Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis.

The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC.

Molecular detection and genetic characteristics of porcine circovirus 3 and porcine circovirus 4 in central China.

Porcine circoviruses (PCVs) are a significant cause of concern for swine health, with four genotypes currently recognized. Two of these, PCV3 and PCV4, have been detected in pigs across all age groups, in both healthy and diseased animals. These viruses have been associated with various clinical manifestations, including porcine dermatitis and nephropathy syndrome (PDNS) and respiratory and enteric signs. In this study, we detected PCV3 and PCV4 in central China between January 2022 and February 2023. We tested fecal swabs and tissue samples from growing-finishing and suckling pigs with or without respiratory and systemic manifestations and found the prevalence of PCV3 to be 15.15% (15/99) and that of PCV3/PCV4 coinfection to be 4.04% (4/99). This relatively low prevalence might be attributed to the fact that most of the clinical samples were collected from pigs exhibiting respiratory signs, with only a few samples having been obtained from pigs with diarrhea. In some cases, PCV2 was also detected, and the coinfection rates of PCV2/3, PCV2/4, and PCV2/3/4 were 6.06% (6/99), 5.05% (5/99), and 3.03% (3/99), respectively. The complete genomic sequences of four PCV3 and two PCV4 isolates were determined. All four of the PCV3 isolates were of subtype PCV3b, and the two PCV4 isolates were of subtype PCV4b. Two mutations (A24V and R27K) were found in antibody recognition domains of PCV3, suggesting that they might be associated with immune escape. This study provides valuable insights into the molecular epidemiology and evolution of PCV3 and PCV4 that will be useful in future investigations of genotyping, immunogenicity, and immune evasion strategies.

Dynamic contrast-enhanced MR imaging in identifying active anal fistula after surgery.

BACKGROUND: It is challenging to identify residual or recurrent fistulas from the surgical region, while MR imaging is feasible. The aim was to use dynamic contrast-enhanced MR imaging (DCE-MRI) technology to distinguish between active anal fistula and postoperative healing (granulation) tissue. METHODS: Thirty-six patients following idiopathic anal fistula underwent DCE-MRI. Subjects were divided into Group I (active fistula) and Group IV (postoperative healing tissue), with the latter divided into Group II (≤ 75 days) and Group III (> 75 days) according to the 75-day interval from surgery to postoperative MRI reexamination. MRI classification and quantitative analysis were performed. Correlation between postoperative time intervals and parameters was analyzed. The difference of parameters between the four groups was analyzed, and diagnostic efficiency was tested by receiver operating characteristic curve. RESULTS: Wash-in rate (WI) and peak enhancement intensity (PEI) were significantly higher in Group I than in Group II (p = 0.003, p = 0.040), while wash-out rate (WO), time to peak (TTP), and normalized signal intensity (NSI) were opposite (p = 0.031, p = 0.007, p = 0.010). Area under curves for discriminating active fistula from healing tissue within 75 days were 0.810 in WI, 0.708 in PEI, 0.719 in WO, 0.783 in TTP, 0.779 in NSI. All MRI parameters were significantly different between Group I and Group IV, but not between Group II and Group III, and not related to time intervals. CONCLUSION: In early postoperative period, DCE-MRI can be used to identify active anal fistula in the surgical area. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR2000033072.

The circHMGCS1-miR-205-5p-ErBB3 axis mediated the Sanggenon C-induced anti-proliferation effects on human prostate cancer.

Prostate cancer (PCa) is associated with a high incidence and metastasis rate globally, resulting in an unsatisfactory prognosis and a huge economic burden due to the current deficient of therapeutic strategies. As the most abundant component of Cortex Mori, Sanggenon C (SC) is well known to possess bioactivities in tumors, but its mechanism is poorly understood. Consequently, we attempted to investigate whether SC could modulate circular RNA(s) levels and hence anti-PCa development. We found that SC dramatically promoted cell apoptosis and induced G0/G1 phase arrest in PCa cell lines via the circHMGCS1-miR-205-5p-ErBB3 axis. In brief, circHMGCS1 is highly expressed in PCa and is positively correlated with the degree of malignancy. Over-expression of circHMGCS1 is not only associated with the proliferation of PCa cells but also blocks SC-induced pro-apoptotic effects. As a verified sponge of circHMGCS1, miR-205-5p is down-regulated in PCa tumors, which negatively regulates PCa cell proliferation by modulating ErBB3 expression. After miR-205-5p mimics or inhibitors were used to transfect PCa cells, the effects of circHMGCS1 OE and SC on PCa cells were completely diminished. Similar to miR-205-5p inhibitors, siErBB3 could oppose SC-triggered pro-apoptotic effects on PCa cells. All these results were confirmed in vivo. Together, SC exerts its anti-tumor effects on PCa by inhibiting circHMGCS1 expression and results in the latter losing the ability to sponge miR-205-5p. Subsequently, unfettered miR-205-5p could mostly down-regulate ErBB3 expression by binding to the 5'UTR of ErBB3 mRNA, which eventually resulted in PCa cell cycle arrest and pro-apoptosis.

