A novel protein encoded by circVPS13D attenuates antiviral innate immunity by targeting MAVS in teleost fish.

IMPORTANCE: The expression of circVPS13D was upregulated with SCRV invasion, which proved that circVPS13D was involved in the regulation of the antiviral immune response. Our study revealed that the existence of circVPS13D promoted the replication of SCRV. Functionally, circVPS13D negatively regulates the antiviral responses of fish. Mechanistically, we confirmed that circVPS13D inhibited RLRs antiviral signaling pathway via the encoded protein VPS13D-170aa by targeting MAVS. Our study provided novel insights into the roles of protein-coding circRNAs and supported VPS13D-170aa as a negative regulator in the antiviral immune responses of teleost fish.

Cytokine Receptor-Like Factor 3 Negatively Regulates Antiviral Immunity by Promoting the Degradation of TBK1 in Teleost Fish.

The cytokine receptor-like factor 3 (Crlf3) belongs to the orphan class I cytokine receptors and is identified as a neuroprotective erythropoietin receptor. In previous studies of Crlf3, few focused on its role in innate immunity. Therefore, this study explored the regulatory role of Crlf3 in innate immunity. TANK-binding kinase 1 (TBK1) is a vital adaptor protein for the activation of the RLRs-MVAS-IRF3 antiviral signaling axis; thus, its expression and activity must be tightly regulated to maintain immune homeostasis and avoid undesirable effects. Here, we report that Crlf3 is a negative regulator of type I interferon production. The expression of Crlf3 is induced by poly(I·C) or Siniperca chuatsi rhabdovirus (SCRV) treatment. Silencing of Crlf3 enhanced poly(I·C)- and SCRV-induced type I interferon production, whereas overexpression of Crlf3 suppressed type I interferon production. Mechanistically, Crlf3 interacted with TBK1 via its N domain and then inhibited type I interferon production by promoting TBK1 proteasomal degradation through K48-linked polyubiquitination. Our study shows that Crlf3 is a key factor for viral escape from innate antiviral immunity in fish and provides a new perspective on mammalian resistance to viral invasion. IMPORTANCE The expression of Crlf3 was upregulated with SCRV invasion, which proved that Crlf3 was involved in the regulation of the antiviral immune response. In this study, we found that the existence of Crlf3 promoted the replication of SCRV. Therefore, it is reasonable to believe that SCRV evades innate immune attack with the assistance of Crlf3. In addition, we report that Crlf3 negatively regulates interferon (IFN) induction by promoting the degradation of TBK1 in fish. We showed that Crlf3 is evenly distributed in the cytoplasm and interacts with TBK1. Further studies showed that Crlf3 specifically mediates K48-linked ubiquitination of TBK1 and promotes TBK1 degradation, resulting in a marked inhibition of retinoic acid-inducible gene I (RIG-I) downstream signaling.

Smyd3 negatively regulates the anti-viral pathway by promoting TAK1 degradation in teleost fish.

IMPORTANCE: In this study, we have found that the existence of Smyd3 promoted the replication of SCRV. Additionally, we report that Smyd3 negatively regulates the NF-κB and IRF3 signaling pathway by facilitating the degradation of TAK1 in fish. Our findings suggest that Smyd3 interacts with TAK1. Further investigations have revealed that Smyd3 specifically mediates K48-linked ubiquitination of TAK1 and enhances TAK1 degradation, resulting in a significant inhibition of the NF-κB and IRF3 signaling pathway. These results not only contribute to the advancement of fish anti-viral immunity but also provide new evidence for understanding the mechanism of TAK1 in mammals.

Statins as a risk factor for diabetic retinopathy: a Mendelian randomization and cross-sectional observational study.

