The Burgeoning Significance of Liquid-Liquid Phase Separation in the Pathogenesis and Therapeutics of Cancers.

Liquid-liquid phase separation (LLPS) is a physiological phenomenon that parallels the mixing of oil and water, giving rise to compartments with diverse physical properties. Biomolecular condensates, arising from LLPS, serve as critical regulators of gene expression and control, with a particular significance in the context of malignant tumors. Recent investigations have unveiled the intimate connection between LLPS and cancer, a nexus that profoundly impacts various facets of cancer progression, including DNA repair, transcriptional regulation, oncogene expression, and the formation of critical membraneless organelles within the cancer microenvironment. This review provides a comprehensive account of the evolution of LLPS from the molecular to the pathological level. We explore the mechanisms by through which biomolecular condensates govern diverse cellular physiological processes, encompassing gene expression, transcriptional control, signal transduction, and responses to environmental stressors. Furthermore, we concentrate on potential therapeutic targets and the development of small-molecule inhibitors associated with LLPS in prevalent clinical malignancies. Understanding the role of LLPS and its interplay within the tumor milieu holds promise for enhancing cancer treatment strategies, particularly in overcoming drug resistance challenges. These insights offer innovative perspectives and support for advancing cancer therapy.

A Bifidobacterium animalis subsp. lactis strain that can suppress Helicobacter pylori: isolation, in vitro and in vivo validation.

The administration of probiotics is an effective approach for treatment of Helicobacter pylori, which is associated with human gastrointestinal diseases and cancers. To explore more effective probiotics for H. pylori infection elimination, bacteria from infant feces were screened in this study. We successfully isolated the Bifidobacterium animalis subsp. lactis strains and evaluated its efficacy to inhibit H. pylori growth in vitro and in vivo. The results showed that a B. animalis strain (named BB18) sustained a high survival rate after incubation in gastric juice. The rapid urease test suggested that B. animalis BB18 reduced pathogen loads in H. pylori-infected Mongolian gerbils. Alleviation of H. pylori infection-induced gastric mucosa damage and decreased levels inflammatory cytokines were observed after the B. animalis BB18 administration. These findings demonstrated that B. animalis BB18 can inhibit H. pylori infection both in vitro and in vivo, suggesting its potential application for the prevention and eradication therapy of H. pylori infection.

Corrigendum: Bibliometric analysis of evolutionary trends and hotspots of super-enhancers in cancer.

[This corrects the article DOI: 10.3389/fphar.2023.1192855.].

Bibliometric analysis of evolutionary trends and hotspots of super-enhancers in cancer.

Introduction: In the past decade, super-enhancer (SE) has become a research hotspot with increasing attention on cancer occurrence, development, and prognosis. To illustrate the hotspots of SE in cancer research and its evolutionary tendency, bibliometric analysis was carried out for this topic. Methods: Literature published before Dec 31, 2022, in WOSCC, was systematically classified, and Citespace, bibliometric.com/app, and GraphPad Prism analyzed the data. Results: After screening out inappropriate documents and duplicate data, 911 publications were selected for further bibliometric analysis. The top five research areas were Oncology (257, 28.211%), Cell Biology (210, 23.052%), Biochemistry Molecular Biology (209, 22.942%), Science Technology Other Topics (138, 15.148%), and Genetics Heredity (132, 14.490%). The United States of America (United States) has the highest number of documents (462, 50.71%), followed by China (303, 33.26%). Among the most productive institutions, four of which are from the United States and one from Singapore, the National University of Singapore. Harvard Medical School (7.68%) has the highest percentage of articles. Young, Richard A, with 32 publications, ranks first in the number of articles. The top three authors came from Whitehead Institute for Biomedical Research as a research team. More than two-thirds of the research are supported by the National Institutes of Health of the United States (337, 37.654%) and the United States Department of Health Human Services (337, 37.654%). And "super enhancer" (525), "cell identity" (258), "expression" (223), "cancer" (205), and "transcription factor" (193) account for the top 5 occurrence keywords. Discussion: Since 2013, SE and cancer related publications have shown a rapid growth trend. The United States continues to play a leading role in this field, as the top literature numbers, affiliations, funding agencies, and authors were all from the United States, followed by China and European countries. A high degree of active cooperation is evident among a multitude of countries. The role of SEs in cell identity, gene transcription, expression, and inhibition, as well as the relationship between SEs and TFs, and the selective inhibition of SEs, have received much attention, suggesting that they are hot issues for research.

