND METHODS: In this post hoc analysis, the glycated haemoglobin (HbA1c) changes were assessed from baseline to week 24 (LixiLan-O-AP) or 30 (LixiLan-L-CN) in subgroups defined by baseline age (<65, ≥65 years) and duration of T2D. The proportion who achieved the composite of HbA1c <7% (<53.0 mmol/mol) without weight gain and without symptomatic hypoglycaemia (plasma glucose ≤3.9 mmol/L) and the incidences of hypoglycaemia and gastrointestinal disorders were also analysed. RESULTS: HbA1c reductions were consistently greater with iGlarLixi versus iGlar or Lixi across all subgroups, including participants aged ≥65 years and those with T2D for ≥15 or ≥20 years. Greater proportions of participants achieved HbA1c <7% (<53.0 mmol/mol) without weight gain or hypoglycaemia with iGlarLixi versus iGlar or Lixi, regardless of age or T2D duration. Hypoglycaemia incidence was similar with iGlarLixi versus iGlar across most subgroups; the incidence of gastrointestinal disorders was lower with iGlarLixi versus Lixi in all subgroups. CONCLUSIONS: iGlarLixi showed consistent efficacy and safety across all age and disease duration subgroups in Asian people with uncontrolled T2D, including older individuals and those with longstanding disease.

Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs.

Vascular remodeling plays a vital role in hypertensive diseases and is an important target for hypertension treatment. Irisin, a newly discovered myokine and adipokine, has been found to have beneficial effects on various cardiovascular diseases. However, the pharmacological effect of irisin in antagonizing hypertension-induced vascular remodeling is not well understood. In the present study, we investigated the protection and mechanisms of irisin against hypertension and vascular remodeling induced by angiotensin II (Ang II). Adult male mice of wild-type, FNDC5 (irisin-precursor) knockout, and FNDC5 overexpression were used to develop hypertension by challenging them with Ang II subcutaneously in the back using a microosmotic pump for 4 weeks. Similar to the attenuation of irisin on Ang II-induced VSMCs remodeling, endogenous FNDC5 ablation exacerbated, and exogenous FNDC5 overexpression alleviated Ang II-induced hypertension and vascular remodeling. Aortic RNA sequencing showed that irisin deficiency exacerbated intracellular calcium imbalance and increased vasoconstriction, which was parallel to the deterioration in both ER calcium dysmetabolism and ER stress. FNDC5 overexpression/exogenous irisin supplementation protected VSMCs from Ang II-induced remodeling by improving endoplasmic reticulum (ER) homeostasis. This improvement includes inhibiting Ca2+ release from the ER and promoting the re-absorption of Ca2+ into the ER, thus relieving Ca2+-dependent ER stress. Furthermore, irisin was confirmed to bind to its receptors, αV/ß5 integrins, to further activate the AMPK pathway and inhibit the p38 pathway, leading to vasoprotection in Ang II-insulted VSMCs. These results indicate that irisin protects against hypertension and vascular remodeling in Ang II-challenged mice by restoring calcium homeostasis and attenuating ER stress in VSMCs via activating AMPK and suppressing p38 signaling.

Home-based exercise in dialysis patients with end-stage renal disease: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Lack of exercise may reduce the quality of life, physical capability, and functional capability of dialysis patients. Home-based exercise seems to be a desirable form of low-cost intervention. But the effectiveness of this intervention in the dialysis population is still unclear. The purpose of this meta-analysis is to provide effective evidence to determine the impact of home-based exercise on functional capacity, physical capacity, muscular strength, biochemical parameters, and health-related quality of life among dialysis patients with end-stage renal disease (ESRD). METHODS: PubMed, Embase, Cochrane Library, and Web of Science were searched from inception to May 2023, to identify potential randomized controlled trials (RCTs) assessing the effectiveness of home-based exercise in dialysis patients with ESRD. Two independent reviewers selected studies, extracted data, and assessed the risk of bias using the Cochrane tool. Evidence summary using fixed or random effects for meta-analysis. RESULTS: Twelve RCTs including 1008 dialysis patients met the inclusion criteria. The meta-analysis showed significant effects of home-based exercise on physical capacity. Seven studies reported the results of the 6-min walking test, compared with short-term (0-3 months) home-based exercise (P = 0.76), long-term (3-6 months) interventions (P < 0.001) can significantly improve the results of the 6-min walking test. The results showed that home-based exercise did significantly improve patients' VO2 peak (P = 0.007). Compared with center-based exercise or usual care, home exercise did not significantly improve handgrip strength, quality of life or CRP and other biochemical parameters (P > 0.05). CONCLUSION: The results showed that long-term home-based exercise can improve walking ability. In addition, home-based exercise had the benefit on the VO2 peak of ESRD patients receiving dialysis patients. However, there was no statistically significant difference in handgrip strength, health-related quality of life, CRP, and other biochemical parameters.

Design, synthesis and evaluation of novel UDCA-aminopyrimidine hybrids as ATX inhibitors for the treatment of hepatic and pulmonary fibrosis.