BACKGROUND: Diabetic retinopathy (DR) is the foremost cause of vision loss among the global working-age population, and statins are among the most frequently prescribed drugs for lipid management in patients with DR. The exact relationship between statins and DR has not been determined. This study sought to validate the causal association between statins usage and diabetic retinopathy. METHODS: The summary-data-based Mendelian randomization (SMR) method and inverse-variance-weighted Mendelian randomization (IVW-MR) were used to identify the causal relationship between statins and DR via the use of expression quantitative trait loci (eQTL) data for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) (31,684 blood samples), low density lipoprotein cholesterol-related GWAS data (sample size: 440,546), and DR-related GWAS data (14,584 cases and 176,010 controls). Additionally, a cross-sectional observational study based on the data from the National Health and Nutrition Examination Survey (NHANES) was conducted to supplement the association between DR and statins (sample size: 106,911). The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) was employed to evaluate the results. RESULTS: Based on the results of the MR analysis, HMGCR inhibitors were causally connected with a noticeably greater incidence of DR (IVW: OR = 0.54, 95% CI [0.42, 0.69], p = 0.000002; SMR: OR = 0.66, 95% CI [0.52, 0.84], p = 0.00073). Subgroup analysis revealed that the results were not affected by the severity of DR. The sensitivity analysis revealed the stability and reliability of the MR analysis results. The results from the cross-sectional study based on NHANES also support the association between not taking statins and a decreased risk of DR (OR = 0.54, 95% CI [0.37, 0.79], p = 0.001). CONCLUSIONS: This study revealed that a significant increase in DR risk was causally related to statins use, providing novel insights into the role of statins in DR. However, further investigations are needed to verify these findings.

Circ-HSP90A expedites cell growth, stemness, and immune evasion in non-small cell lung cancer by regulating STAT3 signaling and PD-1/PD-L1 checkpoint.

BACKGROUND: Circular RNAs (circRNAs) are important participators in tumor progression for their stable structure and high tissue-specific expression. The purpose of this research was to clarify the potential and mechanism of a novel circRNA-circ-HSP90A in non-small cell lung cancer (NSCLC). METHODS: Biological potentials of circ-HSP90A in NSCLC were measured by functional assays. Molecular interaction was assessed by bioinformatics analysis and mechanical assays. RESULTS: Results depicted that circ-HSP90A was cyclization from its host gene heat shock protein 90 alpha (HSP90A) and was up-regulated in NSCLC cells. Circ-HSP90A depletion retarded proliferation, migration, invasion, and immune evasion. Mechanistically, circ-HSP90A recruited ubiquitin specific peptidase 30 (USP30) to stabilize HSP90A and then stimulated the signal transducer and activator of transcription 3 (STAT3) signaling. Meanwhile, circ-HSP90A sponged miR-424-5p to programmed cell death ligand 1 (PD-L1). CONCLUSIONS: Our study firstly showed that circ-HSP90A promoted cell growth, stemness, and immune evasion in NSCLC through regulating STAT3 signaling and programmed cell death 1 (PD-1)/PD-L1 checkpoint, mirroring that targeting circ-HSP90A might become a novel target of immunotherapy in NSCLC.

JMJD6 functions as an oncogene and is associated with poor prognosis in esophageal squamous cell carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors with a high prevalence and poor prognosis. It is an urgent problem to deeply understand the molecular mechanism of ESCC and develop effective diagnostic and prognostic methods. METHODS: Using tumor tissue and corresponding paracancerous samples from 141 resected ESCC patients, we assessed Jumonji domain-containing protein 6 (JMJD6) expression using Immunohistochemical (IHC) staining. Kaplan-Meier survival analysis and univariate or multivariate analysis were used to investigate the relationship between JMJD6 expression and clinicopathological features. The expression status and prognostic value of JMJD6 were analyzed by bioinformatics and enrichment analysis. RESULTS: The expression of JMJD6 in ESCC samples was higher than that in the corresponding paracancerous samples, and high expression of JMJD6 was positively associated with poor prognosis of ESCC patients. In addition, bioinformatics analysis of the expression and prognosis of JMJD6 in a variety of tumors showed that high expression of JMJD6 was significantly associated with poor overall survival (OS) in ESCC patients. Enrichment analysis indicated that the high expression of genes similar to JMJD6, such as Conserved oligomeric Golgi 1(COG1), Major facilitator superfamily domain 11 (MFSD11) and Death Effector Domain Containing 2 (DEDD2), was associated with poor prognosis of ESCC, suggesting that JMJD6 might be involved in the occurrence and prognosis of ESCC. CONCLUSION: Our study found that JMJD6 expression was significantly increased in ESCC patients and positively correlated with prognosis, indicating that targeting JMJD6 might be an attractive prognostic biomarker and provides a potential treatment strategy for ESCC. TRIAL REGISTRATION: The study was approved by Tangdu Hospital ethics committee (No. TDLL-202110-02).

