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Abstract Background Ischemic stroke (IS) is known for its high morbidity, disability and mortality rates, and studies designed to explore its pathophysiological mechanisms and identify novel therapeutic strategies are urgently needed. We aimed to probe the effects of the deubiquitinase OTUD3-IRP2-p53/PTGS2 pathway on cerebral ischemia‒reperfusion (I/R) injury and hippocampal neuron ferroptosis. Methods A cerebral I/R mouse model was established. Furthermore, lentiviral vectors that overexpressed OTUD3 and knocked down IRP2 were constructed, and a series of assays were performed to probe the OTUD3/IRP2/p53/PTGS2 mechanism. An oxygen‒glucose deprivation and reoxygenation (OGD/R) model of mouse hippocampal neurons was constructed. Then, OTUD3 and IRP2 were knocked down and overexpressed, and p53 was overexpressed to explore the mechanism of the OTUD3/IRP2/p53/PTGS2 pathway. Results OTUD3 and IRP2 were expressed at low levels in cerebral I/R models. OTUD3 promoted IRP2 expression to protect damaged hippocampal neurons. Moreover, IRP2 affected ferroptosis in hippocampal neurons. In addition, IRP2 inhibited p53. After IRP2 and p53 were overexpressed, IRP2 regulated the p53/PTGS2 pathway and affected ferroptosis in hippocampal neurons. In vivo, after overexpressing OTUD3 and knocking down IRP2, we found that overexpression of OTUD3 promoted IRP2 expression to reduce ferroptosis in hippocampal neurons and improve cerebral I/R injury via the inhibition of the p53/PTGS2 pathway. Conclusions The deubiquitinase OTUD3 stabilized IRP2 expression to reduce hippocampal neuron ferroptosis via the p53/PTGS2 pathway to subsequently ameliorate cerebral I/R injury.

Abstract Background The Medium and Long-Term Plan for the Prevention and Treatment of Chronic Diseases (2017–2025) in China has highlighted the importance of reducing fat, sodium, and sugar in foods. However, front-of-pack labeling, which enables consumers to assess the health levels of prepackaged foods, is lacking in China. In response to the Zhejiang Provincial Health Commission’s request, we sought to develop a method for efficiently evaluating the health level of prepackaged foods. Methods Through a comprehensive literature review, we established a systematic framework: the Prepackaged Foods Healthiness Ranking Index (PHRI). We determined specific threshold values and grading criteria and conducted two rounds of Delphi survey to refine the index. Using a measurement dataset, we aimed to determine the optimal limit values for assessing the health level of prepackaged foods in real-world settings. Results After two rounds of Delphi surveys, the PHRI underwent multiple revisions until consensus among experts was reached. The final decision regarding the upper limit values set 30% Nutrient Reference Values as the limit for solid foods and 15% Nutrient Reference Values for liquid foods. The calculation of PHRI values was successfully implemented with the dataset, in accord with current nutrition awareness and real-world conditions. Conclusions The PHRI provides a valuable tool for assessing the healthiness of prepackaged foods. This front-of-pack labeling system provides a convenient method for evaluating the nutritional quality of prepackaged foods. Ultimately, the PHRI has the potential to contribute to advancements in health policy, practice, and education in China.

A novel type of tailless FBG smart bolt with good performance is developed. Owe to the innovative design of an integrated FBG sensor comprising a strain measured FBG and a temperature-compensated FBG, the tailless FBG smart bolt serves the purpose of torque monitoring or bolt looseness monitoring. We use a theoretical approach to establish the linear correlation between the applied torque and the central wavelength of the tailless FBG smart bolt. Additionally, a newly designed M24 bolt with a nominal strength has been integrated as a crucial component of the tailless FBG smart bolt. To enable the experimental study, the tailless FBG smart bolt is newly designed, fabricated and tested. The experimental results show a strong linear correlation between the applied torque and the central wavelength of the tailless FBG smart bolt, showing good agreement with the theory.

Summary: Nucleotide oligomerization domain (NOD)-like receptor protein 3 (NLRP3) inflammasome hyperactivation contributes to many human chronic inflammatory diseases, and understanding how NLRP3 inflammasome is regulated can provide strategies to treat inflammatory diseases. Here, we demonstrate that NLRP3 Cys126 is palmitoylated by zinc finger DHHC-type palmitoyl transferase 7 (ZDHHC7), which is critical for NLRP3-mediated inflammasome activation. Perturbing NLRP3 Cys126 palmitoylation by ZDHHC7 knockout, pharmacological inhibition, or modification site mutation diminishes NLRP3 activation in macrophages. Furthermore, Cys126 palmitoylation is vital for inflammasome activation in vivo. Mechanistically, ZDHHC7-mediated NLRP3 Cys126 palmitoylation promotes resting NLRP3 localizing on the trans-Golgi network (TGN) and activated NLRP3 on the dispersed TGN, which is indispensable for recruitment and oligomerization of the adaptor ASC (apoptosis-associated speck-like protein containing a CARD). The activation of NLRP3 by ZDHHC7 is different from the termination effect mediated by ZDHHC12, highlighting versatile regulatory roles of S-palmitoylation. Our study identifies an important regulatory mechanism of NLRP3 activation that suggests targeting ZDHHC7 or the NLRP3 Cys126 residue as a potential therapeutic strategy to treat NLRP3-related human disorders.

The aerodynamic effects of wing corrugation on insect flight have received widespread attention. However, there has hardly been any specific focus on dynamic changes to corrugation angle in the models. The flexible vein joints containing resilin in the wings of dragonflies and damselflies enable the longitudinal veins to rotate and thereby change the corrugation angles throughout flapping cycles. Therefore, a two-dimensional corrugated airfoil with time-varying corrugation angles is proposed and the aerodynamic performance is evaluated in terms of aerodynamic force, power and efficiency. The results indicate that the airfoil with time-varying corrugations outperforms the rigid one in terms of enhancing thrust and reducing power consumption. The aerodynamic performance of time-varying corrugated airfoils is optimal when the angle varies in a specific range, and an excessively large angle variation may have negative effects. In addition, excessive height or a negative leading edge of the corrugation can lead to a reduction in the thrust. A design concept for the 2D airfoil with time-varying corrugations is provided and the findings are of significance for enhancing the aerodynamic performance of biomimetic flexible flapping-wing vehicles.