Real-World Emission Characteristics of Full-Volatility Organics Originating from Nonroad Agricultural Machinery during Agricultural Activities.

Nonroad agricultural machinery (NRAM) emissions constitute a significant source of air pollution in China. Full-volatility organics originating from 19 machines under 6 agricultural activities were measured synchronously. The diesel-based emission factors (EFs) for full-volatility organics were 4.71 ± 2.78 g/kg fuel (average ± standard deviation), including 91.58 ± 8.42% volatile organic compounds (VOCs), 7.94 ± 8.16% intermediate-volatility organic compounds (IVOCs), 0.28 ± 0.20% semivolatile organic compounds (SVOCs), and 0.20 ± 0.16% low-volatility organic compounds (LVOCs). Full-volatility organic EFs were significantly reduced by stricter emission standards and were the highest under pesticide spraying activity. Our results also demonstrated that combustion efficiency was a potential factor influencing full-volatility organic emissions. Gas-particle partitioning in full-volatility organics could be affected by multiple factors. Furthermore, the estimated secondary organic aerosol formation potential based on measured full-volatility organics was 143.79 ± 216.80 mg/kg fuel and could be primarily attributed to higher-volatility-interval IVOCs (bin12-bin16 contributed 52.81 ± 11.58%). Finally, the estimated emissions of full-volatility organics from NRAM in China (2021) were 94.23 Gg. This study provides first-hand data on full-volatility organic EFs originating from NRAM to facilitate the improvement of emission inventories and atmospheric chemistry models.

Real-world emission characteristics of carbonyl compounds from agricultural machines based on a portable emission measurement system.

Emissions of carbonyl compounds from agricultural machines cannot be ignored. Carbonyl compounds can cause the formation of ozone (O3) and secondary organic aerosols, which can cause photochemical smog to form. In this study, 20 agricultural machines were tested using portable emission measurement system (PEMS) under real-world tillage processes. The exhaust gases were sampled using 2,4-dinitrophenylhydrazine cartridges, and 15 carbonyl compounds were analyzed by high-performance liquid chromatography. Carbonyl compound emission factors for agricultural machines were 51.14-3315.62 mg/(kg-fuel), and were 2.58 ± 2.05, 0.86 ± 1.07 and 0.29 ± 0.20 g/(kg-fuel) for China 0, China II and China III emission standards, respectively. Carbonyl compound emission factor for sowing seeds of China 0 agricultural machines was 3.32 ± 1.73 g/(kg-fuel). Formaldehyde, acetaldehyde and acrolein were the dominant carbonyl compounds emitted. Differences in emission standards and tillage processes impact ozone formation potential (OFP). The mean OFP was 20.15 ± 16.15 g O3/(kg-fuel) for the China 0 emission standard. The OFP values decreased by 66.9% from China 0 to China II, and 67.4% from China II to China III. The mean OFP for sowing seeds of China 0 agricultural machines was 25.92 ± 13.84 g O3/(kg-fuel). Between 1.75 and 24.22 times more ozone was found to be formed during sowing seeds than during other processes for China 0 and China II agricultural machines. Total carbonyl compound emissions from agricultural machines in China was 19.23 Gg in 2019. The results improve our understanding of carbonyl compound emissions from agricultural machines in China.

Chemical characterization of volatile organic compounds (VOCs) emitted from multiple cooking cuisines and purification efficiency assessments.