To discover novel anti-fibrotic agents, a series of UDCA-aminopyrimidine hybrids were designed and synthesized as potent ATX inhibitors by molecular hybridization strategy. The ATX inhibitory activities of all synthesized compounds were evaluated using the LPC choline release assay. The preliminary structure-activity relationship was concluded. Among them, 12a and 12h exhibited the strongest ATX inhibitory activities with IC50 values of 7.62 ± 0.62 and 7.51 ± 0.72 nM respectively, which were 9-fold more effective than the positive control drug GLPG-1690. Molecular docking studies revealed that 12a and 12h occupied the hydrophobic pocket and tunnel of the ATX binding site. The cytotoxicity assay of 12a and 12h revealed that they had no obvious toxicity at concentrations up to 80 µM, therefore their anti-hepatic fibrosis and anti-pulmonary fibrosis activities were further investigated. The results suggested that 12a and 12h significantly decreased the gene and protein expression of α-SMA, COL1A1 and FN in both TGF-ß1-induced HSC-LX2 and CCC-HPF-1 cells. In addition, 12a and 12h significantly inhibited cells migration in both TGF-ß1-induced HSC-LX2 and CCC-HPF-1 cells. Preliminary mechanistic studies indicated that 12a and 12h exerted anti-hepatic fibrosis and anti-pulmonary fibrosis effects by inhibiting the TGF-ß/Smad signaling pathway. Overall, our findings suggested that 12a and 12h might be two promising anti-fibrotic agents, or might serve as two new lead compounds for the further development of anti-fibrotic agents.

The effect of Dendrobium officinale extract in inhibiting the senescence of H2 O2 -induced fibroblasts based on the senescence-associated secretory phenotype.

BACKGROUND: Dendrobium officinale is widely used for a long time in China, with effect of antioxidation, antitumor, enhancing immunity and so on. In recent years, Dendrobium officinale has been gradually used in cosmetics due to its powerful beauty effects. AIMS: Based on senescence-associated secretory phenotype (SASP), we studied the antiaging effect of Dendrobium officinale extract (DOE) on skin. METHODS: The senescent model of human skin fibroblasts was established by the induction of H2 O2 , and the content of SASP factors was tested after the treatment of DOE, such as interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-1 (MMP-1). RESULTS: It was found that after the treatment with different concentrations of DOE, the contents of IL-6, MCP-1 and MMP-1 all decreased in different degrees. CONCLUSIONS: It indicated that DOE could inhibit the secretion of SASP factors and was a promising natural antiaging agent.

4-Octyl itaconate alleviates renal ischemia reperfusion injury by ameliorating endoplasmic reticulum stress via Nrf2 pathway.

Renal ischemia-reperfusion injury (IRI) is a common clinical complication of multiple severe diseases. Owing to its high mortality and the lack of effective treatment, renal IRI is still an intractable problem for clinicians. Itaconate, which is a metabolite of cis-aconitate, can exert anti-inflammatory and antioxidant roles in many diseases. As a derivative of itaconate with high cell membrane permeability, 4-octyl itaconate (4-OI) could provide a protective effect for various diseases. However, the role of 4-OI in renal IRI is still unclear. Herein, we examined whether 4-OI afforded kidney protection through attenuating endoplasmic reticulum stress (ERS) via nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. To observe the effects of 4-OI on alleviating renal pathologic injury, improving renal dysfunction, decreasing inflammatory cytokines, and reducing oxidative stress, we utilized C57BL/6J mice with bilateral renal pedicle clamped and HK-2 cells with hypoxia/reoxygenation (H/R) exposure in our study. In addition, through western blot assay, we found 4-OI ameliorated renal IRI-induced ERS, and activated Nrf2 pathway. Moreover, Nrf2-knockout (KO) mice and Nrf2 knockdown HK-2 cells were used to validate the role of Nrf2 signaling pathway in 4-OI-mediated alleviation of ERS caused by renal IRI. We demonstrated that 4-OI relieved renal injury and suppressed ERS in wild-type mice, while the therapeutic role was not shown in Nrf2-KO mice. Similarly, 4-OI could exert cytoprotective effect and inhibit ERS in HK-2 cells after H/R, but not in Nrf2 knockdown cells. Our in vivo and in vitro studies revealed that 4-OI protected renal IRI through attenuating ERS via Nrf2 pathway.

Phase separation underlies signaling activation of oncogenic NTRK fusions.

NTRK (neurotrophic tyrosine receptor kinase) gene fusions that encode chimeric proteins exhibiting constitutive activity of tropomyosin receptor kinases (TRK), are oncogenic drivers in multiple cancer types. However, the underlying mechanisms in oncogenesis that involve various N-terminal fusion partners of NTRK fusions remain elusive. Here, we show that NTRK fusion proteins form liquid-like condensates driven by their N-terminal fusion partners. The kinase reactions are accelerated in these condensates where the complexes for downstream signaling activation are also concentrated. Our work demonstrates that the phase separation driven by NTRK fusions is not only critical for TRK activation, but the condensates formed through phase separation serve as organizational hubs for oncogenic signaling.

Subchronic exposure to di-(2-ethylhexyl) phthalate (DEHP) elicits blood-brain barrier dysfunction and neuroinflammation in male C57BL/6J mice.