In today's dynamic and competitive business landscape, innovation is paramount for companies striving to maintain a competitive edge. Among various innovation strategies, corporate green innovation has gained prominence as an efficient means of achieving sustainable growth. In response to the pressing need for sustainable development, this study investigates the bidirectional cointegration link between green innovation and overall corporate innovation in a panel dataset of Chinese-listed enterprises.As China emphasizes principles like "greening" and "innovation" for twenty-first-century development, this research aligns with the nation's goal of fostering sustainable industry growth through "green innovation". It employs panel cointegration tests, including the Westerlund test, dynamic panel ordinary least square (DOLS), and the panel vector error correction model (VECM), using data from Chinese A-listed firms spanning from 2008 to 2020. The study reveals a robust long-term, bidirectional relationship between corporate innovation and green innovation. Notably, it demonstrates that green innovation causally impacts corporate innovation in both the short and long term. This research also conducts subsample analysis, ensuring the robustness of the main findings across both non-polluted and polluted industries. These findings provide valuable insights into how corporate innovation factors influence corporate green innovation. Consequently, they offer valuable insights for policymakers and organizations, aiding in the formulation of policies that promote environmentally friendly innovation while elevating corporate innovation standards.

Bamboo is one of the fastest-growing plants commonly used in food, fibre, paper, biofuel, ornamental and medicinal industries. Natural hybridization in bamboo is rare due to its long vegetative period followed by gregarious flowering and death of the entire population. In the current study, a new bamboo species, Bambusa changningensis, shows intermediate characteristics of Dendrocalamus farinosus and B. rigida morphologically, but it is unknown whether B. changningensis is a natural hybrid. Moreover, B. changningensis has been identified as a superior variety of Sichuan Province with high pulping yield, fibre length and width. Therefore, we analyzed the morphological characteristics, DNA markers, DNA barcoding and chloroplast genomes to identify the hybrid origin of B. changningensis and possible maternal parent. We have developed the transcriptomic data for B. changningensis and mined the SSR loci. The putative parental lines and hybrid were screened for 64 SSR makers and identified that SSR14, SSR28, SSR31 and SSR34 markers showed both alleles of the parental species in B. changningensis, proving heterozygosity. Sequencing nuclear gene GBSSI partial regions and phylogenetic analysis also confirm the hybrid nature of B. changningensis. Further, we have generated the complete chloroplast genome sequence (139505 bp) of B. changningensis. By analyzing the cp genomes of both parents and B. changningensis, we identified that B. rigida might be the female parent. In conclusion, our study identified that B. changningensis is a natural hybrid, providing evidence for bamboo’s natural hybridization. This is the first report on confirming a natural bamboo hybrid and its parents through SSR and chloroplast genome sequence.

Here the authors revealed a role for the protein deacetylase SIRT2 in Golgi stress, particularly induced by bacterial infection. Shigella secrete effector proteins such as IcsB, which transfers fatty acyl groups to modify host proteins to evade host immune surveillance. The upregulated SIRT2 counteracts this function by removing the fatty acyl groups and enhancing the killing of Shigella.

Albinism is a unique problem encountered in tissue culture experiments, but the underlying mechanism remains unclear in most bamboo species. In this study, we identified the putative regulatory genes in an albino mutant of Bambusa oldhamii using comparative physiology and transcriptome analysis. The degeneration of chloroplasts, low chlorophyll (Chl) content and reduced photosynthetic capacity were observed in albinotic B. oldhamii compared to normal lines. A total of 6191 unigenes were identified that were clearly differentially expressed between albino and normal lines by transcriptome sequencing. Most genes related to chloroplast development (such as Psa, Psb) and pigment biosynthesis (such as LHC, GUN4, ZEP) were downregulated significantly in albinotic lines, which might be responsible for the albino phenotype. Moreover, some transcription factors (TFs) such as PIF and GLK1 were identified to be involved in chloroplast development and Chl synthesis, indicating the involvement of putative regulatory pathways PIF-LHC and GLK1-LHC/Psa/Psb in albinotic B. oldhamii. Finally, the downregulation of some stress responsive TFs (like ICE1 and EREB1) suggested a reduction in stress resistance of albinotic B. oldhamii. The above findings provided new insights into the molecular mechanism of albinism in bamboo.

The combination of hyaluronic acid (HA) and BMP-2 has been reported to promote bone regeneration. However, the interaction of endothelial cells and bone marrow mesenchymal stem cells (BMSCs) during HA + BMP-2 treatment is not fully understood. This study aimed to analyze the direct effect of HA, as well as the paracrine effect of HA-treated endothelial cells, on the BMP-2-mediated osteogenic differentiation of BMSCs. The angiogenic differentiation potential of HA at different molecular weights and different concentrations was tested. The direct effect of HA, as well as the indirect effect of HA-treated human umbilical cord endothelial cells (HUVECs, i.e., conditioned medium (CM)-based co-culture) on the BMP-2-mediated osteogenic differentiation of BMSCs was analyzed using alkaline phosphatase (ALP) staining and activity, alizarin red S (ARS) staining, and RT-qPCR of osteogenic markers. Angiogenic differentiation markers were also analyzed in HUVECs after treatment with HA + BMP-2. The bone regeneration potential of BMP-2 and HA + BMP-2 was analyzed in a rat ectopic model. We found that 1600 kDa HA at 300 µg/mL promoted tube formation by HUVECs in vitro and upregulated the mRNA expression of the angiogenic markers CD31, VEGF, and bFGF. HA inhibited, but conditioned medium from HA-treated HUVECs promoted, the BMP-2-mediated osteogenic differentiation of BMSCs, as indicated by the results of ALP staining and activity, ARS staining, and the mRNA expression of the osteogenic markers RUNX-2, ALP, COLI, and OPN. HA + BMP-2 (50 ng/mL) upregulated the expression of the angiogenesis-related genes VEGF and bFGF in HUVECs and bone regeneration in vivo compared to BMP-2 treatment. In conclusion, the paracrine effect of hyaluronic acid-treated endothelial cells promotes BMP-2-mediated osteogenesis, suggesting the application potential of HA + BMP-2 in bone tissue engineering.