Cooking process can produce abundant volatile organic compounds (VOCs), which are harmful to environment and human health. Therefore, we conducted a comprehensive analysis in which VOCs emissions from multiple cuisines have been sampled based on the simulation and acquisition platform, involving concentration characteristics, ozone formation potential (OFP) and purification efficiency assessments. VOCs emissions varied from 1828.5 to 14,355.1 µg/m3, with the maximum and minimum values from Barbecue and Family cuisine, respectively. Alkanes and alcohol had higher contributions to VOCs from Sichuan and Hunan cuisine (64.1%), Family cuisine (66.3%), Shandong cuisine (69.1%) and Cantonese cuisine (69.8%), with the dominant VOCs species of ethanol, isobutane and n-butane. In comparison, alcohols (79.5%) were abundant for Huaiyang cuisine, while alkanes (19.7%), alkenes (35.9%) and haloalkanes (22.9%) accounted for higher proportions from Barbecue. Specially, carbon tetrachloride, n-hexylene and 1-butene were the most abundant VOCs species for Barbecue, ranging from 8.8% to 14.6%. The highest OFP occurred in Barbecue. The sensitive species of OFP for Huaiyang cuisine were alcohols, while other cuisines were alkenes. Purification efficiency assessments shed light on the removal differences of individual and synergistic control technologies. VOCs emissions exhibited a strong dependence on the photocatalytic oxidation, with the removal efficiencies of 29.0%-54.4%. However, the high voltage electrostatic, wet purification and mechanical separation techniques played a mediocre or even counterproductive role in the VOCs reduction, meanwhile collaborative control technologies could not significantly improve the removal efficiency. Our results identified more effective control technologies, which were conductive to alleviating air pollution from cooking emissions.

Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway.

RATIONALE: SNX10 (sorting nexin 10) has been reported to play a critical role in regulating macrophage function and lipid metabolism. OBJECTIVE: To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms. METHODS AND RESULTS: SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques. Myeloid cell-specific SNX10 knockdown mice were crossed onto the APOE-/- (apolipoprotein E) background and atherogenesis (high-cholesterol diet-induced) was monitored for 16 weeks. We found that SNX10 expression was increased in atherosclerotic lesions of aortic specimens from humans and APOE-/- mice. Myeloid cell-specific SNX10 deficiency (Δ knockout [KO]) attenuated atherosclerosis progression in APOE-/- mice. The population of anti-inflammatory monocytes/macrophages was increased in the peripheral blood and atherosclerotic lesions of ΔKO mice. In vitro experiments showed that SNX10 deficiency-inhibited foam cell formation through interrupting the internalization of CD36, which requires the interaction of SNX10 and Lyn-AKT (protein kinase B). The reduced Lyn-AKT activation by SNX10 deficiency promoted the nuclear translocation of TFEB (transcription factor EB), thereby enhanced lysosomal biogenesis and LAL (lysosomal acid lipase) activity, resulting in an increase of free fatty acids to fuel mitochondrial fatty acid oxidation. This further promoted the reprogramming of macrophages and shifted toward the anti-inflammatory phenotype. CONCLUSIONS: Our data demonstrate for the first time that SNX10 plays a crucial role in diet-induced atherogenesis via the previously unknown link between the Lyn-Akt-TFEB signaling pathway and macrophage reprogramming, suggest that SNX10 may be a potentially promising therapeutic target for atherosclerosis treatment.

Paeoniflorin prevents aberrant proliferation and differentiation of intestinal stem cells by controlling C1q release from macrophages in chronic colitis.

The pathological features of inflammatory bowel disease necessitate therapeutic strategies aimed at restoring intestinal mucosal barrier function in addition to controlling inflammation. Paeoniflorin, a bioactive herbal constituent isolated from the root of Paeonia albiflora Pall, has been reported to protect against acute colitis in mice. However, the direct molecular target of paeoniflorin in preventing colitis remains elusive. Here, we evaluated the therapeutical effects of Paeoniflorin using IL-10-/- chronic colitis model, and explored the precise mechanism of action involved. Our results demonstrated that intragastric administration of Paeoniflorin significantly ameliorated inflammatory response and restored the aberrant intestinal proliferation and differentiation in IL-10-/-colitis mice. By utilizing a chemical biology approach, we identified C1qa, a crucial component of C1q, is the direct target of Paeoniflorin. Binding of Paeoniflorin to C1qa prevented the cleavage of C1q on macrophages, resulting in the aggregation of surface membrane-anchored C1q and the diminished C1q secretion. The excessive surface membrane-anchored C1q significantly enhanced the phagocytic capability of macrophages and promoted the elimination of infiltrated bacteria and inflammatory cells in mouse colon. The reduced C1q secretion conferred by Paeoniflorin dampened Wnt/ß-catenin signaling activation, thereby rectifying the aberrant proliferation and differentiation of intestinal stem cells (ISCs). In summary, our study demonstrates that Paeoniflorin can orchestrate mucosal healing and intestinal inflammation elimination through C1q-bridged macrophage-ISCs crosstalk, highlighting a novel strategy to treat chronic colitis by restoring mucosal homeostasis via targeting C1q.