Artificial intelligence-driven radiomics study in cancer: the role of feature engineering and modeling.

Modern medicine is reliant on various medical imaging technologies for non-invasively observing patients' anatomy. However, the interpretation of medical images can be highly subjective and dependent on the expertise of clinicians. Moreover, some potentially useful quantitative information in medical images, especially that which is not visible to the naked eye, is often ignored during clinical practice. In contrast, radiomics performs high-throughput feature extraction from medical images, which enables quantitative analysis of medical images and prediction of various clinical endpoints. Studies have reported that radiomics exhibits promising performance in diagnosis and predicting treatment responses and prognosis, demonstrating its potential to be a non-invasive auxiliary tool for personalized medicine. However, radiomics remains in a developmental phase as numerous technical challenges have yet to be solved, especially in feature engineering and statistical modeling. In this review, we introduce the current utility of radiomics by summarizing research on its application in the diagnosis, prognosis, and prediction of treatment responses in patients with cancer. We focus on machine learning approaches, for feature extraction and selection during feature engineering and for imbalanced datasets and multi-modality fusion during statistical modeling. Furthermore, we introduce the stability, reproducibility, and interpretability of features, and the generalizability and interpretability of models. Finally, we offer possible solutions to current challenges in radiomics research.

The Emerging Role of Super-enhancers as Therapeutic Targets in The Digestive System Tumors.

Digestive system tumors include malignancies of the stomach, pancreas, colon, rectum, and the esophagus, and are associated with high morbidity and mortality. Aberrant epigenetic modifications play a vital role in the progression of digestive system tumors. The aberrant transcription of key oncogenes is driven by super-enhancers (SEs), which are characterized by large clusters of enhancers with significantly high density of transcription factors, cofactors, and epigenetic modulatory proteins. The SEs consist of critical epigenetic regulatory elements, which modulate the biological characteristics of digestive system tumors including tumor cell identity and differentiation, tumorigenesis, environmental response, immune response, and chemotherapeutic resistance. The core transcription regulatory loop of the digestive system tumors is complex and a high density of transcription regulatory complexes in the SEs and the crosstalk between SEs and the noncoding RNAs. In this review, we summarized the known characteristics and functions of the SEs in the digestive system tumors. Furthermore, we discuss the oncogenic roles and regulatory mechanisms of SEs in the digestive system tumors. We highlight the role of SE-driven genes, enhancer RNAs (eRNAs), lncRNAs, and miRNAs in the digestive system tumor growth and progression. Finally, we discuss clinical significance of the CRISPR-Cas9 gene editing system and inhibitors of SE-related proteins such as BET and CDK7 as potential cancer therapeutics.

Supporting nanoscale zero-valent iron onto shrimp shell-derived N-doped biochar to boost its reactivity and electron utilization for selenite sequestration.

Nanoscale zero-valent iron (nZVI) has been widely used in the reductive removal of contaminants from water, yet it still fights against the inherent passive cover and the raise of medium pH. In this study, nZVI was supported onto a nitrogen-doped biochar (NBC) that was prepared by pyrolyzing shrimp shell for efficiently sequestrating aqueous selenite (Se(IV)). The resultant composite (NBC-nZVI) revealed a higher reactivity and electron utilization efficiency (EUE) than the bare nZVI in Se(IV) sequestration because of the positive charge, the buffering effect and the good conductivity of NBC. The kinetic rate and EUE of NBC-nZVI were increased by 143.4% and 15.3% compared to the bare nZVI, respectively, at initial pH of 3.0. The high removal capacity of 605.4 mg g-1 for NBC-nZVI was obtained at Se(IV) concentration of 1000 mg L-1, initial pH of 3.0, NBC-nZVI dosage of 1.0 g L-1 and contact time of 12 h. Moreover, NBC-nZVI exhibited a strong tolerance to solution pHs and coexisting compounds (e.g., humic acid) and could reduce the Se(IV) concentration from 5.0 mg L-1 to below the limit of drinking water (50 µg L-1) in real-world samples. This work exemplified a utilization of shrimp shell-derived NBC to simultaneously enhance the reactivity and EUE of nZVI for reductively removing contaminants.

Superenhancers as master gene regulators and novel therapeutic targets in brain tumors.

