Advances in natural and synthetic macromolecules with stem cells and extracellular vesicles for orthopedic disease treatment.

Serious orthopedic disorders resulting from myriad diseases and impairments continue to pose a considerable challenge to contemporary clinical care. Owing to its limited regenerative capacity, achieving complete bone tissue regeneration and complete functional restoration has proven challenging with existing treatments. By virtue of cellular regenerative and paracrine pathways, stem cells are extensively utilized in the restoration and regeneration of bone tissue; however, low survival and retention after transplantation severely limit their therapeutic effect. Meanwhile, biomolecule materials provide a delivery platform that improves stem cell survival, increases retention, and enhances therapeutic efficacy. In this review, we present the basic concepts of stem cells and extracellular vesicles from different sources, emphasizing the importance of using appropriate expansion methods and modification strategies. We then review different types of biomolecule materials, focusing on their design strategies. Moreover, we summarize several forms of biomaterial preparation and application strategies as well as current research on biomacromolecule materials loaded with stem cells and extracellular vesicles. Finally, we present the challenges currently impeding their clinical application for the treatment of orthopedic diseases. The article aims to provide researchers with new insights for subsequent investigations.

LOC646762 Is Involved in Adipogenic Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells.

Long noncoding RNA (lncRNA) has been shown to participate in adipogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs). In this study, we aimed to investigate the role of lncRNA-LOC646762 in adipogenic differentiation of BMSCs. Transcriptome sequencing revealed a positive correlation between LOC646762 transcription and expression of adipogenic marker genes in adipogenic differentiation. Moreover, LOC646762 overexpression did not negatively impact the cell proliferation of BMSCs. Besides, LOC646762 plays a crucial role in adipogenic differentiation, as evidenced by its positive correlation with adipogenic marker gene expression. Its possible interaction with its proposed target C/EBPß suggests its involvement in essential pathways governing adipogenesis. Collectively, our study outcomes provide valuable insights into the molecular mechanisms underlying the adipogenic differentiation of BMSCs and lay a strong foundation for further research in regenerative medicine.

Antibacterial microneedle patch releases oxygen to enhance diabetic wound healing.

Cell growth and metabolism require an adequate supply of oxygen. However, obtaining sufficient oxygen from the blood circulating around diabetic wounds is challenging. Nevertheless, achieving a continuous and stable oxygen supply is required for these wounds to heal. Hence, in this study, we report a novel antibacterial oxygen-producing silk fibroin methacryloyl hydrogel microneedle (MN) patch comprising tips encapsulated with calcium peroxide and catalase and a base coated with antibacterial Ag nanoparticles (AgNPs). The tip of the MN patch continuously releases oxygen and inhibits the production of reactive oxygen species. This accelerates diabetic wound healing by promoting cellular accretion and migration, macrophage M2 polarization, and angiogenesis. The AgNPs at the base of the MN patch effectively combat microbial infection, further facilitating wound repair. These findings suggest that using this multifunctional oxygen-producing MN patch may be a promising strategy for diabetic wound healing in clinical settings.

Multifunctional self-healing peptide hydrogel for wound healing.

The complete healing of wounds remains a challenge in clinical care. In addition, various complications such as inflammation and infection that may occur during skin wound healing can impede the healing process. Here, we constructed a multifunctional self-repairing hydrogel by utilizing Schiff base bonds. This hydrogel exhibited good self-healing properties and could cope with destructive external influences. The self-healing hydrogel was injectable, ensuring that the hydrogel dressing adhered to the wound. Carboxymethyl chitosan and oxidized chondroitin sulfate demonstrated good biocompatibility and multiple bioactivities and were successfully used to prepare self-healing hydrogels. Meanwhile, the SIKVAV biopeptide was less expensive and more morphologically stable than vascular endothelial growth factor and had a high pro-angiogenic activity. Thus, the SIKVAV biopeptide was cross-linked to the oxidized chondroitin sulfate of the hydrogel through covalent bonding to avoid rapid biopeptide degradation, achieving a slow release of the drug. This peptide hydrogel exhibited good biocompatibility and antimicrobial properties; moreover, experiments conducted on mice revealed that it could effectively promote angiogenesis and skin tissue repair. These findings suggest that the injectable self-repairing peptide hydrogel may facilitate skin wound healing and other applications.

Potential Application of Self-Assembled Peptides and Proteins in Breast Cancer and Cervical Cancer.