Abstract Background Molecular breeding accelerates the speed of animal breeding. Screening molecular markers that can affect economic traits through genome-wide association studies (GWAS) can provide a theoretical basis for molecular breeding. At present, a large number of molecular markers have been screened in poultry research, but few reports on how molecular markers affect economic traits exist. It is particularly important to reveal the action mechanisms of molecular markers, which can provide more accurate information for molecular breeding. Results The aim of this study was to investigate the relationships between two indels (NUDT15-indel-2777 and NUDT15-indel-1673) in the promoter region of NUDT15 and growth and carcass traits in chickens and to explore the regulatory mechanism of NUDT15. Significant differences were found in genotype and allele frequencies among commercial broilers, commercial laying hens and dual-purpose chickens. The results of association analyses showed that these two indel loci could significantly affect growth traits, such as body weight, and carcass traits. Tissue expression profiling at E12 showed that the expression of NUDT15 was significantly higher in skeletal muscle, and time-expression profiling of leg muscle showed that the expression of NUDT15 in myoblasts was significantly higher in the E10 and E12 proliferation stages than in other stages. Promoter activity analysis showed that pro-1673-I and pro-1673-D significantly inhibited promoter activity, and the promoter activity of pro-1673-D was significantly lower than that of pro-1673-I. In addition, when NUDT15 was overexpressed or underwent interference in chicken primary myoblasts (CPMs), NUDT15 could inhibit the proliferation of CPMs. Conclusion The results suggest that the studied indels in the promoter region of NUDT15 may regulate the proliferation of CPMs by affecting NUDT15 expression, ultimately affecting the growth and carcass traits of chickens. These indel polymorphisms may be used together as molecular markers for improving economic traits in chickens.

The survival path mapping approach has been proposed for dynamic prognostication of cancer patients using time-series survival data. The SurvivalPath R package was developed to facilitate building personalized survival path models. The package contains functions to convert time-series data into time-slices data by fixed interval based on time information of input medical records. After the pre-processing of data, under a user-defined parameters on covariates, significance level, minimum bifurcation sample size and number of time slices for analysis, survival paths can be computed using the main function, which can be visualized as a tree diagram, with important parameters annotated. The package also includes function for analyzing the connections between exposure/treatment and node transitions, and function for screening patient subgroup with specific features, which can be used for further exploration analysis. In this study, we demonstrate the application of this package in a large dataset of patients with hepatocellular carcinoma, which is embedded in the package. The SurvivalPath R package is freely available from CRAN, with source code and documentation hosted at https://github.com/zhangt369/SurvivalPath.

Abstract Spinal cord injury (SCI) is often accompanied by muscle atrophy; however, its underlying mechanisms remain unclear. Here, the molecular mechanisms of muscle atrophy following SCI were investigated. The GSE45550 gene expression profile of control (before SCI) and experimental (14 days following SCI) groups, consisting of Sprague–Dawley rat soleus muscle (n = 6 per group), was downloaded from the Gene Expression Omnibus database, and then differentially expressed gene (DEG) identification and Gene Ontology, pathway, pathway network, and gene signal network analyses were performed. A total of 925 differentially expressed genes, 149 biological processes, and 55 pathways were screened. In the pathway network analysis, the 10 most important pathways were citrate cycle (TCA cycle), pyruvate metabolism, MAPK signalling pathway, fatty acid degradation, propanoate metabolism, apoptosis, focal adhesion, synthesis and degradation of ketone bodies, Wnt signalling, and cancer pathways. In the gene signal network analysis, the 10 most important genes were Acat1, Acadvl, Acaa2, Hadhb, Acss1, Oxct1, Hadha, Hadh, Acaca, and Cpt1b. Thus, we screened the key genes and pathways that may be involved in muscle atrophy after SCI and provided support for finding valuable markers for this disease.

The flexibility of insect wings should be considered in the design of bionic micro flapping-wing aircraft. The honeybee is an ideal biomimetic object because its wings are small and possess a concise vein pattern. In this paper, we focus on resilin, an important flexible factor in honeybees’ forewings. Both resilin joints and resilin stripes are considered in the finite element model, and their mechanical behaviors are studied comprehensively. Resilin was found to increase the static deflections in chordwise and spanwise directions by 1.4 times and 1.9 times, respectively. In modal analysis, natural frequencies of the first bending and first torsional modes were found to be decreased significantly—especially the latter, which was reduced from 500 Hz to 217 Hz—in terms of resilin joints and stripes, closely approaching flapping frequency. As a result, the rotational angle amplitude in dynamic responses is remarkable, with an amplification ratio of about six. It was also found that resilin joints and stripes together lead to well-cambered sections and improve the stress concentrations in dynamic deformation. As resilin is widespread in insect wings, the study could help our understanding of the flexible mechanism of wing structure and inspire the development of flexible airfoils.

Skeletal muscle is an essential tissue in meat-producing animals, and meat-producing traits have been a hot topic in chicken genetic breeding research. Current research shows that creatine kinase M-type-like (CKM) is one of the most abundant proteins in skeletal muscle and plays an important role in the growth and development of skeletal muscle, but its role in the development of chicken skeletal muscle is still unclear. Via RNA sequencing (RNA-seq), we found that CKM was highly expressed in chicken breast muscle tissue. In this study, the expression profile of CKM was examined by quantitative real-time PCR (qPCR), and overexpression and RNA interference techniques were used to explore the functions of CKM in the proliferation, apoptosis and differentiation of chicken primary myoblasts (CPMs). It was shown that CKM was specifically highly expressed in breast muscle and leg muscle and was highly expressed in stage 16 embryonic muscle, while CKM inhibited proliferation, promoted the apoptosis and differentiation of CPMs and was involved in regulating chicken myogenesis. Transcriptome sequencing was used to identify genes that were differentially expressed in CPMs after CKM disruption, and bioinformatics analysis showed that CKM was involved in regulating chicken myogenesis. In summary, CKM plays an important role in skeletal muscle development during chicken growth and development.

Pleurocidin-family cationic antimicrobial peptide NRC-03 exhibits potent and selective cytotoxicity towards cancer cells. However, the anticancer effect of NRC-03 in oral squamous cell carcinoma (OSCC) and the molecular mechanism of NRC-03 induced cancer cell death is still unclear. This study focused to investigate mitochondrial oxidative stress-mediated altered mitochondrial function involved in NRC-03-induced apoptosis of OSCC cells. NRC-03 entered the OSCC cells more easily than that of normal cells and bound to mitochondria as well as the nucleus, causing cell membrane blebbing, mitochondria swelling, and DNA fragmentation. NRC-03 induced high oxygen consumption, reactive oxygen species (ROS) release, mitochondrial dysfunction, and apoptosis in OSCC cells. Non-specific antioxidant N-acetyl-l-cysteine (NAC), or mitochondria-specific antioxidant mitoquinone (MitoQ) alleviated NRC-03-induced apoptosis and mitochondrial dysfunction indicated that NRC-03 exerts a cytotoxic effect in cancer cells via inducing cellular and mitochondrial oxidative stress. Moreover, the expression of cyclophilin D (CypD), the key component of mitochondrial permeability transition pore (mPTP), was upregulated in NRC-03-treated cancer cells. Blockade of CypD by siRNA-mediated depletion or pharmacological inhibitor cyclosporine A (CsA) significantly suppressed NRC-03-induced mitochondrial oxidative stress, mitochondrial dysfunction, and apoptosis. NRC-03 also activated MAPK/ERK and NF-κB pathways. Importantly, intratumoral administration of NRC-03 inhibited the growth of CAL-27 cells-derived tumors on xenografted animal models. Taken together, our study indicates that NRC-03 induces apoptosis in OSCC cells via the CypD-mPTP axis mediated mitochondrial oxidative stress.

