Low-Temperature and Fast-Charge Sodium Metal Batteries.

Low-temperature operation of sodium metal batteries (SMBs) at the high rate faces challenges of unstable solid electrolyte interphase (SEI), Na dendrite growth, and sluggish Na+ transfer kinetics, causing a largely capacity curtailment. Herein, low-temperature and fast-charge SMBs are successfully constructed by synergetic design of the electrolyte and electrode. The optimized weak-solvation dual-salt electrolyte enables high Na plating/stripping reversibility and the formation of NaF-rich SEI layer to stabilize sodium metal. Moreover, an integrated copper sulfide electrode is in situ fabricated by directly chemical sulfuration of copper current collector with micro-sized sulfur particles, which significantly improves the electronic conductivity and Na+ diffusion, knocking down the kinetic barriers. Consequently, this SMB achieves the reversible capacity of 202.8 mAh g-1 at -20 °C and 1 C (1 C = 558 mA g-1). Even at -40 °C, a high capacity of 230.0 mAh g-1 can still be delivered at 0.2 C. This study is encouraging for further exploration of cryogenic alkali metal batteries, and enriches the electrode material for low-temperature energy storage.

Synthesis and pharmacodynamic evaluation of Dihydropteridone derivatives against PDCoV in vivo and in vitro.

Porcine Delta Coronavirus (PDCoV) infection can induce serious dehydration, diarrhea and even death of piglets, which has caused huge losses to the breeding industry. PDCoV has been reported to have the potential for cross species transmission, and even reports of infecting humans have emerged. At present, there are still no effective prevention and control measures for PDCoV. In this study, we have designed and synthesized a series of unreported Dihydropteridone derivatives. All of these compounds were evaluated for the against PDCoV in vivo and in vitro for the first time. In this study, antiviral activity (17.34 ± 7.20 µM) and low cytotoxicity (>800 µM) was found in compound W8. Compound W8 exerts antiviral effect on PDCoV by inhibiting cell apoptosis and inflammatory factors caused by virus infection in vitro. In addition, lung and small intestinal lesions caused by PDCoV infection in mice could be significantly reduced by compound W8. These findings highlight the potential of compound W8 as a valuable therapeutic option against PDCoV infection, and lay a foundation for further research and development in this field.

Lysine demethylase LSD1 delivered via small extracellular vesicles promotes gastric cancer cell stemness.

Several studies have examined the functions of nucleic acids in small extracellular vesicles (sEVs). However, much less is known about the protein cargos of sEVs and their functions in recipient cells. This study demonstrates the presence of lysine-specific demethylase 1 (LSD1), which is the first identified histone demethylase, in the culture medium of gastric cancer cells. We show that sEVs derived from gastric cancer cells and the plasma of patients with gastric cancer harbor LSD1. The shuttling of LSD1-containing sEVs from donor cells to recipient gastric cancer cells promotes cancer cell stemness by positively regulating the expression of Nanog, OCT4, SOX2, and CD44. Additionally, sEV-delivered LSD1 suppresses oxaliplatin response of recipient cells in vitro and in vivo, whereas LSD1-depleted sEVs do not. Taken together, we demonstrate that LSD1-loaded sEVs can promote stemness and chemoresistance to oxaliplatin. These findings suggest that the LSD1 content of sEV could serve as a biomarker to predict oxaliplatin response in gastric cancer patients.

Synthesis and evaluation of alkoxy-substituted enamides against influenza A virus in vitro and in vivo.

Alkoxy-substituted enamides are often used as synthetic intermediates due to their special reactivity. To the best our knowledge, the biological activity of alkoxy-substituted amines has never been reported so far. We have synthesized a series of alkoxy-substituted enamides to study their anti-influenza A virus activity in vitro and in vivo. Among these compounds, compound E-2o had the best antiviral activity (EC50 = 2.76 ± 0.67 µM) and low cytotoxicity (CC50 = 662.87 ± 24.85 µM). The mechanism of action of this compound was preliminarily explored by us. It alleviated the cytopathic effects and cell death caused by different subtypes of influenza A virus. Different drug delivery methods and timed dosing experiments had shown that E-2o had the best therapeutic effect and mainly played a role in the early stages of virus replication. The expansion of influenza viruses in cells was inhibited by reducing ROS accumulation, cell apoptosis, and autophagy. Alkoxy-substituted enamide E-2o reduced the production of interferon and other pro-inflammatory factors in the RIG-Ⅰ pathway and its downstream NF-κB was induced by influenza A virus in vitro and in vivo. It avoided damage in the mice which was caused by excessive inflammatory factors. In addition, the weight loss and lung lesion damage in mice caused by influenza virus were improved by compound E-2o. Therefore, Alkoxy-substituted enamide E-2o could inhibit the replication of influenza viruses in vivo and in vitro, and has the potential to be developed into a drug for treating influenza.