Multifunctional fish gelatin hydrogel inverse opal films for wound healing.

BACKGROUND: Wound healing has become a worldwide healthcare issue. Attempts in the area focus on developing patches with the capabilities of avoiding wound infection, promoting tissue remolding, and reporting treatment status that are of great value for wound treatment. RESULTS: In this paper, we present a novel inverse opal film (IOF) patch based on a photo-crosslinking fish gelatin hydrogel with the desired features for wound healing and dynamic monitoring. The film with vibrant structure colors was constructed by using the mixture of fish gelatin methacryloyl, chitosan, and polyacrylic acid (PAA) to replicate colloidal crystal templates. As the structures of these natural biomolecules are well-retained during the fabrication, the resultant IOF was with brilliant biocompatibility, low immunogenicity, antibacterial property, as well as with the functions of promoting tissue growth and wound healing. In addition, the IOF presented interconnected nanopores and high specific surface areas for vascular endothelial growth factor loading, which could further improve its angiogenesis capability. More attractively, as the pH-responsive PAA was incorporated, the IOF patch could report the wound healing status through its real-time structural colors or reflectance spectra. CONCLUSIONS: These features implied the practical value of the multifunctional fish gelatin hydrogel IOFs in clinical wound management.

Deacetylase-independent function of SIRT6 couples GATA4 transcription factor and epigenetic activation against cardiomyocyte apoptosis.

SIRT6 deacetylase activity improves stress resistance via gene silencing and genome maintenance. Here, we reveal a deacetylase-independent function of SIRT6, which promotes anti-apoptotic gene expression via the transcription factor GATA4. SIRT6 recruits TIP60 acetyltransferase to acetylate GATA4 at K328/330, thus enhancing its chromatin binding capacity. In turn, GATA4 inhibits the deacetylase activity of SIRT6, thus ensuring the local chromatin accessibility via TIP60-promoted H3K9 acetylation. Significantly, the treatment of doxorubicin (DOX), an anti-cancer chemotherapeutic, impairs the SIRT6-TIP60-GATA4 trimeric complex, blocking GATA4 acetylation and causing cardiomyocyte apoptosis. While GATA4 hyperacetylation-mimic retains the protective effect against DOX, the hypoacetylation-mimic loses such ability. Thus, the data reveal a novel SIRT6-TIP60-GATA4 axis, which promotes the anti-apoptotic pathway to prevent DOX toxicity. Targeting the trimeric complex constitutes a new strategy to improve the safety of DOX chemotherapy in clinical application.

Remembering online and offline: the effects of retrieval contexts, cues, and intervals on autobiographical memory.

The current study examined the impact of social media as a retrieval context (in contrast to private recall) on the retention of autobiographical memory. At session 1, participants (N = 177) generated recent life events in response to cue words and then described the event details as if they were writing about the events either on WeChat or in their diaries. They received a surprise memory test for the events at session 2 either one week or two weeks later, either with or without the original cue words. Participants in the WeChat condition recalled less consistent memories between the two sessions than those in the diary condition, especially when the memory test took place at the one-week interval and when there were no cues to assist recall at the two-week interval. It appears that memories recalled on social media are subject to greater reconstruction in subsequent offline recall, and that the timing of recall and the presence of memory cues interact with the reconstructive process. These findings shed new light on autobiographical remembering in the digital age.

Digital soil mapping of soil total nitrogen based on Landsat 8, Sentinel 2, and WorldView-2 images in smallholder farms in Yellow River Basin, China.