Early diagnosis and treatment of oral cancer are vital for patient survival. Since the oral cavity accommodates the second largest and most diverse microbiome community after the gut, the diagnostic and therapeutic approaches with low invasiveness and minimal damage to surrounding tissues are keys to preventing clinical intervention-related infections. Gold nanoparticles (AuNPs) are widely used in the research of cancer diagnosis and therapy due to their excellent properties such as surface-enhanced Raman spectroscopy, surface plasma resonance, controlled synthesis, the plasticity of surface morphology, biological safety, and stability. AuNPs had been used in oral cancer detection reagents, tumor-targeted therapy, photothermal therapy, photodynamic therapy, and other combination therapies for oral cancer. AuNPs-based noninvasive diagnosis and precise treatments further reduce the clinical intervention-related infections. This review is focused on the recent advances in research and application of AuNPs for early screening, diagnostic typing, drug delivery, photothermal therapy, radiotherapy sensitivity treatment, and combination therapy of oral cancer. Distinctive reports from the literature are summarized to highlight the latest advances in the development and application of AuNPs in oral cancer diagnosis and therapy. Finally, this review points out the challenges and prospects of possible applications of AuNPs in oral cancer diagnosis and therapy.

ObjectiveTo explore the utility of the scoring system for screening and early warning of cervical cancer based on big data analysis.MethodsA total of 420 women undergoing physical examination in Shenyang from January 2021 to January 2022 were screened by convenient sampling as the study subjects. All females accepted the human papilloma virus (HPV) tests and thin-prep cytology test (TCT), a Rating Questionnaire for Screening and Early Warning of Cervical Cancer was developed, and a warning threshold was derived according to the scores of the questionnaire and the goodness of fit for the results of HPV+TCT tests. The patients were graded according to the threshold, and corresponding intervention strategies for patients of different grades were developed.ResultsAmong the 420 people undergoing physical examination, 92 (21.90%) obtained scores ≥8 points, and 328 (78.10%) obtained scores < 8 points; in diagnosing cervical cancer, the Rating Questionnaire for Screening and Early Warning of Cervical Cancer had an AUC value of 0.848, specificity of 97.22%, and sensitivity of 86.46%; after scientific intervention, HPV test results showed a significant decrease in both high-risk positive cases and low-risk positive cases (p < 0.05), and TCT results showed that there was a significant difference in the number of patients with CIN I before and after intervention (p < 0.05).ConclusionThe scoring system for screening and early warning of cervical cancer based on big data analysis presents certain clinical value in the clinical screening of cervical cancer, which can further improve the screening coverage, is of great significance for the diagnosis and treatment of disease, and helps physician implement hierarchical diagnosis and treatment quickly and precisely.

Abstract Background The SH3RF2 gene is a protein-coding gene located in a quantitative trait locus associated with body weight, and its deletion has been shown to be positively associated with body weight in chickens. Results In the present study, CNV in the SH3RF2 gene was detected in 4079 individuals from 17 populations, including the “Gushi ×Anka” F2 resource population and populations of Chinese native chickens, commercial layers, and commercial broilers. The F2 resource population was then used to investigate the genetic effects of the chicken SH3RF2 gene. The results showed that the local chickens and commercial layers were all homozygous for the wild-type allele. Deletion mutation individuals were detected in all of the commercial broiler breeds except Hubbard broiler. A total of, 798 individuals in the F2 resource group were used to analyze the effects of genotype (DD/ID/II) on chicken production traits. The results showed that CNV was associated with 2-, 6-, 10-, and 12-week body weight (P = 0.026, 0.042, 0.021 and 0.039 respectively) and significantly associated with 8-week breast bone length (P = 0.045). The mutation was significantly associated with 8-week body weight (P = 0.007) and 4-week breast bone length (P = 0.010). CNV was significantly associated with evisceration weight, leg muscle weight, carcass weight, breast muscle weight and gizzard weight (P = 0.032, 0.033, 0.045, 0.004 and 0.000, respectively). Conclusions CNV of the SH3RF2 gene contributed to variation in the growth and weight gain of chickens.

Small extracellular vesicles (sEVs) secreted by mesenchymal stem cells (MSCs) have shown great therapeutic potential in cerebral ischemia-reperfusion injury (CIRI). In this study, we firstly performed a systematic review to evaluate the efficacy of MSCs-derived sEV for experimental cerebral ischemia/reperfusion injury. 24 studies were identified by searching 8 databases from January 2012 to August 2022. The methodological quality was assessed by using the SYRCLE ‘s risk of bias tool for animal studies. All the data were analyzed using RevMan 5.3 software. As a result, the score of study quality ranged from 3 to 9 in a total of ten points. Meta-analyses showed that MSCs-derived sEVs could effectively alleviate neurological impairment scores, reduced the volume of cerebral infarction and brain water content, and attenuated neuronal apoptosis. Additionally, the possible mechanisms of MSCs-derived sEVs for attenuating neuronal apoptosis were inhibiting microglia-mediated neuroinflammation. Thus, MSCs-derived sEVs might be regarded as a novel insight for cerebral ischemic stroke. However, further mechanistic studies, therapeutic safety, and clinical trials are required. Systematic review registration. PROSPERO CRD42022312227.