Ongoing research is gradually broadening the idea of cancer treatment, with attention being focused on nanoparticles to improve the stability, therapeutic efficacy, targeting, and other important metrics of conventional drugs and traditional drug delivery methods. Studies have demonstrated that drug delivery carriers based on biomaterials (e.g., protein nanoparticles and lipids) and inorganic materials (e.g., metal nanoparticles) have potential anticancer effects. Among these carriers, self-assembled proteins and peptides, which are highly biocompatible and easy to standardize and produce, are strong candidates for the preparation of anticancer drugs. Breast cancer (BC) and cervical cancer (CC) are two of the most common and deadly cancers in women. These cancers not only threaten lives globally but also put a heavy burden on the healthcare system. Despite advances in medical care, the incidence of these two cancers, particularly CC, which is almost entirely preventable, continues to rise, and the mortality rate remains steady. Therefore, there is still a need for in-depth research on these two cancers to develop more targeted, efficacious, and safe therapies. This paper reviews the types of self-assembling proteins and peptides (e.g., ferritin, albumin, and virus-like particles) and natural products (e.g., soy and paclitaxel) commonly used in the treatment of BC and CC and describes the types of drugs that can be delivered using self-assembling proteins and peptides as carriers (e.g., siRNAs, DNA, plasmids, and mRNAs). The mechanisms (including self-assembly) by which the natural products act on CC and BC are discussed. The mechanism of action of natural products on CC and BC and the mechanism of action of self-assembled proteins and peptides have many similarities (e.g., NF-KB and Wnt). Thus, natural products using self-assembled proteins and peptides as carriers show potential for the treatment of BC and CC.

A liquid chromatography-tandem mass spectrometry method for comprehensive determination of metabolites in the purine pathway of rat plasma and its application in anti-gout effects of Lycium ruthenicum Murr.

It has been proved that purine metabolites are implicated in various biological syndromes and disorders. Therefore, the realization of panoramic detection of purine metabolites will be of great significance to the pathogenesis of purine metabolic disorders. In the present study, an ultra-high performance liquid chromatography with tandem mass spectrometry method was developed for the comprehensive quantification of purine metabolites in rat plasma. The 17 purine metabolites were separated and quantified in the short running time of 15 min. The proposed method was strictly validated by applying SeraSub solution as a matrix and proved to be linear (R2 ≥ 0.9944), accurate (the recoveries of all analytes ranged from 85.3% to 103.0%, with relative standard deviation values ≤ 9.3%), and precise (the intra- and inter-day precisions were less than 10.8% and 12.4%, respectively). The method was then successfully applied to the qualification of the endogenous purine metabolites in acute gouty arthritis rats, as well as colchicine and anthocyanin-intervened rats. Results showed that uric acid, xanthine, hypoxanthine, and xanthine were considered the key factors of acute gouty arthritis. The established method and measurement of purines in rat plasma might help the investigation of the action mechanisms between purine disorders and related diseases.

Epidemic spreading on multi-layer networks with active nodes.

Investigations on spreading dynamics based on complex networks have received widespread attention these years due to the COVID-19 epidemic, which are conducive to corresponding prevention policies. As for the COVID-19 epidemic itself, the latent time and mobile crowds are two important and inescapable factors that contribute to the significant prevalence. Focusing on these two factors, this paper systematically investigates the epidemic spreading in multiple spaces with mobile crowds. Specifically, we propose a SEIS (Susceptible-Exposed-Infected-Susceptible) model that considers the latent time based on a multi-layer network with active nodes which indicate the mobile crowds. The steady-state equations and epidemic threshold of the SEIS model are deduced and discussed. And by comprehensively discussing the key model parameters, we find that (1) due to the latent time, there is a "cumulative effect" on the infected, leading to the "peaks" or "shoulders" of the curves of the infected individuals, and the system can switch among three states with the relative parameter combinations changing; (2) the minimal mobile crowds can also cause the significant prevalence of the epidemic at the steady state, which is suggested by the zero-point phase change in the proportional curves of infected individuals. These results can provide a theoretical basis for formulating epidemic prevention policies.

Suprachiasmatic nucleus functional connectivity related to insomnia symptoms in adolescents with major depressive disorder.