Anti-VEGF combined with ocular corticosteroids therapy versus anti-VEGF monotherapy for diabetic macular edema focusing on drugs injection times and confounding factors of pseudophakic eyes: A systematic review and meta-analysis.

PURPOSE: To assess the effectiveness and safety of combining intravitreal endothelial growth factor inhibitor (anti-VEGF) and ocular corticosteroids for diabetic macular edema (DME). METHODS: Articles concentrating on the efficacy and safety of combining anti-VEGF and ocular corticosteroids therapy for DME versus anti-VEGF monotherapy was screened systematically. Meta-analysis was conducted on the basis of a protocol registered in the PROSPERO (CRD42023408338) and performed on the extracted continuous variables and dichotomous variables. The outcome was expressed as weighted mean difference (MD) and risk ratio (RR). RESULTS: Add up to 21 studies including 1468 eyes were enrolled in this study. The MD for best-corrected visual acuity (BCVA) improvement at 1/3/6/12-month between the combination therapy group and monotherapy group were 2.56 (95% CI [0.43, 4.70]), 2.46 (95% CI [-0.40, 5.32]), - 1.76 (95% CI [-3.18, -0.34]), - 1.94 (95% CI [-3.87, 0.00]), respectively. The MD for central retinal thickness (CMT) reduction at 1/3/6/12-month between two groups were - 66.27 (95% CI [-101.08, -31.47]), - 33.62 (95% CI [-57.55, -9.70]), - 4.54 (95% CI [-16.84, 7.76]), - 26.67 (95% CI [-41.52, -11.82]), respectively. Additionally, the combination group had higher relative risk of high intraocular pressure and cataract progression events. CONCLUSIONS: Anti-VEGF combined with ocular corticosteroids had a significant advantage over anti-VEGF monotherapy within 3 months of DME treatment, which reached the maximum with increasing anti-VEGF injection times to 3. However, with the prolongation of the treatment cycle, the effect of combined therapy after 6 months was no better than monotherapy, and the side effects of combined therapy were more severe.

Melatonin may suppress lung adenocarcinoma progression via regulation of the circular noncoding RNA hsa_circ_0017109/miR-135b-3p/TOX3 axis.

Melatonin is a hormone synthesized in the pineal gland and has widespread physiological and pharmacological functions. Moreover, it can activate protective receptor-dependent processes. These processes can prevent tissue carcinogenesis and inhibit malignant tumor progression and metastasis. Therefore, we investigated the regulatory effects of melatonin on dysregulated circular RNAs in human lung adenocarcinoma (LUAD) cells. In this study, we treated LUAD cells with melatonin and measured the expression of hsa_circ_0017109, miR-135b-3p, and TOX3 by quantitative reverse transcription polymerase chain reaction. Colony formation and cell counting kit-8 assays were used to determine cell proliferation. The wound-healing assay and Transwell experiment were carried out to evaluate the migration potential and invasive capacity of LUAD cells. Also, cell apoptosis was detected using a cell apoptosis kit, and protein production was identified by Western blot. It was suggested that melatonin could inhibit LUAD progression in vivo and in vitro, and the role of TOX3 in this process was explored. Additionally, hsa_circ_0017109 was found to sponge miR-135b-3p, a downstream factor of circ_0017109, which was demonstrated to target TOX3 in LUAD cells and could promote the Hippo pathway and epithelial-mesenchymal transition pathway. To summarize, we demonstrated that melatonin decreases the expression of circ_0017109 and suppresses the non-small-cell lung cancer cell migration, invasion, and proliferation through decreasing TOX3 expression via direct activation of miR-135b-3p.

PCNA negatively regulates MITA through the autophagy pathway in miiuy croaker (Miichthys miiuy).

Interferon-mediated innate immune response is the first line of defense against foreign pathogen infection. Overexpression of MITA can activate the expression of interferon and promote the innate immune response of the body to the virus. These innate immune responses are tightly controlled to prevent the host from over-immunizing itself. In this study, we reported that structurally highly conserved PCNA negatively regulates MITA. PCNA overexpression can promote MITA degradation and block the expression of interferon, while the autophagy inhibitor 3-MA significantly inhibits MITA degradation, indicating that PCNA can degrade MITA through the autophagy pathway. PCNA inhibits interferon production by targeting MITA and avoids excessive immune response. In summary, our results indicate that PCNA is involved in the immune response by degrading MITA through the autophagy pathway, which will provide new ideas for further studies on the regulatory mechanism of immune signaling pathways in lower vertebrates.