BackgroundIdiopathic pulmonary fibrosis (IPF), acutely or slowly progressing into irreversible pulmonary disease, causes severe damage to patients' lung functions, as well as death. In China, Chinese medicine injections (CMIs) have been generally combined with Western medicine (WM) to treat IPF, which are safe and effective. This study aimed to systematically compare the efficacy of 14 CMIs combined with WM in the treatment of IPF based on a systematic review and network meta-analysis (NMA).Material and methodsPubMed, Web of Science, Embase, Cochrane Library, MEDLINE, and Chinese databases, including the China National Knowledge Infrastructure, Wanfang Database, Scientific Journal Database, and China Biology Medicine Database were searched from inception to October 31, 2021. The inclusion criterion was randomized controlled trials (RCTs) on CMIs with WM for treating IPF. Reviewers independently screened the literature, extracted data, and evaluated the risk of bias in the included studies. RevMan 5.4 software and Stata software (version 16.0) were used for the data analysis. NMA were carried out for calculating the odd ratios (ORs) with 95% confidence intervals (CI), the surface under cumulative ranking curve (SUCRA) and the probabilities of being the best.ResultsA total of 63 eligible RCTs involving 14 CMIs were included in this NMA. More CMIs can significantly improve the clinical effectiveness rate (CER); Shuxuening injection (SXN)+WM (OR 8.91, 95% CI 3.81-20.83), Shuxuetong injection (SXT)+WM (OR 7.36, 95% CI 3.30-16.00), Shenxiong injection (SX)+WM (OR 5.42, 95% CI 2.90-10.13), Danhong injection (DH)+WM (OR 4.06, 95% CI 2.62-6.29), and Huangqi injection (HQ)+WM (OR 3.47, 95% CI 1.55-7.77) were the top five treatment strategies. Furthermore, DH +WM ranked relatively high in the SUCRA value of the nine outcome indicators, oxygen partial pressure (PaO2) (OR -13.39; 95% CI -14.90,-11.89; SUCRA 83.7%), carbon dioxide partial pressure (PaCO2) (OR -4.77; 95% CI -5.55,-3.99; SUCRA 83.3), orced vital capacity (FVC) (OR -1.42; 95% CI -2.47,-0.36; SUCRA 73.5%), total lung capacity (TLC) (OR 0.93; 95% CI 0.51,1.36; SUCRA 89.0%), forced expiratory volume 1/ forced vital capacity (FEV1/FVC%) (OR -10.30; 95% CI -12.98,-7.62; SUCRA 72.7%), type III collagen (IIIC) (OR 13.08; 95% CI 5.11,21.05; SUCRA 54.9%), and transforming growth factor (TGF) (OR -4.22; 95% CI -6.06,-2.37; SUCRA 85.7%) respectively, which seems to indicate that DH+WM had the highest likelihood of being the best treatment.ConclusionsThis review specified several CMIs combined with WM in the treatment of IPF in China. In contrast to glucocorticoids or antioxidants, CMIs combined with WM delayed the decline in lung function, maintained oxygenation and quality of life in patients with IPF. The combined use of DH, SXN, SX, and safflower yellow sodium chloride injection (HHS) with WM exerted a more positive effect in treating IPF than WM alone. However, there were limitations to the conclusions of this study due to quality control differences in the included trials.

With-no-lysine (WNK) kinases play vital roles in abiotic stress response, circadian rhythms, and regulation of flowering time in rice, Arabidopsis, and Glycine max. However, there are no previous reports of WNKs in the Bambusoideae, although genome sequences are available for diploid, tetraploid, and hexaploid bamboo species. In the present study, we identified 41 WNK genes in five bamboo species and analysed gene evolution, phylogenetic relationship, physical and chemical properties, cis-elements, and conserved motifs. We predicted the structure of PeWNK proteins of moso bamboo and determined the exposed, buried, structural and functional amino acids. Real-time qPCR analysis revealed that PeWNK5, PeWNK7, PeWNK8, and PeWNK11 genes are involved in circadian rhythms. Analysis of gene expression of different organs at different developmental stages revealed that PeWNK genes are tissue-specific. Analysis of various abiotic stress transcriptome data (drought, salt, SA, and ABA) revealed significant gene expression levels in all PeWNKs except PeWNK11. In particular, PeWNK8 and PeWNK9 were significantly down- and up-regulated, respectively, after abiotic stress treatment. A co-expression network of PeWNK genes also showed that PeWNK2, PeWNK4, PeWNK7, and PeWNK8 were co-expressed with transcriptional regulators related to abiotic stress. In conclusion, our study identified the PeWNKs of moso bamboo involved in circadian rhythms and abiotic stress response. In addition, this study serves as a guide for future functional genomic studies of the WNK genes of the Bambusoideae.

Bamboo, being an ornamental plant, has myriad aesthetic and economic significance. Particularly, Phyllostachys violascens cv. Viridisulcata contains an internode color phenotype in variation in green and yellow color between the sulcus and culm, respectively. This color variation is unique, but the underlying regulatory mechanism is still unknown. In this study, we used metabolomic and transcriptomic strategies to reveal the underlying mechanism of variation in internode color. A total of 81 metabolites were identified, and among those, prunin as a flavanone and rhoifolin as a flavone were discovered at a high level in the culm. We also found 424 differentially expressed genes and investigated three genes (PvGL, PvUF7GT, and PvC12RT1) that might be involved in prunin or rhoifolin biosynthesis. Their validation by qRT-PCR confirmed high transcript levels in the culm. The results revealed that PvGL, PvUF7GT, and PvC12RT1 might promote the accumulation of prunin and rhoifolin which were responsible for the variation in internode color of P. violascens. Our study also provides a glimpse into phenotypic coloration and is also a valuable resource for future studies.

The existing optical strain sensors based on fiber Bragg grating (FBG) have limitations, such as a complex structure, a limited strain range (±200 με) and poor linearity performance (R-squared value < 0.9920); these limitations affect their potential practical applications. Here, four FBG strain sensors equipped with planar UV-curable resin are investigated. The proposed FBG strain sensors have a simple structure, a large strain range (±1800 με) and excellent linearity performance (R-squared value ≥ 0.9998); they further produce the following performances: (1) good optical properties, including an undistorted Bragg peak shape, narrow bandwidth (−3 dB bandwidth ≤ 0.65 nm) and a high side mode suppression ratio (SMSR, the absolute value of SMSR ≥ 15 dB); (2) good temperature sensing properties with high temperature sensitivities (≥47.7 pm/°C) and a good linearity performance (R-squared value ≥ 0.9990); and (3) excellent strain sensing properties with no hysteresis behavior (hysteresis error ≤ 0.058%) and excellent repeatability (repeatability error ≤ 0.045%). Based on their excellent properties, the proposed FBG strain sensors are expected to be applied as high-performance strain sensing devices.