Background: Insomnia is a commonly seen symptom in adolescents with major depressive disorder (MDD). The suprachiasmatic nucleus (SCN), which is the circadian rhythm regulation center, plays a crucial role in the regulation of sleep-wake circulation. Nevertheless, how SCN function contributes to the exact neural mechanisms underlying the associations between insomnia and depressive symptoms has not been explored in adolescents. In the current study, we aimed to explore the relationship between SCN functional connectivity (FC) and insomnia symptoms in adolescents with MDD using a seed-based FC method. Methods: In the current study, we recruited sixty-eight first-episode drug-naïve adolescents with MDD and classified them into high insomnia (MDD-HI) and low insomnia (MDD-LI) groups according to the sleep disturbance subscale of the Hamilton Depression Rating Scale (HAMD-S). Forty-three age/gender-matched healthy controls (HCs) were also recruited. SCN FC maps were generally for all subjects and compared among three groups using one-way ANOVA with age, gender and adjusted HAMD score as covariates. We used partial correlations to explore associations between altered FC and clinical symptoms, including sleep quality scores. Results: Adolescents with MDD showed worse sleep quality, which positively correlated with the severity of depression. Compared to MDD-LI and HCs, MDD-HI adolescents demonstrated significantly decreased FC between the right SCN and bilateral precuneus, and there was no significant difference between the MDD-LI and HC groups. The HAMD-S scores were negatively correlated with bilateral SCN-precuneus connectivity, and the retardation factor score of HAMD was negatively correlated with right SCN-precuneus connectivity. Conclusion: The altered FC between the SCN and precuneus may underline the neural mechanism of sleep-related symptoms in depressive adolescents and provide potential targets for personalized treatment strategies.

Photocrosslinked methacrylated natural macromolecular hydrogels for tissue engineering: A review.

A hydrogel is a three-dimensional (3D) network structure formed through polymer crosslinking, and these have emerged as a popular research topic in recent years. Hydrogel crosslinking can be classified as physical, chemical, or enzymatic, and photocrosslinking is a branch of chemical crosslinking. Compared with other methods, photocrosslinking can control the hydrogel crosslinking initiation, crosslinking time, and crosslinking strength using light. Owing to these properties, photocrosslinked hydrogels have important research prospects in tissue engineering, in situ gel formation, 3D bioprinting, and drug delivery. Methacrylic anhydride modification is a common method for imparting photocrosslinking properties to polymers, and graft-substituted polymers can be photocrosslinked under UV irradiation. In this review, we first introduce the characteristics of common natural polysaccharide- and protein-based hydrogels and the processes used for methacrylate group modification. Next, we discuss the applications of methacrylated natural hydrogels in tissue engineering. Finally, we summarize and discuss existing methacrylated natural hydrogels in terms of limitations and future developments. We expect that this review will help researchers in this field to better understand the synthesis of methacrylate-modified natural hydrogels and their applications in tissue engineering.

Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin.

Histone lysine acylation, including acetylation and crotonylation, plays a pivotal role in gene transcription in health and diseases. However, our understanding of histone lysine acylation has been limited to gene transcriptional activation. Here, we report that histone H3 lysine 27 crotonylation (H3K27cr) directs gene transcriptional repression rather than activation. Specifically, H3K27cr in chromatin is selectively recognized by the YEATS domain of GAS41 in complex with SIN3A-HDAC1 co-repressors. Proto-oncogenic transcription factor MYC recruits GAS41/SIN3A-HDAC1 complex to repress genes in chromatin, including cell-cycle inhibitor p21. GAS41 knockout or H3K27cr-binding depletion results in p21 de-repression, cell-cycle arrest, and tumor growth inhibition in mice, explaining a causal relationship between GAS41 and MYC gene amplification and p21 downregulation in colorectal cancer. Our study suggests that H3K27 crotonylation signifies a previously unrecognized, distinct chromatin state for gene transcriptional repression in contrast to H3K27 trimethylation for transcriptional silencing and H3K27 acetylation for transcriptional activation.

First report of powdery mildew caused by Erysiphe cruciferarum on spider flower (Tarenaya hassleriana) in China.