Transcriptional deregulation, a cancer cell hallmark, is driven by epigenetic abnormalities in the majority of brain tumors, including adult glioblastoma and pediatric brain tumors. Epigenetic abnormalities can activate epigenetic regulatory elements to regulate the expression of oncogenes. Superenhancers (SEs), identified as novel epigenetic regulatory elements, are clusters of enhancers with cell-type specificity that can drive the aberrant transcription of oncogenes and promote tumor initiation and progression. As gene regulators, SEs are involved in tumorigenesis in a variety of tumors, including brain tumors. SEs are susceptible to inhibition by their key components, such as bromodomain protein 4 and cyclin-dependent kinase 7, providing new opportunities for antitumor therapy. In this review, we summarized the characteristics and identification, unique organizational structures, and activation mechanisms of SEs in tumors, as well as the clinical applications related to SEs in tumor therapy and prognostication. Based on a review of the literature, we discussed the relationship between SEs and different brain tumors and potential therapeutic targets, focusing on glioblastoma.

Two-Step Enzymolysis of Antarctic Krill for Simultaneous Preparation of Value-Added Oil and Enzymolysate.

Antarctic krill is a crucial marine resource containing plenty of high-valued nutrients. However, krill oil as a single product has been developed by the current solvent extraction with high cost. From the perspective of comprehensive utilization of Antarctic krill, this study proposed a novel two-step enzymolysis-assisted extraction in attempt to produce value-added oil and enzymolysate simultaneously. After two-step chitinase/protease hydrolysis, the lipid yield increased from 2.09% to 4.18%, reaching 112% of Soxhlet extraction. The method greatly improved the yields of main components while reducing the impurity content without further refining. After optimization, the oil contained 246.05 mg/g of phospholipid, 80.96 mg/g of free eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and 0.82 mg/g of astaxanthin. The by-product enzymolysate was abundant in water-soluble proteins (34.35 mg/g), oligopeptides (13.92 mg/g), amino acids (34.24 mg/g), and carbohydrates (5.79 mg/g), which was a good source of functional nutrients. In addition, both oil and enzymolysate showed high antioxidant capacity. This novel method could simultaneously provide oil and enzymolysate amounting for 58.61% of dried krill.

Small Interfering RNA for Gliomas Treatment: Overcoming Hurdles in Delivery.

Gliomas are central nervous system tumors originating from glial cells, whose incidence and mortality rise in coming years. The current treatment of gliomas is surgery combined with chemotherapy or radiotherapy. However, developing therapeutic resistance is one of the significant challenges. Recent research suggested that small interfering RNA (siRNA) has excellent potential as a therapeutic to silence genes that are significantly involved in the manipulation of gliomas' malignant phenotypes, including proliferation, invasion, metastasis, therapy resistance, and immune escape. However, it is challenging to deliver the naked siRNA to the action site in the cells of target tissues. Therefore, it is urgent to develop delivery strategies to transport siRNA to achieve the optimal silencing effect of the target gene. However, there is no systematic discussion about siRNAs' clinical potential and delivery strategies in gliomas. This review mainly discusses siRNAs' delivery strategies, especially nanotechnology-based delivery systems, as a potential glioma therapy. Moreover, we envisage the future orientation and challenges in translating these findings into clinical applications.

Recycling reaction and separation for FACylation of loxenatide by trade-off between miscibility and immiscibility of reactants and product in methanol solution.

The growing demand and scale of production for fatty acid chain modified (FACylated) polypeptide has sparked the interest in novel production technologies. In this study, a recycling reaction and separation process was proposed and applied to the fatty acid chain modification (FACylation) of loxenatide (LOX), which was based on the difference in solubility between reactants and FACylated product. Especially, the mixed PBS-Methanol (MeOH) solution was designed to meet the demands for FACylation of LOX as well as separation of FACylated LOX and residual modifier. In order to ensure the efficient FACylation, a mixed 10% PBS-90% MeOH (v/v) solution was chosen to provide a good miscibility for two reactants, LOX and N-tetradecylmaleimide (C14-MAL). On the other hand, the immiscibility between reactant (C14-MAL) and FACylated product (N-tetradecyl-Loxenatide (C14-LOX)) could realize the separation of C14-LOX when the MeOH concentration was less than 30% (v/v). Based on this strategy, the recycling reaction and separation process for FACylation of LOX was established by adjusting the MeOH concentration in the mixed solution. The reaction yield and recovery of C14-LOX exceeded 97% and 94%, and the excess reactant C14-MAL could be recycled with a recovery of more than 80%. Furthermore, after purification by reversed-phase chromatography, C14-LOX showed good pharmacokinetic and pharmacodynamic properties in vivo. This study will have great application prospects in industrial production of C14-LOX.