A Novel Intelligent Fault Diagnosis Method for Self-Priming Centrifugal Pumps.

The real-time diagnostic monitoring of self-priming centrifugal pumps is essential to ensure their safe operation. Nevertheless, owing to the intricate structure and complex operational conditions inherent in such pumps, existing fault diagnosis methods encounter challenges in effectively extracting crucial fault feature information and accurately identifying fault types. Consequently, this paper introduces an intelligent fault diagnosis method tailored for self-priming centrifugal pumps. The approach amalgamates refined time-shift multiscale fluctuation dispersion entropy, cosine pairwise-constrained supervised manifold mapping, and adaptive chaotic Aquila optimization support vector machine techniques. To begin with, refined time-shift multiscale fluctuation dispersion entropy is employed to extract fault-related features, adeptly mitigating concerns related to entropy domain deviations and instability. Subsequently, the application of cosine pairwise-constrained supervised manifold mapping serves to reduce the dimensionality of the extracted fault features, thereby bolstering the efficiency and precision of the ensuing identification process. Ultimately, the utilization of an adaptive chaotic Aquila optimization support vector machine facilitates intelligent fault classification, leading to enhanced accuracy in fault identification. The experimental findings unequivocally affirm the efficacy of the proposed method in accurately discerning among various fault types in self-priming centrifugal pumps, achieving an exceptional recognition rate of 100%. Moreover, it is noteworthy that the average correct recognition rate achieved by the proposed method surpasses that of five existing intelligent fault diagnosis techniques by a significant margin, registering a notable increase of 15.97%.

Discovery and pharmacodynamic evaluation of the novel butene lactone derivative M355 against influenza A virus in vitro and in vivo.

A new series of butene lactone derivatives were designed according to an influenza neuraminidase target and their antiviral activities against H1N1 infection of Madin-Darby canine kidney cells were evaluated. Among them, a compound that was given the name M355 was identified as the most potent against H1N1 (EC50 = 14.7 µM) with low toxicity (CC50 = 538.13 µM). It also visibly reduced the virus-induced cytopathic effect. Time-of-addition analysis indicated that H1N1 was mostly suppressed by M355 at the late stage of its infectious cycle. M355 inhibited neuraminidase in a dose-dependent fashion to a similar extent as oseltamivir, which was also indicated by a computer modeling experiment. In a mouse model, lung lesions and virus load were reduced and the expression of nucleoprotein was moderated by M355. The enzyme-linked immunosorbent assay and quantitative real-time polymerase chain reaction analyses revealed that the levels of interferon-γ, interferon regulatory factor-3, Toll-like receptor-3, tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, and IL-8 were downregulated in the M355-treated groups, whereas the levels of IL-10 and IL-13 were upregulated. Similarly, IgG was found to be increased in infected mice plasma. These results demonstrate that M355 inhibit the expression of H1N1 in both cellular and animal models. Thus, M355 has the potential to be effective in the treatment of influenza A virus infection.

Screening and pharmacodynamic evaluation of the antirespiratory syncytial virus activity of steroidal pyridine compounds in vitro and in vivo.

Respiratory syncytial virus (RSV) causes serious lower respiratory tract infections and there are currently no safer or more effective drugs available. It is important to find novel medications for RSV infection. A series of steroidal pyridines were synthesized for screening and evaluation of their antiviral activity and investigation of their antiviral mechanism of action. Compound 3l had the highest antiviral activity, with a half-maximal effective concentration (EC50 ) of 3.13 µM. Compound 3l was explored for its effects in vitro on RSV 2 h before infection (pretreatment), at the time of infection (competition), and 2 h after infection (postinfection). Toll-like receptor (TLR)-3, retinoic acid-inducible gene (RIG)-I, interleukin (IL)-6, and interferon (IFN)-ß were suppressed at the cellular level. Mouse lung tissue was subjected to hematoxylin and eosin (HE) staining and immunohistochemistry, which showed that RSV antigen and M gene expression could be reduced by compound 3l. Decreased expression of TLR-3, RIG-I, IL-6, IFN-ß, and IL-10 was also found in vivo. The results indicated that compound 3l exerted its antiviral effects mainly through inhibition of viral replication and downregulation of inflammatory factors.