Analyzing marker-assisted breeding is an important method utilized in modern molecular breeding. Recent studies have determined that a large number of molecular markers appear to explain the impact of “lost heritability” on human height. Therefore, it is necessary to locate molecular marker sites in poultry and investigate the possible molecular mechanisms governing their effects. In this study, we found a 104-bp insertion/deletion polymorphism in the 5′UTR of the ADPRHL1 gene through resequencing. In cross-designed F2 resource groups, the indel was significantly associated with weight at 0, 2, 4, 6, and 10 weeks and a number of other traits [carcass weight (CW), semi-evisceration weight (SEW), evisceration weight (EW), claw weight (CLW), wings weight (DWW), gizzard weight (GW), pancreas weight (PW), chest muscle weight (CMW), leg weight (LW), leg muscle weight (LMW), shedding Weight (SW), liver rate (LR), and leg muscle rate (LMR)] (P < 0.05). In brief, the insertion-insertion (II) genotype was significantly associated with the greatest growth traits and meat quality traits, whereas the values associated with the insertion-deletion (ID) genotype were the lowest in the F2 reciprocal cross chickens. The mutation sites were genotyped in 4,526 individuals from 12 different chicken breeds and cross-designed F2 resource groups. The II genotype is the most important genotype in commercial broilers, and the I allele frequency observed in these breeds is relatively high. Deletion mutations tend to be fixed in commercial broilers. However, there is still considerable great potential for breeding in dual-purpose chickens and commercial laying hens. A luciferase reporter assay showed that the II genotype of the ADPRHL1 gene possessed 2.49-fold higher promoter activity than the DD genotype (P < 0.05). We hypothesized that this indel might affect the transcriptional activity of ADPRHL1, thereby affecting the growth traits of chickens. These findings may help to elucidate the function of the ADPRHL1 gene and facilitate enhanced reproduction in the chicken industry.

Oxytocin (OT), a neuropeptide produced in the supraoptic (SON) and paraventricular (PVN) nuclei, is not only essential for lactation and maternal behavior but also for normal immunological activity. However, mechanisms underlying OT regulation of maternal behavior and its association with immunity around parturition, particularly under mental and physical stress, remain unclear. Here, we observed effects of OT on maternal behavior in association with immunological activity in rats after cesarean delivery (CD), a model of reproductive stress. CD significantly reduced maternal interests to the pups throughout postpartum day 1-8. On postpartum day 5, CD decreased plasma OT levels and thymic index but increased vasopressin, interleukin (IL)-1β, IL-6 and IL-10 levels. CD had no significant effect on plasma adrenocorticotropic hormone and corticosterone levels. In the hypothalamus, CD decreased corticotropin-releasing hormone contents in the PVN but increased OT contents in the PVN and SON and OT release from hypothalamic implants. CD also increased c-Fos expression, particularly in the cytoplasm of OT neurons. Lastly, CD depolarized resting membrane potential and increased spike width while increasing the variability of the firing rate of OT neurons in brain slices. Thus, CD can increase hypothalamic OT contents and release but reduce pituitary release of OT into the blood, which is associated with depressive-like maternal behavior, increased inflammatory cytokine release and decreased relative weight of the thymus.

Pyroptosis is a form of programmed cell death, in which gasdermin E (GSDME) plays an important role in cancer cells, which can be induced by activated caspase-3 on apoptotic stimulation. Triclabendazole is a new type of imidazole in fluke resistance and has been approved by the FDA for the treatment of fascioliasis and its functions partially acting through apoptosis-related mechanisms. However, it remains unclear whether triclabendazole has obvious anti-cancer effects on breast cancer cells. In this study, to test the function of triclabendazole on breast cancer, we treated breast cancer cells with triclabendazole and found that triclabendazole induced lytic cell death in MCF-7 and MDA-MB-231, and the dying cells became swollen with evident large bubbles, a typical sign of pyroptosis. Triclabendazole activates apoptosis by regulating the apoptoic protein levels including Bax, Bcl-2, and enhanced cleavage of caspase-8/9/3/7 and PARP. In addition, enhanced cleavage of GSDME was also observed, which indicates the secondary necrosis/pyroptosis is further induced by active caspase-3. Consistent with this, triclabendazole-induced GSDME–N-terminal fragment cleavage and pyroptosis were reduced by caspase-3–specific inhibitor (Ac-DEVD-CHO) treatment. Moreover, triclabendazole induced reactive oxygen species (ROS) elevation and increased JNK phosphorylation and lytic cell death, which could be rescued by the ROS scavenger (NAC), suggesting that triclabendazole-induced GSDME-dependent pyroptosis is related to the ROS/JNK/Bax-mitochondrial apoptotic pathway. Besides, we showed that triclabendazole significantly reduced the tumor volume by promoting the cleavage of caspase-3, PARP, and GSDME in the xenograft model. Altogether, our results revealed that triclabendazole induces GSDME-dependent pyroptosis by caspase-3 activation at least partly through augmenting the ROS/JNK/Bax-mitochondrial apoptotic pathway, providing insights into this on-the-market drug in its potential new application in cancer treatment.

Stat6 promotes M2 macrophage polarization. Here the authors characterize Trim24-CBP-Stat6 circuit regulating M2 macrophage polarization via Stat6 acetylation, and show it contributes to pro-tumorigenic macrophage activity in mice.

Panax notoginseng saponins (PNS) are a commonly used traditional medicine to treat diabetes in China. Recent studies have confirmed their anti‐diabetic effects, but the underlying mechanisms have remained unclear. The present study was designed to explore whether PNS decrease hyperglycemia by improving insulin sensitivity in skeletal muscle and to elucidate the molecular mechanisms. The anti‐diabetic effects of PNS were analyzed in a skeletal myoblast cell line, C2C12, and in high fat diet‐induced diabetic KKAy mice. C2C12 cells were treated with PNS (50, 100, and 200 μg·L−1) and examined for glucose uptake, cell viability and expression of components of the phosphoinositide 3‐kinase (PI3K)–protein kinase B (AKT) signaling pathway. KKAy mice were intraperitoneally injected with PNS (200 mg·kg−1) for 6 weeks. Body weight, blood glucose, serum insulin, serum lipid, glucose and insulin tolerance were measured to evaluate the anti‐diabetic effects of PNS. Pathological changes, apoptosis and the PI3K–AKT signaling pathway were analyzed in KKAy skeletal muscle. PNS significantly increased insulin‐induced glucose uptake, but did not affect the cell viability of C2C12 cells. In addition, PNS reduced blood glucose and serum insulin levels and improved glucose tolerance and insulin tolerance of KKAy mice. Pathological changes and apoptosis of skeletal muscle were relieved by PNS treatment. Moreover, PNS treatment enhanced expression of mRNA encoding IRS1 and GLUT4, as well as the protein expression of phosphorylated (p) ‐insulin receptor substrate 1 (IRS1), p‐PI3K, p‐AKT and glucose transporter type 4 (GLUT4) in C2C12 and KKAy mouse muscle. Collectively, these data indicate that PNS reduces hyperglycemia and insulin resistance through up‐regulating GLUT4 expression and the IRS1–PI3K–AKT signaling pathway. Furthermore, PNS alleviated diabetes skeletal muscle pathological damage. Thus, our data suggest that PNS may be promising anti‐diabetic compounds.