NOP56 negatively regulates MyD88-mediated NF-κB signaling in miiuy croaker, Miichthys miiuy.

MyD88 is a critical adaptor in the TLRs signaling pathway, which can activate NF-κB signaling pathway and promote proinflammatory cytokines production. However, the molecular mechanisms that modulate MyD88 expression, especially in teleost, remain largely unknown. In this study, we showed that NOP56 serve as a negative regulator of the MyD88-mediated NF-κB signaling pathway. NOP56 overexpression inhibited the protein expression of MyD88. Whereas, siRNA knockdown of NOP56 had opposite effect. Furthermore, we found that the NOSIC domain is responsible for the suppressive effect of NOP56 in MyD88 expression at protein level. Therefore, we identified NOP56 as a negative regulator of MyD88-mediated NF-κB signaling by inhibiting MyD88 expression and provided new insight into the regulation mechanism in teleost fish.

hnRNPub inhibits LPS-induced NF-κB pathway by targeting TRAF6 for K48-linked ubiquitination in miiuy croaker (Miichthys miiuy).

As an important adaptor protein in innate immunity, TRAF6 is not only responsible for the transduction of signal pathways, but its E3 ligase activity to transfer ubiquitination has also been widely studied. Under LPS stimulation, TRAF6 transfers the K63-linked ubiquitination chain to TAK1, which in turn activates the transcription factor NF-κB and cell signaling factors downstream of the signaling pathway. However, how TRAF6 expression is regulated remains largely unknown, especially in teleost. In this study, we identified hnRNPub as a suppressor of TRAF6 expression. The mRNA level of hnRNPub significantly increased under LPS stimulation, and hnRNPub inhibited NF-κB signaling pathway by targeting TRAF6. Knockdown of hnRNPub potentiated inflammatory cytokines, such as TNFα,IL-1ß,IL-8. Mechanistically, hnRNPub inhibited NF-κB signaling pathway through mediating K48-linked ubiquitination and proteasomal degradation of TRAF6. Thus, our findings reveal that hnRNPub limits LPS-induced innate activation by promoting K48-linked polyubiquitination and proteasomal degradation of TRAF6.

IRF11 enhances the inhibitory effect of IκBα on NF-κB activation in miiuy croaker.

NF-κB is a typical transcription factor that regulates expression of various genes involved in inflammatory and immune responses. Therefore, it is essential that NF-κB signaling tightly regulated to maintain immune balance. Compared with those of mammals, the regulatory mechanisms of NF-κB signaling is rarely reported in teleost fish. IκBα is a prominent negative feedback regulator in the NF-κB signaling system. In this study, we determined that IRF11 enhances the inhibitory effect of IκBα on NF-κB activation in teleost fish. Overexpression of IRF11 can inhibit IκBα degradation, whereas its knockdown has the opposite effect of IκBα. Our study further indicates that IκBα was regulated via ubiquitin-proteasome degradation pathway, IRF11 inhibits IκBα in ubiquitin-proteasome degradation. This study provides a novel evidence on the regulation of innate immune signaling pathways in teleost fish and thus provides new insights into the regulatory mechanisms in mammals.

Responsiveness and minimal clinically important difference of the EQ-5D-5L in cervical intraepithelial neoplasia: a longitudinal study.