Screening and pharmacodynamic evaluation of the anti-respiratory syncytial virus activity of butene lactones in vitro and in vivo.

A series of butene lactones were synthesized and these compounds were tested for anti-respiratory syncytial virus (RSV) activity in vitro. Three compounds exhibited an antiviral effect, the highest of which was compound 6b3 with an effective concentration 50% of 6.35 µM. The effects of 6b3 were then evaluated in vivo and a significant reduction in the lung index caused by RSV was detected. Reduced inflammatory infiltration and necrosis of the lungs were revealed by histopathology and gross pathology. Activation of an early immune response by 6b3 was also observed by cytokine analysis via a real-time polymerase chain reaction. These results indicated that 6b3 has an anti-RSV effect both in vitro and in vivo, and is a possible candidate compound for the development of an anti-RSV drug in the future.

Development of a SYBR green I-based duplex real-time PCR assay for detection of pseudorabies virus and porcine circovirus 3.

In the present study, a specific and reliable duplex SYBR green I-based quantitative real-time polymerase chain reaction assay was established to detect pseudorabies virus (PRV) and porcine circovirus 3 (PCV3) simultaneously. Viral genomes of PRV and PCV3 in one specimen were identified by their different melting temperatures with melting peaks at 87 °C and 81 °C for PRV and PCV3 respectively, whilst other non-targeted swine pathogens exhibited no fluorescent signals. The assay displayed a high degree of linearity (R2 > 0.997), and the limits of detection were 37.8 copies/µL, 30.6 copies/µL and 60 copies/µL for PRV, PCV3 and the mixture of two recombinant plasmids, respectively. It had good repeatability and reproducibility, and the coefficients of variation in intra-batch and inter-batch assays were all less than 2.0%. In this research, the duplex assay was further evaluated using 117 clinical tissue specimens from diseased pigs in the field. The results revealed the infection rates of PRV and PCV3 were 23.08% (27/117) and 55.56% (65/117) respectively, and PRV and PCV3 co-infection rate was 14.53% (17/117). The assay could be utilized as a diagnostic tool with specificity, sensitivity, and reliability for molecular epidemiological surveillance of PRV and PCV3.

Simultaneous detection of porcine reproductive and respiratory syndrome virus and porcine circovirus 3 by SYBR Green І-based duplex real-time PCR.

The SYBR Green І-based duplex real-time PCR assay was developed for simultaneous detection of porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus 3 (PCV-3) genomes. PRRSV and PCV-3 were distinguished in the same sample by their distinctive melting temperature (Tm) which was 84 °C for PRRSV and 81.5 °C for PCV-3, and other non-targeted swine viruses showed no specific melting peaks. The detection limits of this assay were 46.1copies/µL for PRRSV and 49.3copies/µL for PCV-3, respectively. Thirty-three lung samples of porcine with respiratory and reproductive failure symptoms were collected and confirmed by the SYBR Green І-based real-time PCR assay and conventional PCR assay. The real-time PCR detection results showed that the PRRSV positive rate was 45.45%, the PCV-3 positive rate was 63.63%, the PRRSV and PCV-3 co-infection positive rate was 36.36%, which were more sensitive than conventional PCR detection. This duplex real-time PCR assay could be a rapid, sensitive and reliable method for the detection of PRRSV and PCV-3 co-infection.

Gut microbiota profiles of commercial laying hens infected with tumorigenic viruses.

BACKGROUND: Studies have shown that some viral infections cause structural changes in the intestinal microflora, but little is known about the effects of tumorigenic viral infection on the intestinal microflora of chickens. RESULTS: A 29-week commercial layer flock positive for avian leukosis virus-J (ALV-J), Marek's disease virus (MDV) and avian reticuloendotheliosis virus (REV) was selected, and fresh fecal samples were collected and examined for the composition of the gut microflora by Illumina sequencing of the V3-V4 region of the 16S rRNA gene. The operational taxonomic units (OTUs) of the fecal microbiota differentiated the chickens infected with only ALV-J and those coinfected with ALV-J and MDV or REV from infection-negative chickens. The enrichment and diversity of cloacal microflora in chickens infected with ALV-J alone were slightly different from those in the infection-negative chickens. However, the diversity of cloacal microflora was significantly increased in chickens coinfected with both ALV-J and MDV or REV. CONCLUSIONS: The intestinal microbiota was more strongly disturbed in chickens after coinfection with ALV-J and MDV or REV than after infection with ALV-J alone, and there may be underlying mechanisms by which the capacity for the stabilization of the intestinal flora was impaired due to viral infection and tumorigenesis.