Bamboo is an important model plant to study the molecular mechanisms of rapid shoot growth and flowering once in a lifetime. However, bamboo research about protein functional characterization is largely lagged behind, mainly due to the lack of gene transformation platforms. In this study, a protoplast transient gene expression system in moso bamboo has been first established. Using this reliable and efficient system, we have generated a set of multicolored fluorescent markers based on the targeting sequences from endogenous proteins, which have been validated by their comparative localization with Arabidopsis organelle markers, in a combination with pharmaceutical treatments. Moreover, we further demonstrated the power of this multicolor marker set for rapid, combinatorial analysis of the subcellular localization of uncharacterized proteins, which may play potential functions in moso bamboo flowering and fast growth of shoots. Finally, this protoplast transient gene expression system has been elucidated for functional analysis in protein–protein interaction by fluorescence resonance energy transfer (FRET) and co-immunoprecipitation analysis. Taken together, in combination with the set of moso bamboo organelle markers, the protoplast transient gene expression system could be used for subcellular localization and functional study of unknown proteins in bamboo and will definitely promote rapid progress in diverse areas of research in bamboo plants.

Multiple sclerosis is a chronic autoimmune disease involving the central nervous system, and shows a high disability rate. Its pathogenesis is complicated, and there is no good treatment. In recent years, with in-depth studies on the regulation of gastrointestinal flora, the relationship between the mammalian immune system and the intestinal flora has been extensively explored. Changes in the composition and structure of the gastrointestinal flora can affect the characteristics and development of the host immune system and even induce a series of central nervous system inflammation events. The occurrence and development of multiple sclerosis are closely related to the continuous destruction of the intestinal barrier caused by intestinal dysbacteriosis. In this study, we analyzed Lactobacillus acidipiscis in a mouse model of experimental autoimmune encephalomyelitis (EAE). We found that the amount of L. acidipiscis in the intestinal tract was inversely proportional to the progress of EAE development. In addition, the number of CD4+ FOXP3+ regulatory T cells in the mesenteric lymph nodes of mice increased significantly after the mice were fed with L. acidipiscis, and the differentiation of CD4+ T cells to Th1 and Th17 cells was inhibited. However, the protective effect of L. acidipiscis was lost in γδ T cell-deficient mice and hence was concluded to depend on the presence of regulatory γδ T cells in the intestinal epithelium. Moreover, including L. acidipiscis enhanced the development of Vγ1+γδ T cells but suppressed that of Vγ4+γδ T cells. In summary, our results demonstrated the ability of L. acidipiscis to induce generation of regulatory γδ T cells that suppress the development of the encephalomyelitic Th1 and Th17 cells and the progress of EAE.

SLIT2, a member of neuronal guidance cues, has been reported to regulate inflammation and cancer progression. Periodontitis is an oral inflammatory disease that degenerates periodontal tissue, alveolar bone and tooth. This study aims to explore the expression pattern of SLIT2 in periodontitis and its role in disease progression and bone loss. Gingival tissue of 20 periodontitis patients and 20 healthy-controls was obtained. Ligature-induced periodontitis (LIP) mice-model was developed in Slit2-Tg and wild-type mice. The effect of SLIT2 on inflammation, immune cell infiltration, M1 macrophage polarization, and alveolar bone loss in periodontitis was analyzed extensively. In periodontitis-affected gingival-tissue, SLIT2 expression was 4.4-fold higher compared to healthy-volunteers. LIP enhanced SLIT2 expression in mice periodontitis-affected periodontal tissue (PAPT) and blood circulation of wild-type mice by 4. 6-, and 5.0-fold, respectively. In Slit2-Tg-mice PAPT, SLIT2 expression was 1.8-fold higher compared to wild-type mice. Micro-CT and histomorphometric analysis revealed a 1.3-fold higher cement-enamel-junction to the alveolar-bone-crest (CEJ-ABC) distance and alveolar bone loss in LIP Slit2-Tg-mice compare to LIP wild-type mice. Results from RNA-sequencing, RT-qPCR, and ELISA showed a higher expression of Cxcr2, Il-18, TNFα, IL-6, and IL-1β in Slit2-Tg-mice PAPT compared to wild-type-mice. Slit2-Tg-mice PAPT showed a higher number of osteoclasts, M1 macrophages, and the upregulation of Robo1 expression. Slit2-Tg-mice PAPT showed upregulation of M1 macrophage marker CD16/32 and osteoclastogenic markers Acp5, Ctsk, and Nfatc1, but osteogenic markers (Alp, Bglap) remained unchanged. Immunohistochemistry unveiled the higher vasculature and infiltration of leucocytes and macrophages in Slit2-Tg-mice PAPT. RNA-sequencing, GO-pathway enrichment analysis, and western blot analysis revealed the activation of the MAPK signaling pathway in Slit2-Tg mice PAPT. In conclusion, SLIT2 overexpression in periodontitis intensifies inflammation, immune cells infiltration, M1 macrophage polarization, osteoclastogenesis, and alveolar bone loss, possibly via activation of MAPK signaling, suggesting the role of SLIT2 on exacerbation of periodontitis and alveolar bone loss.

Bambusa rigida is a tropical woody bamboo widely distributed in Sichuan and southeastern of China with important economic and ecological values. We performed a complete chloroplast (cp) genome of B. rigida using Illumina NovaSeq PE150 platform. The length of complete cp sequence is 139,500 bp in size with a pair of inverted repeat (IR) regions of 43,587 bp, which separates a large single-copy (LSC) region of 83,036 bp and a small single-copy (SSC) region of 12,875 bp. Plastid genome contains 132 genes, including 84 protein-coding genes, 40 tRNA genes, and 8 rRNA genes. Phylogenetic analysis based on 30 cp genomes indicates that B. rigida is closely related to Bambusa ventricosa in Bambuseae.

In this paper, we propose a novel high-dimensional mapping scheme based on erroneous bits minimization. Analysis and simulation results show that the proposed mapping can improve the bit-error-rate (BER) performance in comparison with random mapping and Millar mapping. It is also shown that the computational complexity of erroneous bits minimization mapping is much lower than that of Millar mapping.