BACKGROUND: With the widespread clinical application of the five-level version of the EuroQol five-dimensional questionnaire (EQ-5D-5L), whether the questionnaire scores are responsive to changes in patients' health and how much changes in questionnaire scores represent patients' real health changes require consideration. Consequently, we assessed responsiveness and estimated the minimal clinically important difference (MCID) of the EQ-5D-5L in surgically treated patients with cervical intraepithelial neoplasia (CIN) to determine the relationship between MCID and minimal detectable change (MDC). METHODS: We conducted a longitudinal, observational study. Participants were patients with CIN from the gynecology inpatient department of a grade-A tertiary hospital in Shihezi, Xinjiang, China. Participants completed the EQ-5D-5L and the Global Rating of Change Questionnaire (GRCQ) at baseline and one month post-surgery. The Wilcoxon signed-rank test was used to compare EQ-5D-5L scores pre- and post-treatment. We calculated the effect size (ES) and the standardized response mean (SRM) to quantitatively assess responsiveness. Distribution-based, anchor-based, and instrument-defined methods were used to estimate MCID. MCID to MDC ratios at individual- and group-levels were also calculated. RESULTS: Fifty patients with CIN completed the follow-up investigation (mean age 44.76 ± 8.72 years; mean follow-up time 32.28 ± 1.43 days). The index value and EQ visual analogue scale (EQ VAS) of the EQ-5D-5L improved by 0.025 and 6.92 (all p < 0.05) at follow-up as compared to baseline respectively. The ES and the SRM of the index value were 0.47 and 0.42 respectively, indicating small responsiveness; while the ES and the SRM of EQ VAS were 0.50 and 0.49 respectively, indicating small to moderate responsiveness. The average (range) of MCIDs for index value and EQ VAS were 0.039 (0.023-0.064) and 5.35 (3.12-6.99) respectively. These values can only be used to determine whether patients have experienced clinically meaningful health improvements at the group level. CONCLUSIONS: The EQ-5D-5L has only small to moderate responsiveness in post-surgical patients with CIN, and the MCIDs developed in this study can be used for group-level health assessment. However, further study is needed concerning health changes at the individual level.

Forkhead box O proteins: Crucial regulators of cancer EMT.

The epithelial-mesenchymal transition (EMT) is an acknowledged cellular transition process in which epithelial cells acquire mesenchymal-like properties that endow cancer cells with increased migratory and invasive behavior. Forkhead box O (FOXO) proteins have been shown to orchestrate multiple EMT-associated pathways and EMT-related transcription factors (EMT-TFs), thereby modulating the EMT process. The focus of the current review is to evaluate the latest research progress regarding the roles of FOXO proteins in cancer EMT. First, a brief overview of the EMT process in cancer and a general background on the FOXO family are provided. Next, we present the interactions between FOXO proteins and multiple EMT-associated pathways during malignancy development. Finally, we propose several novel potential directions for future research. Collectively, the information compiled herein should serve as a comprehensive repository of information on this topic and should aid in the design of additional studies and the future development of FOXO proteins as therapeutic targets.

ImagePy: an open-source, Python-based and platform-independent software package for bioimage analysis.

Summary: This note presents the design of a scalable software package named ImagePy for analysing biological images. Our contribution is concentrated on facilitating extensibility and interoperability of the software through decoupling the data model from the user interface. Especially with assistance from the Python ecosystem, this software framework makes modern computer algorithms easier to be applied in bioimage analysis. Availability and implementation: ImagePy is free and open source software, with documentation and code available at https://github.com/Image-Py/imagepy under the BSD license. It has been tested on the Windows, Mac and Linux operating systems.

Pterostilbene: Mechanisms of its action as oncostatic agent in cell models and in vivo studies.

Pterostilbene, a natural dimethylated analog of resveratrol, exerts pleiotropic anticancer effects against a variety of cancer types. Due to the better lipophilic and oral absorption, higher cellular uptake and a longer half-life than resveratrol, pterostilbene may have a good prospect in the future clinic application. In this review, we summarize the previous in vitro and in vivo studies about the anticancer actions of pterostilbene on malignances, and we also evaluate the evidence related to the effects of pterostilbene on blocking normal cell carcinogenesis. Special focus is placed on the oncostatic effects of pterostilbene, including inhibition of tumor growth, metastasis, angiogenesis and cancer stem cells, activation of apoptosis, and enhancement of immunotherapy. We then clarify the emerging investigations about pterostilbene and chemotherapy and radiotherapy. Taken together, the information complied herein may serve as a comprehensive reference for the anticancer mechanisms of pterostilbene and may advance it as a future adjuvant therapeutic agent for cancer.

Dual stimuli-responsive nano-structure transition of three-arm branched amphiphilic polymers containing ferrocene (Fc) and azobenzene (Azo) moieties in aqueous solution.