Elevated dietary zinc oxide levels do not have a substantial effect on porcine reproductive and respiratory syndrome virus (PPRSV) vaccination and infection.

BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important infectious agents for the swine industry worldwide. Zinc (Zn) salts, which are widely used as a dietary supplement in swine nutrition, have shown antiviral effects in vitro as well as in vivo. The purpose of this study was to determine the influence of dietary zinc oxide supplementation on vaccination and challenge infection with PRRSV. FINDINGS: The clinical course of PRRS and the success of vaccination with an experimental inactivated vaccine were compared between animals receiving a conventional diet (50 ppm Zn, control group) and diets supplemented with Zn oxide (ZnO) at final Zn concentrations of 150 or 2,500 ppm. Pigs receiving higher dietary Zn levels showed a tendency towards higher neutralizing antibody levels after infection, while dietary Zn levels did not substantially influence the number of antiviral IFN-gamma secreting cells (IFN-gamma-SC) or percentages of blood immune cell subsets after infection. Finally, feeding higher dietary Zn levels reduced neither clinical symptoms nor viral loads. CONCLUSIONS: Our results suggest that higher levels of dietary ZnO do not have the potential to stimulate or modulate systemic immune responses after vaccination and heterologous PRRSV infection to an extent that could improve the clinical and virological outcome.

High-dose dietary zinc oxide mitigates infection with transmissible gastroenteritis virus in piglets.

BACKGROUND: Zinc (Zn) supplementation has been shown to reduce the incidence of diarrhea and to protect animals from intestinal diseases, but the mechanisms of this protective effect against virus infection in vivo have not yet been elucidated. Transmissible gastroenteritis virus (TGEV) causes diarrhea in piglets with an age-dependent decrease of severity. RESULTS: We used 60 weaned piglets that were divided into three groups to evaluate the effect of different Zn levels added to a conventional diet (50 mg Zn/kg diet, Znlow, control group). The other groups received the diet supplemented with ZnO at final concentrations of 150 mg Zn/kg diet (Znmed), or 2,500 mg/kg diet (Znhigh). Oral challenge infection with TGEV was performed when the pigs had been fed for 1 week with the respective diet. Half of the piglets of each group were sacrificed at day 1 and 18 after challenge infection. Fecal consistency was improved and body weights increased in the Znhigh group when compared to the other groups, but no direct effect of Zn concentrations in the diet on fecal TGEV shedding and mucosal immune responses was detectable. However, in the Znhigh group, we found a prevention of villus atrophy and decreased caspase-3-mediated apoptosis of jejunal epithelium. Furthermore, pigs receiving high Zn diet showed a down-regulation of interferon (IFN)-α, oligoadenylate synthetase (OAS), Zn transporter SLC39A4 (ZIP4), but up-regulation of metallothionein-1 (MT1), as well as the Zn transporters SLC30A1 (ZnT1) and SLC30A5 (ZnT5). In addition, forskolin-induced chloride secretion and epithelial resistance were controlled at a physiological level in the Znhigh but not the other groups. Finally, in the Znhigh group, we documented an earlier and higher systemic TGEV-specific serum antibody response. CONCLUSIONS: These results suggest that high dietary Zn could provide enhanced protection in the intestinal tract and stimulate the systemic humoral immune response against TGEV infection.

Dissociative photoionization of ß-pinene: an experimental and theoretical study.

We investigated the photoionization and dissociation photoionization of the ß-pinene molecular using time-of-flight mass spectrometry with a tunable vacuum ultraviolet source in the region from 8.00eV to 15.50eV. The experimental ionization energy (IE) value is 8.60eV using electron impact as the ionization source which is not in good agreement with theoretical value (8.41 eV) with a G3MP2 method. We obtained the accurate IE of ß-pinene (8.45 ± 0.03eV) derived from the efficiency spectrum which is in good agreement with the theoretical value (8.38eV) of the CBS-QB3 method. We elucidated the dissociation pathways of primary fragment ions from the ß-pinene cation on the basis of experimental observations in combination with theoretical calculations. Most of the dissociation pathways occur via a rearrangement reaction prior to dissociation. We also determined the structures of the transition states and intermediates for those isomerization processes.