Spider flower (Tarenaya (Cleome) hassleriana (Chodat) Iltis, Cleomaceae) is an excellent ornamental landscape plant and has an extensive flowering period, and therefore, plays an important role in horticulture (Parma et al. 2022). In May 2020 and April 2021, severe powdery mildew symptoms were observed on spider flower plants in a public garden (22.35°N and 113.56°E) in Shenzhen, China. Approximately 60 % of the plants were infected, and the adaxial surface of diseased leaves were covered with irregular white patches, which developed on tender to old leaves. In severe infections, drying and premature defoliation of infected leaves were observed. Microscopic examinations of mycelia showed irregularly lobed hyphal appressoria. Conidiophores (n = 30) were straight, unbranched, 65.65-92.11 µm long, and consisted of two to three cells. Conidia were formed singly on the top of conidiophores, cylindrical to oblong, 32.15-42.60 × 14.88-18.43 µm (mean 38.26 × 16.89, n = 50), and without distinct fibrosin bodies. Chasmothecia were not observed. The internal transcribed spacer (ITS) region and 28S rDNA was amplified using the primer sets ITS1/ITS5 and NL1/NL4, respectively. The representative sequences of ITS and 28S rDNA (GenBank accession nos.: MW879365 for ITS and MW879435 for 28S rDNA) analyzed by BLASTN search and showed 100 % identity with the sequences from Erysiphe cruciferarum found in GenBank (accession nos.: LC009943 for ITS and MF192846 for 28S rDNA). Phylogenetic analyses were conducted for further confirmation by using the combined sequences of ITS and 28S rDNA and indicated that the isolate ZDH046 grouped in a clade with isolates of E. cruciferarum (Figure S2). Based on morphological and molecular characteristics, this fungus was identified as E. cruciferarum (Braun and Cook, 2012). Koch's postulates were confirmed by gently pressing conidia from diseased leaves onto 30 leaves of healthy spider flower plants. After incubating for 10 d in a greenhouse (25 ℃ and 75 % relative humidity), similar symptoms to the diseased plants appeared on all inoculated leaves, whereas control leaves remained symptomless. Powdery mildew caused by E. cruciferarum on T. hassleriana has so far only been reported from France (Ale-Agha et al. 2008), Germany (Jage et al. 2010), Italy (Garibaldi et al. 2009), and New Zealand (Pennycook 1989, E. polygoni). To our knowledge, this is the first report of E. cruciferarum causing powdery mildew on T. hassleriana in China. This finding expands the known host range of E. cruciferarum in China and indicates a potential threat to plantations of T. hassleriana in China.

Association Between Physical Activity and Prevalence/Mortality of Non-Alcoholic Fatty Liver Disease in Different Socioeconomic Settings.

Objectives: We aimed to investigate the effect of physical activity (PA) on non-alcoholic fatty liver disease (NAFLD) prevalence and long-term survival, particularly in some specific population such as those with different socioeconomic status (SES). Methods: Multivariate regression and interaction analyses were conducted to deal with confounders and interacting factors. Results: Active PA was associated with lower prevalence of NAFLD in both cohorts. Individuals with active-PA had better long-term survival compared to those with inactive-PA in both cohorts, and the results were only statistically significant in NAFLD defined by US fatty liver index (USFLI). We found clear evidence that the beneficial role of PA was more obvious in individuals with better SES, and the statistical significances were presented in both two hepatic steatosis index (HSI)-NAFLD cohorts from the NHANES III and NHANES 1999-2014. Results were consistent in all sensitivity analyses. Conclusion: We demonstrated the importance of PA in decrease the prevalence and mortality of NAFLD, and highlights the need for improving SES simultaneously to increase the protective effect of PA.

Perfluoroalkyl substance (PFAS) exposure and risk of nonalcoholic fatty liver disease in the elderly: results from NHANES 2003-2014.

This study aimed to investigate the association between perfluoroalkyl substance (PFAS) exposure and the risk of nonalcoholic fatty liver disease (NAFLD) in the elderly. Our sample included 1420 participants (≥ 60 years) from the 2003-2014 NHANES study with available serum PFASs, covariates, and outcomes. NAFLD was defined based on the hepatic steatosis index. Weighted binary logistic regression was utilized to calculate the odds ratio (OR) and 95% confidence intervals for each chemical. Results suggested that increase in PFOA concentrations was positively associated with risk of NAFLD in adjusted models. PFNA was also significantly associated with NAFLD development in adjusted linear regression. The effect of PFOA or PFNA on NAFLD development was found to be linear in the trend test. This study added novel evidence that exposure to PFASs (PFOA and PFNA) might be associated with NAFLD development.

How green finance reduces CO2 emissions for green economic recovery: empirical evidence from E7 economies.

The present study examines the effects of green finance on green economic performance index in the presence of income per capita, corporate social responsibilities, green energy, and technical innovations in emerging seven (E7) countries from 2005 to 2018. This study employed second-generation panel cointegration methodologies. The result of the cross-sectional dependency and slope heterogeneity test confirms that the panels are correlated and there exists slope heterogeneity. The results for the short- and long-run confirm the relationship between green economic performance index, green finance, GDPC, technological innovation, CSR, and green energy. In both the short- and long-run, green finance, technological innovation, and CSR decrease the carbon emissions and increase green economic growth, whereas income per capita and GDPC significantly increase the carbon emissions. The robustness check findings obtained D-H panel causality test validate the results. Reducing energy usage by adopting efficient technologies should be encouraged through green financing reforms implemented by policymakers.