Effects of carboxymethyl chitosan adsorption on bioactive components of Antarctic krill oil.

High acid value (AV) and fluorine content of Antarctic krill oil (AKO) extracted from frozen krill by ethanol limit its product development. In this study, a method was proposed to reduce the AV and fluorine content of AKO by carboxymethyl chitosan (CMCS) adsorption. The optimal adsorption condition was 12.5% (w/v) of CMCS at 30℃ for 15 min. At this condition, AV and fluorine content decreased by 78.0% and 61.4%, respectively. It is interesting that CMCS adsorption showed specificity to particular substances. Although free fatty acids content showed a significant reduction, free EPA and DHA, phospholipid and astaxanthin remained almost constant. Moreover, CMCS adsorption showed no influence on neuroprotective activity of AKO against H2O2-induced neuro-damage of PC12 cells. The reclaimed CMCS showed an undiminished antimicrobial activity against both Gram-positive and Gram-negative bacteria. The CMCS adsorption shows a potential development for refining AKO and other oils in food industry.

Super-enhancers: a new frontier for epigenetic modifiers in cancer chemoresistance.

Although new developments of surgery, chemotherapy, radiotherapy, and immunotherapy treatments for cancer have improved patient survival, the emergence of chemoresistance in cancer has significant impacts on treatment effects. The development of chemoresistance involves several polygenic, progressive mechanisms at the molecular and cellular levels, as well as both genetic and epigenetic heterogeneities. Chemotherapeutics induce epigenetic reprogramming in cancer cells, converting a transient transcriptional state into a stably resistant one. Super-enhancers (SEs) are central to the maintenance of identity of cancer cells and promote SE-driven-oncogenic transcriptions to which cancer cells become highly addicted. This dependence on SE-driven transcription to maintain chemoresistance offers an Achilles' heel for chemoresistance. Indeed, the inhibition of SE components dampens oncogenic transcription and inhibits tumor growth to ultimately achieve combined sensitization and reverse the effects of drug resistance. No reviews have been published on SE-related mechanisms in the cancer chemoresistance. In this review, we investigated the structure, function, and regulation of chemoresistance-related SEs and their contributions to the chemotherapy via regulation of the formation of cancer stem cells, cellular plasticity, the microenvironment, genes associated with chemoresistance, noncoding RNAs, and tumor immunity. The discovery of these mechanisms may aid in the development of new drugs to improve the sensitivity and specificity of cancer cells to chemotherapy drugs.

Synergistic effect of the anti-PD-1 antibody with blood stable and reduction sensitive curcumin micelles on colon cancer.

Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a potent anticancer drug with versatile biological activities, while the clinical translation of curcumin is severely limited due to its hydrophobicity, rapid elimination, and metabolism in the blood circulation. Herein, we aim to unravel the potential of curcumin as a synergistic agent with immunotherapy in the treatment of cancers. In an effort to minimize premature release and improve the systemic bioavailability, a superior blood stable and reduction sensitive curcumin micellar formulation, of which the release can be triggered by cancer cells, is rationally designed. We have synthesized a telodendrimer (mPEG-PLA-(LA)4) capable of forming reversible disulfide crosslinked micelles (DCMs). The curcumin loaded DCMs (Cur/DCMs) are spherical with a uniform size of 24.6 nm. The in vitro release profile demonstrates that curcumin releases significantly slower from DCMs than that from non-crosslinked micelles (NCMs), while the release can be accelerated with the increasing concentration of reducing agent glutathione (GSH). Intravenous administration of Cur/DCMs stably retains curcumin in the bloodstream and efficiently improves the systemic bioavailability. Furthermore, Cur/DCMs exhibit synergistic anticancer efficacy when combined with the anti-PD-1 antibody in an MC-38 colon cancer xenograft model. Our results potentiate the integration of blood stable curcumin nanoformulation and immunotherapy for cancer treatment.

Imaging findings of primary pulmonary synovial sarcoma with secondary distant metastases: A case report.