Development of Phloroglucinol-Linked Tris-Quaternary Ammonium Salt Antimicrobial Peptide Mimics with Low Cytotoxicity and Broad-Spectrum Antibacterial Activity.

Encouraged by the significantly different toxicities and antibacterial activities of diverse linkers, such as alkyl and aromatic nuclei linkers, and the unique structure of phloroglucinol, we synthesized a series of tris-quaternary ammonium salt (tris-QAS) antibacterial peptide mimics based on the marketed drug phloroglucinol. Among them, 2f displayed excellent activity against Staphylococcus aureus (MIC = 0.5 µg/mL) and high selectivity (SI > 2560). Surprisingly, the cytotoxicity of 2f (CC50 = 152.7 µg/mL) was dramatically better than those of alkyl QAS I and hydroquinone QAS II. Additionally, 2f possessed rapid bactericidal capability, was not prone to inducing bacterial resistance, and also exhibited excellent activity against S. aureus biofilms and persistent bacteria. Mechanistic research and transcriptome analysis revealed that 2f can interfere with the normal metabolism of bacterial cells, and it can specifically bind with phosphatidylglycerol to destroy the cell membrane. Importantly, 2f exhibited potent in vivo antibacterial activity in a mouse subcutaneous methicillin-resistant S. aureus (MRSA) infection model.

Electroacupuncture pretreatment inhibits ferroptosis and inflammation after middle cerebral artery occlusion in rats by activating Nrf2.

OBJECTIVE: Electroacupuncture (EA) pretreatment can effectively increase the tolerance of the brain to ischemic stroke. The mechanism of ischemic tolerance induced by EA is related to Nrf2, but its specific mechanism has not been elucidated. This paper was designed to explore the effect of EA pretreatment on brain injury and the related mechanisms. METHODS: Rats were pretreated with EA before middle cerebral artery occlusion (MCAO) modeling. The symptoms of neurological deficit and the volume of cerebral infarction were measured. The levels of inflammatory factors, oxidative stress-related factors, LPO, ROS, and Fe2+ were evaluated by the corresponding kits. Cell apoptosis was determined through TUNEL staining. The mRNA expression of inflammatory factors was examined by RT-qPCR, and the protein expression of ferroptosis-related factors, pyroptosis-related proteins, Keap1, Nrf2, HO-1, and NQO1 by western blotting. RESULTS: EA pretreatment improved the symptoms of neurological deficit and reduced the volume of cerebral infarction. EA pretreatment significantly inhibited oxidative stress, inflammatory response, ferroptosis, pyroptosis, and apoptosis in brain tissues of MCAO rats. Mechanistically, EA pretreatment could activate Nrf2 expression and reduce Keap1 expression. CONCLUSION: EA pretreatment reduced inflammation and oxidative stress and inhibited ferroptosis by activating Nrf2 expression, ultimately delaying the development of ischemic stroke.

A ddPCR platform based on a microfluidic chip with a dual-function flow-focusing structure for sample-to-result DNA quantification analysis.

Droplet digital PCR (ddPCR) is a powerful method for absolute nucleic acid quantification with high precision and accuracy. However, complicated operational steps have hampered the use and diffusion of ddPCR. Therefore, an automated, easy-to-use, low-sample-consumption, and portable ddPCR platform is urgently needed. This paper proposes a microfluidic ddPCR platform based on a microfluidic chip that can realize the sample-to-result function by switching the rotary valve, achieving the dual function of the flow-focusing structure for droplet generation and readout. Sample, generation oil, and analysis oil were pre-added to the reservoirs. Droplets were generated due to focusing flow, and after passing through the integrated temporary storage bin in the rotary valve, the droplets and oil subsequently entered the collecting tube, improving the droplet-to-oil volume ratio for enhanced thermal cycle performance. Droplets with an average diameter of 107.44 µm and a CV of 2.38% were generated using our chip under the optimal pressures. High-performance thermal cycling was achieved through improvements of the droplet-to-oil volume ratio of the sample, the integrated heating lid, the pure copper heating base, and the temperature-controlling algorithm. Gradient quantification experiments were conducted for the HER2 and CEP17 genes extracted from breast cancer cells, yielding strong linear correlations with R2 values of 0.9996 for FAM and 0.9989 for CY5. Moreover, pronounced linearity was obtained between the detected concentrations of HER2 and CEP17, indicated by a slope of 1.0091 and an R2 of 0.9997, signifying consistent HER2 : CEP17 ratios across various sample dilutions. The outcomes of the quantitative analysis, encompassing the dynamic range and the consistency of the HER2 : CEP17 ratio using our ddPCR platform, meet the standards required for breast cancer assessment and therapy. Our ddPCR platform is automated, portable, and capable of stable droplet generation, high-efficiency amplification, realization of the sample-to-result function based on dual-function flow-focusing structure, and accuracy absolute quantification, underscoring its significant potential for ddPCR analysis in clinical diagnostics.