BACKGROUND: Exposure to di-(2-ethylhexyl) phthalate (DEHP) can cause neurotoxicity but the mechanism is not clear. Blood brain barrier (BBB) is one of the most important tissues to protect the brain. However, whether DEHP can disrupt the BBB or not remains unclear. The objective of this study is to investigate the potential effects of subchronic DEHP exposure on BBB integrity and discuss the role of BBB in DEHP inducible neurotoxicity with an emphasis on neuroinflammatory responses. Male adult C57BL/6J mice were orally administered with vehicle or 200 or 750 mg/kg/day DEHP for 90 days. Subchronic exposure to high-dose DEHP increased water intake but decreased body weight and brain weight. The concentrations of DEHP metabolites increased in serum from all DEHP-exposed groups while increased in brain only from the high-dose group. DEHP induced neurobehavioural alterations and damaged hippocampal neurons. DEHP increased BBB permeability by Evans blue (EB) extravasation and decreased tight junction proteins (ZO-1, occludin, and claudin-5) while presenting a neuroinflammatory feature characterized by the upregulated inflammatory mediators TNF-α and the NLRP3/caspase-1/IL-1ß inflammasome pathway. Our data provide new insights into neurotoxicity caused by subchronic DEHP exposure, which is probably involved in BBB dysfunction and neuroinflammatory responses.

Carboxy-Functionalized Covalent Organic Framework as a Carrier for Lipase Immobilization and Its Application in Inhibitors Screening.

Covalent organic frameworks (COFs) with large specific surface areas, high porosity, good stability, and designable structure are promising carriers for immobilized enzymes. It is important to explore lipase inhibitors from natural foods as lipase inhibitors are closely related to the treatment of obesity. In this work, a carboxyl functionalized covalent organic framework (TpBD-3COOH) was prepared by solvothermal method for covalent immobilization of porcine pancreatic lipase (PPL) and obtained the enzyme-decorated COF (PPL@COF). The immobilized lipase showed wider pH and temperature tolerance with the same optimal pH and temperature of 7.5 and 50 ℃ compared to free lipase. After 6 successive reuses, the PPL@COF maintained 53.0% of its original activity. Immobilized lipase also displayed enhanced storage stability (55.4% after 14 days at 4 ℃). When p-nitrophenyl acetate was applied as the substrate, the calculated Michaelis constant was 3.57 mM and the half maximal inhibitory concentration of orlistat was 3.20 µM. Finally, the PPL@COF was used for enzyme inhibitors screening from natural foods combined with UV spectrophotometry, and Hawthorn was screened for excellent lipase inhibitory activity.

Hypoxia tolerance in fish depends on catabolic preference between lipids and carbohydrates.

Hypoxia is a common environmental stress factor in aquatic organisms, which varies among fish species. However, the mechanisms underlying the ability of fish species to tolerate hypoxia are not well known. Here, we showed that hypoxia response in different fish species was affected by lipid catabolism and preference for lipid or carbohydrate energy sources. Activation of biochemical lipid catabolism through peroxisome proliferator-activated receptor alpha (Pparα) or increasing mitochondrial fat oxidation in tilapia decreased tolerance to acute hypoxia by increasing oxygen consumption and oxidative damage and reducing carbohydrate catabolism as an energy source. Conversely, lipid catabolism inhibition by suppressing entry of lipids into mitochondria in tilapia or individually knocking out three key genes of lipid catabolism in zebrafish increased tolerance to acute hypoxia by decreasing oxygen consumption and oxidative damage and promoting carbohydrate catabolism. However, anaerobic glycolysis suppression eliminated lipid catabolism inhibition-promoted hypoxia tolerance in adipose triglyceride lipase (atgl) mutant zebrafish. Using 14 fish species with different trophic levels and taxonomic status, the fish preferentially using lipids for energy were more intolerant to acute hypoxia than those preferentially using carbohydrates. Our study shows that hypoxia tolerance in fish depends on catabolic preference for lipids or carbohydrates, which can be modified by regulating lipid catabolism.

Design, synthesis and evaluation of ursodeoxycholic acid-cinnamic acid hybrids as potential anti-inflammatory agents by inhibiting Akt/NF-κB and MAPK signaling pathways.

A series of ursodeoxycholic acid (UDCA)-cinnamic acid hybrids were designed and synthesized. The anti-inflammatory activity of these derivatives was screened through evaluating their inhibitory effects of LPS-induced nitric oxide production in RAW264.7 macrophages. The preliminary structure-activity relationship was concluded. Among them, 2m showed the best inhibitory activity against NO (IC50 = 7.70 µM) with no significant toxicity. Further study revealed that 2m significantly decreased the levels of TNF-α, IL-1ß, IL-6 and PGE2, down-regulated the expression of iNOS and COX-2. Preliminary mechanism study indicated that the anti-inflammatory activity of 2m was related to the inhibition of the Akt/NF-κB and MAPK signaling pathway. Furthermore, 2m reduced inflammation by a mouse model of LPS-induced inflammatory disease in vivo. In brief, our findings indicated that 2m might serve as a new lead compound for further development of anti-inflammatory agents.