Amphiphilic polymers can self-assemble into various nanostructures in solution, which can find applications in many fields such as nanotechnology, drug delivery, and template synthesis. Herein, we report the controlled self-assembly and dual stimuli-responsive nanostructure transition of a class of three-arm branched amphiphilic polymers (AzoFcPEO) containing ferrocene (Fc) and azobenzene (Azo) moieties in aqueous solution. These amphiphilic polymers were synthesized by an esterification reaction of a variety of polyethylene oxide methyl ethers (Me-PEO) with 3-(6-ferrocenyhexyloxyl)-5-(6-azobenzenehexyloxy) benzoic acid. Both the isomerization of Azo and redox of Fc moieties can respectively change the amphiphilicity of these polymers to different degrees. Consequently, these amphiphilic polymers in aqueous solution can self-assemble into various nanostructures, such as spherical micelle, worm-like micelle, spherical compound micelle, rod-like compound micelle and vesicle dependent on the PEO molecular weight, applied stimuli, and polymer concentration. This work can offer tremendous possibilities not only for the fundamental science of the controlled self-assembly but also for establishing a suitable method for regulating the nanostructures of amphiphilic polymers in aqueous solution.

Histone deacetylase 9 downregulation decreases tumor growth and promotes apoptosis in non-small cell lung cancer after melatonin treatment.

Histone deacetylase 9 functions as an oncogene in a variety of cancers, but its role on non-small cell lung cancer (NSCLC) has not been reported. Melatonin was proven to possess anticancer actions, whereas its effect on NSCLC and underlying mechanisms remains poorly understood. In this study, 337 patients with complete clinicopathologic characteristics who underwent NSCLC surgery were recruited for the study. We found that NSCLC patients with high HDAC9 expression were correlated with worse overall survival and poor prognosis. HDAC9 knockdown significantly reduced NSCLC cell growth and induced apoptosis both in vivo and in vitro. Melatonin application also markedly inhibited cell proliferation, metastasis, and invasion and promoted apoptosis in NSCLC cells. Moreover, RNA-seq, real-time quantitative polymerase chain reaction, and western blot analyses showed that melatonin treatment decreased the HDAC9 level in NSCLC cells. A mechanistic study revealed that HDAC9 knockdown further enhanced the anticancer activities of melatonin treatment, whereas HDAC9 overexpression partially reversed the melatonin's anticancer effects. Additionally, the in vivo study found melatonin exerted anti-proliferative and pro-apoptotic effects on xenograft tumors which were also strengthened by HDAC9 knockdown. These results indicated that HDAC9 downregulation mediated the anti-NSCLC actions of melatonin, and targeting HDAC9 may be the novel therapeutic strategy for NSCLC.

Author Correction: Melatonin and mitochondrial function during ischemia/reperfusion injury.

In the original publication, affiliations were incorrectly published for the authors.

Berberine ameliorates lipopolysaccharide-induced acute lung injury via the PERK-mediated Nrf2/HO-1 signaling axis.

A fundamental element of acute lung injury (ALI) is the inflammatory response, which can affect the entire respiratory system, including the respiratory tract and alveoli. Berberine has gained attention because of its anti-inflammatory effects. Nuclear factor-erythroid 2-related factor 2 (Nrf2) and endoplasmic reticulum (ER) stress are involved in lung injury. Nrf2 also acts as a protein kinase-like ER kinase (PERK) substrate in heart disease. Therefore, this study investigated the effect of berberine against lipopolysaccharide (LPS)-induced ALI and the role of the PERK-mediated Nrf2/HO-1 signaling axis. Berberine promoted Nrf2 nuclear translocation and phosphorylation in vitro. After LPS stimulation, this effect was further enhanced, whereas inflammatory factor (IL-6 and IL-8) release and reactive oxygen species generation were significantly decreased. Berberine effectively alleviated lung injury by reducing lung edema and neutrophil infiltration. Berberine also significantly reduced histopathological inflammatory changes via inhibition of ER stress and activation of Nrf2 signaling. Thapsigargin-induced ER stress and small interference RNA (siRNA)-mediated Nrf2 inhibition abrogated the protective effects of berberine in vitro, whereas siRNA-mediated suppression of ER stress and sulforaphane-induced Nrf2 activation further improved those effects. Importantly, ER stress induction led to Nrf2 activation, whereas PERK depletion partly reduced the level of Nrf2 phosphorylation and translocation in LPS-induced cells. Therefore, berberine inhibits LPS-induced ALI through the PERK-mediated Nrf2/HO-1 signaling axis.