BACKGROUND: Synovial sarcoma (SS) accounting for 6%-10% of primary soft tissue malignancies mainly occurs in deep soft tissue adjacent to joints of the limbs. Primary pulmonary SS (PPSS) is rare and has a poor prognosis. Cases of secondary distant metastases of PPSS occur rarely and there is a lack of corresponding imaging reports. We summarized the imaging findings of PPSS with multiple metastases confirmed by surgery and pathology, and shared valuable information on PPSS. CASE SUMMARY: A 43-year-old female patient had a solid space occupying lesion in the right upper lobe of the lung. The results of a hemogram, erythrocyte sedimentation rate (ESR) and tumor markers were all within the normal range, tuberculin skin test (5 TU PPD) was negative (-). Chest computed tomography examination showed similar round soft tissue density in the posterior segment of the right upper lobe. Thoracoscopic-assisted wedge resection of the right upper lobe of the lung, right upper lobe resection and lymph node dissection were performed. Nine months after surgery, ultrasound examination showed multiple metastases on the chest wall and kidney. CONCLUSION: PPSS is a rare malignant lung tumor with strong invasiveness, early distant metastasis and poor prognosis. There are very few imaging reports. PPSS is often manifested as irregular tumor and calcification, and the metastases have extremely low echo on ultrasonography. Contrast-enhanced ultrasound indicates that the arterial phase of tumor metastases shows rapid centripetal high enhancement, manifested as "fast forward and fast regression".

Drug-interactive mPEG-b-PLA-Phe(Boc) micelles enhance the tolerance and anti-tumor efficacy of docetaxel.

Docetaxel (DTX) is one of the most promising chemotherapeutic agents for a variety of solid tumors. However, the clinical efficacy of the marketed formulation, Taxotere®, is limited due to its poor aqueous solubility, side effects caused by the emulsifier, and low selective DTX distribution in vivo. Here a facile, well-defined, and easy-to-scale up DTX-loaded N-(tert-butoxycarbonyl)-L-phenylalanine end-capped methoxy-poly(ethylene glycol)-block-poly(D,L-lactide) (mPEG-b-PLA-Phe(Boc)) micelles (DTX-PMs) were prepared in an effort to develop a less toxic and more efficacious docetaxel formulation. The physicochemical properties, pharmacokinetics, biodistribution, and in vivo anti-tumor efficacy were evaluated in comparison to the marketed DTX formulation Taxotere®. DTX was successfully encapsulated in the hydrophobic micellar core with a high encapsulation efficiency (> 95%) and a high drug loading capacity (4.81 ± 0.08%). DTX-PMs exhibited outstanding stability in the aqueous environment due to the strong interactions between the terminal amino acid residues and docetaxel. The pharmacokinetic study in Sprague-Dawley rats revealed higher DTX concentrations in both whole blood and plasma for the group treated with DTX-PMs than that treated with Taxotere® due to the improved stability of the micellar formulation. In human non-small cell lung cancer (A549) tumor-bearing Balb/c nude mice, DTX-PMs significantly improved DTX accumulation and stalled DTX elimination in tumors than in bone marrow. Furthermore, only by half of the DTX dosage, our DTX/mPEG-b-PLA-Phe(Boc) micelles can achieve similar therapeutic effects as Taxotere®. Altogether, DTX-PMs hold great promise as a simple and effective drug delivery system for cancer chemotherapy.

Therapeutic applications of adipose-derived mesenchymal stem cells on acute liver injury in canines.

In this study, canine adipose-derived mesenchymal stem cells (cADSCs) therapeutic potential was investigated in artificially induced acute liver injury model by CCl4 in canines. The primary cADSCs cells were cultured and then intravenously administered into the canine animal model. Six cross-breed dogs were divided into three groups including blank control group, CCl4 model group, CCl4 induced cADSCs transplantation group. The results showed that after intraperitoneal injection of CCl4 solution, the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and Albumin (ALB) in peripheral blood of experimental canines confirmed the correct induction of acute liver injury. Moreover, the liver structure showed clear macroscopic damage. The cADSCs were homed in the liver of the administered animals. The AST, ALT and ALB in the peripheral blood rapidly decreased. H&E and PAS histological evaluation showed that both the structure of canine liver tissue and the ability to synthesize hepatic glycogen could be restored to the control level after cADSCs transplantation. Therefore, cADSCs can play a therapeutic role in the recovery of liver injury. Overall, this study demonstrates that the primary cADSCs transplantation into the acute liver injury model induced by intravenous injection can play a certain therapeutic role in the recovery of liver in canines. These results may provide a new treatment idea for acute liver disease in pets clinically.

MiR-4500 Regulates PLXNC1 and Inhibits Papillary Thyroid Cancer Progression.