The MYB transcription factor (TF) is one of the largest gene families in plants and involved to multiple biological processes. However, little is known about the MYB family and its functional role in the genome of moso bamboo. In the present study, a total of 114 R2R3MYB genes were first identified from moso bamboo genome and full-length non-chimeric (FLNC) reads. Phylogenetic analysis coupled with gene structure analysis and motif determination resulted in the division of these PheR2R3MYBs into 17 subgroups. The position of eight proteins along an external branch in the phylogenetic tree suggested their relatively ancient origin. The genes in this group were all substituted by (Met, M)/(Arg, R) at conservative W residues in both R2 and R3 repeats, and half were found to possess no transcriptional activation activity. The analysis of evolutionary patterns and divergence suggests that the expansion of PheMYBs was mainly attributable to whole genome duplication (WGD) under different selection pressures. Expressional analysis based on microarray and qRT-PCR data performed diverse expression patterns of R2R3MYBs in response to both various abiotic stimuli and flower development. Furthermore, the co-expression analysis of R2R3MYBs suggested an intricate interplay of growth- and stress-related responses. Finally, we found a hub gene, PheMYB4, was involved in a complex proteins interaction network. Further functional analysis indicated that ectopic overexpression of its homologous gene, PheMYB4-1, could increase tolerance to cold treatment and sensitivity to drought and salt treatment of transgenic Arabidopsis seedlings. These findings provide comprehensive insights into the MYB family members in moso bamboo and offer candidate MYB genes for further studies on their roles in stress resistance.

Social functions of oxytocin (OT) have been explored extensively; however, relationship between the effect of intranasally applied OT (nasal OT) on the social preference (SP) and intracerebral actions of endogenous OT remains unclear. To resolve this question, we first observed effects of nasal OT on the SP of virgin young adult male rats toward unfamiliar virgin estrous female (EF) vs. virgin male rats. The results showed that the test male rats exhibited significantly more times and longer duration accessing the female than the male, which were acutely eliminated by nasal OT. Then, we examined the approaches mediating nasal OT effects on the activity of potential brain targets in Western blots and found that nasal OT activated the olfactory bulbs (OBs) and the supraoptic nucleus (SON), but not the piriform cortex, amygdala and hippocampus as shown by significant changes in the expression of c-Fos and/or phosphorylated extracellular signal-regulated protein kinase (pERK) 1/2. Moreover, microinjection of TTX into the OBs blocked nasal OT-evoked increases in pERK1/2 levels as well as the molecular association between ERK1/2 and OT-neurophysin in the SON. Electrolytic lesions of the lateral olfactory tract did not significantly change the basal levels of pERK 1/2 in the SON; however, upon nasal OT, pERK 1/2 levels in the SON reduced significantly. Lastly, microinjection of L-aminoadipic acid (gliotoxin) into the SON to reduce OT levels reduced the duration of the test male’s accessing the EF and blocked the nasal OT-evoked increase in the duration of test male’s accessing the male while significantly increasing pERK1/2 levels in the amygdala. These findings reveal for the first time that nasal OT acutely eliminates virgin males’ SP to EFs via the OB-SON route and that OT neurons could mediate the social effects of nasal OT by suppressing social phobia generated in the amygdala.

Mini chromosome maintenance 1, agamous, deficiens, and serum response factor (MADS)-box genes are transcription factors which play fundamental roles in flower development and regulation of floral organ identity. However, till date, identification and functions of MADS-box genes remain largely unclear in Phyllostachys edulis. In view of this, we performed a whole-genome survey and identified 34 MADS-box genes in P. edulis, and based on phylogeny, they were classified as MIKCC, MIKC∗, Mα, and Mβ. The detailed analysis about gene structure and motifs, phylogenetic classification, comparison of gene divergence and duplication are provided. Interestingly, expression patterns for most genes were found similar to those of Arabidopsis and rice, indicating that the well-established ABCDE model can be applied to P. edulis. Moreover, we overexpressed PheMADS15, an AP1-like gene, in Arabidopsis, and found that the transgenic plants have early flowering phenotype, suggesting that PheMADS15 might be a regulator of flowering transition in P. edulis. Taken together, this study provides not only insightful comprehension but also useful information for understanding the functions of MADS-box genes in P. edulis.

Cysteine palmitoylation or S-palmitoylation catalyzed by the ZDHHC family of acyltransferases regulates the biological function of numerous mammalian proteins as well as viral proteins. However, understanding of the role of S-palmitoylation in antiviral immunity against RNA viruses remains very limited. The adaptor protein MAVS forms functionally essential prion-like aggregates upon activation by viral RNA-sensing RIG-I-like receptors. Here, we identify that MAVS, a C-terminal tail-anchored mitochondrial outer membrane protein, is S-palmitoylated by ZDHHC7 at Cys508, a residue adjacent to the tail-anchor transmembrane helix. Using superresolution microscopy and other biochemical techniques, we found that the mitochondrial localization of MAVS at resting state mainly depends on its transmembrane tail-anchor, without regulation by Cys508 S-palmitoylation. However, upon viral infection, MAVS S-palmitoylation stabilizes its aggregation on the mitochondrial outer membrane and thus promotes subsequent propagation of antiviral signaling. We further show that inhibition of MAVS S-palmitoylation increases the host susceptibility to RNA virus infection, highlighting the importance of S-palmitoylation in the antiviral innate immunity. Also, our results indicate ZDHHC7 as a potential therapeutic target for MAVS-related autoimmune diseases. [ABSTRACT FROM AUTHOR]

Sirt2 is a nicotinamide adenine dinucleotide (NAD+)- dependent protein lysine deacylase that can remove both acetyl group and long- chain fatty acyl groups from lysine residues of many proteins. It was reported to affect inflammatory bowel disease (IBD) symptoms in a mouse model. However, conflicting roles were reported, with genetic knockout aggravating while pharmacological inhibition alleviating IBD symptoms. These seemingly conflicting reports cause confusion and deter further efforts in developing Sirt2 inhibitors as a potential treatment strategy for IBD. We investigated these conflicting reports and elucidated the role of Sirt2 in the mouse model of IBD. We essentially replicated these conflicting results and confirmed that Sirt2 inhibitors' protective effect is not through off- targets as two very different Sirt2 inhibitors (TM and AGK2) showed similar protection in the IBD mouse model. We believe that the differential effects of inhibitors and knockout are due to the fact that the Sirt2 inhibitors only inhibit some but not all the activities of Sirt2. This hypothesis is confirmed by the observation that a PROTAC degrader of Sirt2 did not protect mice in the IBD model, similar to Sirt2 knockout. Our study provides an interesting example where genetic knockout and pharmacological inhibition do not align and emphasizes the importance of developing substrate- dependent inhibitors. Importantly, we showed that the effect of Sirt2 inhibition in IBD is through regulating the gut epithelium barrier by inhibiting Arf6- mediated endocytosis of E- cadherin, a protein important for the intestinal epithelial integrity. This mechanistic understanding further supports Sirt2 as a promising therapeutic target for treating IBD. [ABSTRACT FROM AUTHOR]