Predicting spatial explicit information of soil nutrients is critical for sustainable soil management and food security under climate change and human disturbance in agricultural land. Digital soil mapping (DSM) techniques can utilize soil-landscape information from remote sensing data to predict the spatial pattern of soil nutrients, and it is important to explore the effects of remote sensing data types on DSM. This research utilized Landsat 8 (LT), Sentinel 2 (ST), and WorldView-2 (WV) remote sensing data and employed partial least squares regression (PLSR), random forest (RF), and support vector machine (SVM) algorithms to characterize the spatial pattern of soil total nitrogen (TN) in smallholder farm settings in Yellow River Basin, China. The overall relationships between TN and spectral indices from LT and ST were stronger than those from WV. Multiple red edge band-based spectral indices from ST and WV were relevant variables for TN, while there were no red band-based spectral indices from ST and WV identified as relevant variables for TN. Soil moisture and vegetation were major driving forces of soil TN spatial distribution in this area. The research also concluded that farmlands of crop rotation had relatively higher TN concentration compared with farmlands of monoculture. The soil prediction models based on WV achieved relatively lower model performance compared with those based on ST and LT. The effects of remote sensing data spectral resolution and spectral range on enhancing soil prediction model performance are higher than the effects of remote sensing data spatial resolution. Soil prediction models based on ST can provide location-specific soil maps, achieve fair model performance, and have low cost. This research suggests DSM research utilizing ST has relatively high prediction accuracy, and can produce soil maps that are fit for the spatial explicit soil management for smallholder farms.

Comparative genomic analysis of a naturally born serpentized pig reveals putative mutations related to limb and bone development.

BACKGROUND: It is believed that natural selection acts on the phenotypical changes caused by mutations. Phenotypically, from fishes to amphibians to reptiles, the emergence of limbs greatly facilitates the landing of ancient vertebrates, but the causal mutations and evolutionary trajectory of this process remain unclear. RESULTS: We serendipitously obtained a pig of limbless phenotype. Mutations specific to this handicapped pig were identified using genome re-sequencing and comparative genomic analysis. We narrowed down the causal mutations to particular chromosomes and even several candidate genes and sites, such like a mutation-containing codon in gene BMP7 (bone morphogenetic protein) which was conserved in mammals but variable in lower vertebrates. CONCLUSIONS: We parsed the limbless-related mutations in the light of evolution. The limbless pig shows phenocopy of the clades before legs were evolved. Our findings might help deduce the emergence of limbs during vertebrate evolution and should be appealing to the broad community of human genetics and evolutionary biology.

Variation characteristics of fine particulate matter and its components in diesel vehicle emission plumes.

A rapid reaction occurs near the exhaust nozzle when vehicle emissions contact the air. Twenty diesel vehicles were studied using a new multipoint sampling system that is suitable for studying the exhaust plume near the exhaust nozzle. The variation characteristics of fine particle matter (PM2.5) and its components in diesel vehicle exhaust plumes were analyzed. The PM2.5 emissions gradually increased with increasing distance from the nozzle in the plume. Elemental carbon emissions remained basically unchanged, organic carbon and total carbon (TC) increased with increasing distance. The concentrations of SO42-, NO3- and NH4+ (SNA) directly emitted by the vehicles were very low but increased rapidly in the exhaust plume. The selective catalytic reduction (SCR) reduced 42.7% TC, 40% NO3- emissions, but increased 104% SO42- and 36% NH4+ emissions, respectively. In summary, the SCR reduced 29% primary PM2.5 emissions for the tested diesel vehicles. The NH4NO3 particle formation maybe more important in the plume, and there maybe other forms of formation of NH4+ (eg. NH4Cl). The generation of secondary organic carbon (SOC) plays a leading role in the generation of secondary PM2.5. The SCR enhanced the formation of SOC and SNA in the plume, but comprehensive analysis shows that the SCR more enhanced the SNA formation in the plume, which is mainly new particles formation process. The inconsistency between secondary organic aerosol (SOA) and primary organic aerosol definitions is one of the important reasons for the difference between SOA simulation and observation.

Sirt6 deacetylase activity regulates circadian rhythms via Per2.

Circadian clock relies on a transcription and translation feedback loop (TTFL). Two transcription factors, i.e. Bmal1 and Clock, activate the transcription of Period (Per) and Cryptochrome (Cry), which inhibit their own transcription when accumulated to a critical concentration. NAD+-dependent deacylase Sirt1 deacetylates Bmal1 and Per2 to regulate circadian rhythms. Sirt6 interacts with Bmal1 to regulate clock-controlled gene (CCG) expression by local chromatin remodeling. Whether Sirt6 directly modify clock components is elusive. Here, we found that loss of Sirt6 jeopardizes circadian phase. At molecular level, Sirt6 interacts with and deacetylates Per2, thus preventing its proteasomal degradation. These data highlight an important function of Sirt6 in the direct regulation of TTFL and circadian rhythms.

Developing natural polymers for skin wound healing.