Expression analysis and functional characterization of tomato Tubby-like protein family.

Tubby-like protein (TLP) plays an important role in plant growth and development. In this investigation, the characteristics of 11 members in the SlTLP family were studied. SlTLP genes were classified into two subgroups, and the members containing the F-box domain were renamed SlTLFPs. Subcellular localization indicated that most of the SlTLPs were localized in the nucleus. Expression pattern analysis revealed that eight genes (SlTLFP1, 3, 5, 7-10, and SlTLP11) showed differential expression across various tissues, while SlTLFP2, 4, and 6 were widely expressed in all the organs tested. Most SlTLP genes were induced by biotic and abiotic stress treatments such as Botrytis cinerea, temperature, MeJA, and ABA. TLP proteins in tomato have no transcriptional activation activity, and most members with an F-box domain could interact with SUPPRESSOR OF KINETOCHORE PROTEIN 1 (SlSkp1) or Cullin1 (Cul1) or both. Experiments on CRISPR edited SlTLFP8 showed that the N-terminal F-box domain was necessary for its function such as DNA ploidy and stomata size regulation. Our findings suggested that the F-box domain interacts with Skp1 and Cul1 to form the SCF complex, suggesting that SlTLFPs, at least SlTLFP8, function mainly through the F-box domain as an E3 ligase.

Utility analysis of digital villages to empower balanced urban-rural development based on the three-stage DEA-Malmquist model.

Rural subjects, the agricultural industrial structure, public services and rural governance are fully empowered by digital villages. This empowerment effectively compensates for the urban-rural digital divide and promotes the equalization of urban-rural income, consumption, education, medical care, and governance. Based on the three-stage data envelopment analysis (DEA) model and Malmquist index, this article conducts an in-depth study of the static and dynamic efficiency trends of digital villages that empower urban-rural balanced development in 31 provinces in China from 2015 to 2020. The results show that comprehensive technical efficiency of 31 provinces is weak DEA effective, and that the scale efficiency is the main factor affecting comprehensive technical efficiency. The educational level, local finance and industrial structure optimization have a significant positive impact on efficiency evaluation, but technological innovation and the urbanization level have a significant negative impact. Total factor productivity shows diminishing marginal utility based on the Malmquist index and its decomposition change. Restricted by the change in technological progress, the efficiency of digital villages in China in enabling urban-rural equilibrium needs to be further improved.

Green Credit and Total Factor Carbon Emission Performance-Evidence from Moderation-Based Mediating Effect Test.

To achieve China's new development pattern and the "dual carbon" goals, it is necessary to boost emission reduction and high-quality economic development simultaneously. Green credit (GC), consisting of environmental regulation and economic leverage, has a profound impact on improving total factor carbon emission performance (TFCEP). By selecting the panel data of 30 provinces and municipalities in China from 2001 to 2020, this paper constructs a series of panel models to analyze the transmission path of GC to TFCEP. The results indicate that the relationship between GC and TFCEP showed an "inverted-U-shaped" relationship. This is mainly because "energy-saving and emission reduction" first appeared in the government planning outline in 2006, and transition-friendly enterprises successfully transformed with low-interest green credit, thereby effectively improving their TFCEP. However, as environmental regulations continue to increase and the scale of green credit continues to expand, the efficiency of green credit allocation and internal conflicts with other environmental regulation policies are also emerging. At the same time, the advancement of industrial structure and green technology innovation had a significant mediating effect between GC and TFCEP; government quality has a strong moderating effect on the second stage of the mediating process. When GC reaches a certain scale, it tends to restrain TFCEP more in central and western China than in eastern China. Therefore, it is of great significance to continuously increase the scale of GC, promote the advancement of clean energy industrial structure, and improve green technology innovation.

Ginsenoside Rd protects transgenic Caenorhabditis elegans from ß-amyloid toxicity by activating oxidative resistant.