In situ implantable DNA hydrogel for diagnosis and therapy of postoperative rehemorrhage following intracerebral hemorrhage surgery.

Postoperative rehemorrhage following intracerebral hemorrhage surgery is intricately associated with a high mortality rate, yet there is now no effective clinical treatment. In this study, we developed a hemoglobin (Hb)-responsive in situ implantable DNA hydrogel comprising Hb aptamers cross-linked with two complementary chains and encapsulating deferoxamine mesylate (DFO). Functionally, the hydrogel generates signals upon postoperative rehemorrhage by capturing Hb, demonstrating a distinctive "self-diagnosis" capability. In addition, the ongoing capture of Hb mediates the gradual disintegration of the hydrogel, enabling the on-demand release of DFO without compromising physiological iron-dependent functions. This process achieves self-treatment by inhibiting the ferroptosis of neurocytes. In a collagenase and autologous blood injection model-induced mimic postoperative rehemorrhage model, the hydrogel exhibited a 5.58-fold increase in iron absorption efficiency, reducing hematoma size significantly (from 8.674 to 4.768 cubic millimeters). This innovative Hb-responsive DNA hydrogel not only offers a therapeutic intervention for postoperative rehemorrhage but also provides self-diagnosis feedback, holding notable promise for enhancing clinical outcomes.

TRIM56 protects against nonalcoholic fatty liver disease by promoting the degradation of fatty acid synthase.

Nonalcoholic fatty liver disease (NAFLD) encompasses a disease continuum from simple steatosis to nonalcoholic steatohepatitis (NASH). However, there are currently no approved pharmacotherapies for NAFLD, although several drugs are in advanced stages of clinical development. Because of the complex pathophysiology and heterogeneity of NAFLD, the identification of potential therapeutic targets is clinically important. Here, we demonstrated that tripartite motif 56 (TRIM56) protein abundance was markedly downregulated in the livers of individuals with NAFLD and of mice fed a high-fat diet. Hepatocyte-specific ablation of TRIM56 exacerbated the progression of NAFLD, while hepatic TRIM56 overexpression suppressed it. Integrative analyses of interactome and transcriptome profiling revealed a pivotal role of TRIM56 in lipid metabolism and identified the lipogenesis factor fatty acid synthase (FASN) as a direct binding partner of TRIM56. TRIM56 directly interacted with FASN and triggered its K48-linked ubiquitination-dependent degradation. Finally, using artificial intelligence-based virtual screening, we discovered an orally bioavailable small-molecule inhibitor of FASN (named FASstatin) that potentiates TRIM56-mediated FASN ubiquitination. Therapeutic administration of FASstatin improved NAFLD and NASH pathologies in mice with an optimal safety, tolerability, and pharmacokinetics profile. Our findings provide proof of concept that targeting the TRIM56/FASN axis in hepatocytes may offer potential therapeutic avenues to treat NAFLD.

Multispecies transcriptomics identifies SIKE as a MAPK repressor that prevents NASH progression.

Nonalcoholic fatty liver (NAFL) remains relatively benign, but high-risk to end-stage liver diseases become highly prevalent when it progresses into nonalcoholic steatohepatitis (NASH). Our current understanding of the development of NAFL to NASH remains insufficient. In this study, we revealed MAP kinase (MAPK) activation as the most notable molecular signature associated with NASH progression across multiple species. Furthermore, we identified suppressor of IKKε (SIKE) as a conserved and potent negative controller of MAPK activation. Hepatocyte-specific overexpression of Sike prevented NASH progression in diet- and toxin-induced mouse NASH models. Mechanistically, SIKE directly interacted with TGF-ß-activated kinase 1 (TAK1) and TAK1-binding protein 2 (TAB2) to interrupt their binding and subsequent TAK1-MAPK signaling activation. We found that indobufen markedly up-regulated SIKE expression and effectively improved NASH features in mice and macaques. These findings identify SIKE as a MAPK suppressor that prevents NASH progression and provide proof-of-concept evidence for targeting the SIKE-TAK1 axis as a potential NASH therapy.