Although most patients with papillary thyroid cancer (PTC) are curable, there are still a few patients showing poor outcomes and increased risk of secondary cancers after therapies. In this study, we aimed to investigate the correlation between miR-4500 and PTC and to explore its molecular functions. A total of 50 patients were included, and sonography and histological examinations were used for diagnosis. Quantitative real-time polymerase chain reaction (qRT-PCR) was applied for detection of mRNA levels while Western blotting was used for measuring protein expression. Cell proliferation was tested using CCK-8 and colony formation assays. Caspase-3 activity and nucleosomal fragmentation assays were employed to test cell apoptosis. Cell invasive ability was measured using transwell assay. MiR-4500 target was identified using luciferase assay and RNA pull-down assay. MiR-4500 expression was significantly decreased in five PTC cell lines compared with Nthy-ori 3-1 cells and in PTC tissues compared with adjacent normal thyroid tissues, respectively. Decreased expression of miR-4500 showed lower survival rate, higher cancer stage, and lymphatic metastasis. Therefore, our results implied that miR-4500 could serve as a potential biomarker for PTC prognosis. Overexpression of miR-4500 repressed colony formation, proliferation, and invasiveness of PTC cells whereas increased cell apoptosis. We identified that PLXNC1 was a direct target of miR-4500. PLXNC1 knockdown showed similar effects on cell viability, colony formation, and cell apoptosis as overexpression of miR-4500 in PTC cells. In conclusion, miR-4500 inhibits the malignant transformation of PTC cells by directly targeting and repressing PLXNC1.

Efficacy of fluoxetine for anorexia nervosa caused by chemotherapy in patients with cholangiocarcinoma.

BACKGROUND: Fluoxetine has been reported to treat anorexia nervosa (AN) caused by chemotherapy in patients with cholangiocarcinoma effectively. However, no study systematically investigated its efficacy and safety. Thus, this study will systematically assess its efficacy and safety for AN caused by chemotherapy in patients with cholangiocarcinoma. METHODS: A comprehensive literature search for relevant studies will be conducted from the following databases from inception to the present: MEDILINE, EMBASE, Cochrane Library, Web of Science, PSYCINFO, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. All randomized controlled trials on assessing the efficacy and safety of fluoxetine for AN caused by chemotherapy in patients with cholangiocarcinoma will be considered for inclusion in this study. RevMan V.5.3 software will be used for risk of bias assessment and statistical analysis. RESULTS: This study will summarize the latest evidence of fluoxetine for AN caused by chemotherapy in patients with cholangiocarcinoma through assessing outcomes of weight, depression, anxiety, and quality of life. Additionally, any adverse events will also be analyzed. CONCLUSION: The findings of this study will provide most recent evidence of fluoxetine for AN caused by chemotherapy in patients with cholangiocarcinoma. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019131583.

Melatonin prevents senescence of canine adipose-derived mesenchymal stem cells through activating NRF2 and inhibiting ER stress.

Transplantation of adipose-derived mesenchymal stem cells (ADMSCs) can aid in the treatment of numerous diseases in animals. However, natural aging during in vitro expansion of ADMSCs prior to their use in transplantation restricts their beneficial effects. Melatonin is reported to exert biorhythm regulation, anti-oxidation, and anti-senescence effects in various animal and cell models. Herein, by using a senescent canine ADMSCs (cADMSCs) cell model subjected to multiple passages in vitro, we investigated the effects of melatonin on ADMSCs senescence. We found that melatonin alleviates endoplasmic reticulum stress (ERS) and cell senescence. MT1/MT2 melatonin receptor inhibitor, luzindole, diminished the mRNA expression levels and rhythm expression amplitude of Bmal1 and Nrf2 genes. Nrf2 knockdown blocked the stimulatory effects of melatonin on endoplasmic reticulum-associated degradation (ERAD)-related gene expression and its inhibitory effects on ERS-related gene expression. At the same time, the inhibitory effects of melatonin on the NF-κB signaling pathway and senescence-associated secretory phenotype (SASP) were blocked by Nrf2 knockdown in cADMSCs. Melatonin pretreatment improved the survival of cADMSCs and enhanced the beneficial effects of cADMSCs transplantation in canine acute liver injury. These results indicate that melatonin activates Nrf2 through the MT1/MT2 receptor pathway, stimulates ERAD, inhibits NF-κB and ERS, alleviates cADMSCs senescence, and improves the efficacy of transplanted cADMSCs.