Alzheimer's disease (AD) is a serious public health issue but few drugs are currently available for the disease, and these only target the symptoms. It is well established that oxidative stress plays a crucial role in AD, and there is compelling evidence linking oxidative stress to ß-amyloid (Aß). An exciting source of potential new AD therapeutic medication possibilities is medicinal plants. Ginsenoside Rd (GS-Rd) is one of the main bioactive substances in ginseng extracts. In our study, we used a network pharmacology analysis to identify overlapping GS-Rd (therapeutic) and AD (disease)-relevant protein targets, gene ontology (GO) and bio-process annotation, and the KEGG pathway analysis data predicted that GS-Rd impacts multiple targets and pathways, such as the MAPK signal pathway and the JAT-STAT3 signaling pathway. We then assessed the role of GS-Rd in C. elegans and found that GS-Rd prolongs lifespan, improves resistance to heat stress, delays physical paralysis and increases oxidative stress responses. Overall, these results suggest that GS-Rd protects against the toxicity of Aß. The RNA-seq analysis revealed that GS-Rd achieves its effects by regulating gene expressions like daf-16 and skn-1, as well as by participating in many AD-related pathways like the MAPK signaling pathway. In addition, in CL4176 worms, GS-Rd decreased reactive oxygen species (ROS) levels and increased SOD activity. Additional research with transgenic worms showed that GS-Rd aided in the movement of DAF-16 from the cytoplasm to the nucleus. Taken together, the results indicate that GS-Rd significantly reduces Aß aggregation by targeting the MAPK signal pathway, induces nuclear translocation of DAF-16 to activate downstream signaling pathways and increases resistance to oxidative stress in C. elegans to protect against Aß-induced toxicity.

Sauchinone alleviates dextran sulfate sodium-induced ulcerative colitis via NAD(P)H dehydrogenase [quinone] 1/NF-kB pathway and gut microbiota.

Objective: This study evaluated the effects of sauchinone on dextran sulfate sodium (DSS)-induced ulcerative colitis (UC) mice model and investigated the underlying mechanisms of the downstream pathway and gut microbiota. Methods: The UC mice model was induced by DSS. The disease phenotypes were determined through pathological symptoms (body weight and disease activity index score), inflammation markers (histological and inflammatory factor detections), and colonic mucosal barrier damage (detection of tight junction proteins). The level of the NF-κB pathway was detected through marker proteins. Database and bioinformatics analyses were used to predict sauchinone-mediated downstream molecules that were previously identified by expression analysis. Mouse feces were collected to detect the V3-V4 region of the 16S rRNA gene. Results: In DSS-induced UC mice, sauchinone alleviated pathological symptoms, inhibited inflammation, and prevented mucosal barrier damage. Sauchinone further inhibited the NF-κB pathway by upregulating NAD (P) H dehydrogenase [quinone] 1 (NQO1) in DSS-induced UC mice. Moreover, sauchinone regulated the diversity and composition of the gut microbiota in mice, stimulating the growth of Firmicutes and inhibiting the growth of Proteobacteria and Bacteroidetes. Conclusion: Therefore, sauchinone exerted therapeutic effects on UC in mice by regulating the NQO1/NF-κB pathway and altering the gut microbiota. This provides a theoretical basis for developing sauchinone as a therapeutic agent and extends our understanding of its bioactivity.

Hepatectomy is associated with survival in intrahepatic cholangiocarcinoma: An observational study by instrumental variable analysis.

ABSTRACT: Liver resection (LR) is a major treatment modality in select patients with stage I-III Intrahepatic cholangiocarcinoma (ICC), yet many studies demonstrated low rates of resection. The aim of the present study is to evaluate whether increasing resection rates would result in an increase in average survival in patients with stage I-III ICC.Surveillance, Epidemiology, and End Results 18 registry database for 2004 through 2015 was retrieved for the present study. Propensity score matching was performed to eliminate possible bias. In addition, instrumental variable (IV) analysis was utilized to adjust for both measured and unmeasured confounders.Among 2341 patients with clinical stage I-III ICC, we identified 1577 (67.4%) and 764 (32.6%) patients who received no treatment or LR, respectively. In the multivariable adjusted cohort, a clear prognostic advantage of LR was observed in overall survival (OS) (P < .001) and disease-specific survival (DSS) (P < .001) compared to patients who received no treatment. Estimates based on the IV analysis indicated that patients treated with LR had a significantly longer OS (P < .001) and DSS (P < .001) after adjusting confounding factors. In IV analyses stratified by American Joint Committee on Cancer tumor stage, we found that the better survival effects of LR on OS and DSS were consistent across all subgroups.Our outcomes indicated that LR was associated with a survival benefit for marginal patients with stage I-III ICC.