Natural polymers are complex organic molecules that occur in the natural environment and have not been subjected to artificial synthesis. They are frequently encountered in various creatures, including mammals, plants, and microbes. The aforementioned polymers are commonly derived from renewable sources, possess a notable level of compatibility with living organisms, and have a limited adverse effect on the environment. As a result, they hold considerable significance in the development of sustainable and environmentally friendly goods. In recent times, there has been notable advancement in the investigation of the potential uses of natural polymers in the field of biomedicine, specifically in relation to natural biomaterials that exhibit antibacterial and antioxidant characteristics. This review provides a comprehensive overview of prevalent natural polymers utilized in the biomedical domain throughout the preceding two decades. In this paper, we present a comprehensive examination of the components and typical methods for the preparation of biomaterials based on natural polymers. Furthermore, we summarize the application of natural polymer materials in each stage of skin wound repair. Finally, we present key findings and insights into the limitations of current natural polymers and elucidate the prospects for their future development in this field.

Dynamic Restructuring of Cu7S4/Cu for Efficient CO2 Electro-reduction to Formate.

Optimized catalytic properties and reactant adsorption energy played a crucial role in promoting CO2 electrocatalysis. Herein, Cu7S4/Cu underwent in situ dynamic restructuring to generate S-Cu2O/Cu hybrid catalyst for effective electrochemical CO2 reduction to formate that outperformed Cu2O/Cu and Cu7S4. Thermodynamic and in situ Raman spectra revealed that the optimized adsorption of the HCOO* intermediate on S-Cu2O/Cu was regulated and the H2 pathway (surface H) was suppressed by S-doping. Meanwhile, Cu7S4/Cu nanoflowers created abundant boundaries for ECR and strengthened the CO2 adsorption by inducing Cu. These findings provide a new perspective on synthetic methods for various electrocatalytic reduction processes.

A Current Understanding of FXR in NAFLD: The multifaceted regulatory role of FXR and novel lead discovery for drug development.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) has reached 30 %, with an annual increase. The incidence of NAFLD-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. However, there are currently no US Food and Drug Administration-approved drugs for NAFLD. Increasing evidence underscores the close association between NAFLD and bile acid metabolism disorder, highlighting the feasibility of targeting the bile acid signaling pathway for NAFLD treatment. The farnesoid X receptor (FXR) is an endogenous receptor for bile acids that exhibits favorable effects in ameliorating the metabolic imbalance of bile acids, lipid disorders, and disruption of intestinal homeostasis, all of which are key characteristics of NAFLD, making FXR a promising therapeutic target for NAFLD. The present review provides a comprehensive overview of the diverse mechanisms through which FXR improves NAFLD, with particular emphasis on its involvement in regulating bile acid homeostasis and the recent advancements in drug development targeting FXR for NAFLD treatment.

Gentisic acid prevents colorectal cancer metastasis via blocking GPR81-mediated DEPDC5 degradation.

BACKGROUND: Metastasis driven by epithelial-mesenchymal transition (EMT) remains a significant contributor to the poor prognosis of colorectal cancer (CRC), and requires more effective interventions. GPR81 signaling has been linked to tumor metastasis, while lacks an efficient specific inhibitor. PURPOSE: Our study aimed to investigate the effect and mechanism of Gentisic acid on colorectal cancer (CRC) metastasis. STUDY DESIGN: A lung metastasis mouse model induced by tail vein injection and a subcutaneous graft tumor model were used. Gentisic acid (GA) was administered by an intraperitoneal injection. HCT116 was treated with lactate to establish an in vitro model. METHODS: MC38 cells with mCherry fluorescent protein were injected into tail vein to investigate lung metastasis ability in vivo. GA was administered by intraperitoneal injection for 3 weeks. The therapeutic effect was evaluated by survival rates, histochemical analysis, RT-qPCR and live imaging. The mechanism was explored using small interfering RNA (siRNA), Western blotting, RT-qPCR and immunofluorescence. RESULTS: GA had a therapeutic effect on CRC metastasis and improved survival rates and pathological changes in dose-dependent manner. GA emerged as an GPR81 inhibitor, effectively suppressed EMT and mTOR signaling in CRC induced by lactate both in vivo and in vitro. Mechanistically, GA halted lactate-induce degradation of DEPDC5 through impeding the activation of Chaperone-mediated autophagy (CMA). CONCLUSION: CMA-mediated DEPDC5 degradation is crucial for lactate/GPR81-induced CRC metastasis, and GA may be a promising candidate for metastasis by inhibiting GPR81 signaling.