Post-translational protein lactylation modification in health and diseases: a double-edged sword.

As more is learned about lactate, it acts as both a product and a substrate and functions as a shuttle system between different cell populations to provide the energy for sustaining tumor growth and proliferation. Recent discoveries of protein lactylation modification mediated by lactate play an increasingly significant role in human health (e.g., neural and osteogenic differentiation and maturation) and diseases (e.g., tumors, fibrosis and inflammation, etc.). These views are critically significant and first described in detail in this review. Hence, here, we focused on a new target, protein lactylation, which may be a "double-edged sword" of human health and diseases. The main purpose of this review was to describe how protein lactylation acts in multiple physiological and pathological processes and their potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. Our work aims to provide new ideas for treating different diseases and accelerate translation from bench to bedside.

SUMOylation at the crossroads of gut health: insights into physiology and pathology.

SUMOylation, a post-translational modification involving the covalent attachment of small ubiquitin-like modifier (SUMO) proteins to target substrates, plays a pivotal role at the intersection of gut health and disease, influencing various aspects of intestinal physiology and pathology. This review provides a comprehensive examination of SUMOylation's diverse roles within the gut microenvironment. We examine its critical roles in maintaining epithelial barrier integrity, regulating immune responses, and mediating host-microbe interactions, thereby highlighting the complex molecular mechanisms that underpin gut homeostasis. Furthermore, we explore the impact of SUMOylation dysregulation in various intestinal disorders, including inflammatory bowel diseases and colorectal cancer, highlighting its implications as a potential diagnostic biomarker and therapeutic target. By integrating current research findings, this review offers valuable insights into the dynamic interplay between SUMOylation and gut health, paving the way for novel therapeutic strategies aimed at restoring intestinal equilibrium and combating associated pathologies.

MicroRNAs in Helicobacter pylori-infected gastric cancer: Function and clinical application.

Gastric cancer (GC) is the leading cause of cancer-related death worldwide, and it is associated with a combination of genetic, environmental, and microbial risk factors. Helicobacter pylori (H. pylori) is classified as a type I carcinogen, however, the exact regulatory mechanisms underlying H. pylori-induced GC are incompletely defined. MicroRNAs (miRNAs), one of small non-coding RNAs, negatively regulate gene expression through binding to their target genes. Dysregulation of miRNAs is crucial in human cancer. A noteworthy quantity of aberrant miRNAs induced by H. pylori through complex regulatory networks have been identified. These miRNAs substantially affect genetic instability, cell proliferation, apoptosis, invasion, metastasis, autophagy, chemoresistance, and the tumor microenvironment, leading to GC development and progression. Importantly, some H. pylori-associated miRNAs hold promise as therapeutic tools and biomarkers for GC prevention, diagnosis, and prognosis. Nonetheless, clinical application of miRNAs remains in its infancy with multiple issues, including sensitivity and specificity, stability, reliable delivery systems, and off-target effects. Additional research on the specific molecular mechanisms and more clinical data are still required. This review investigated the biogenesis, regulatory mechanisms, and functions of miRNAs in H. pylori-induced GC, offering novel insights into the potential clinical applications of miRNA-based therapeutics and biomarkers.

Research progress in photodynamic therapy for Helicobacter pylori infection.

Helicobacter pylori (H. pylori) is a pathogenic microorganism that colonizes the human gastric mucosa and can lead to various gastric disorders, including gastritis, gastric ulcers, and gastric cancer. However, the increasing prevalence of antibiotic resistance in H. pylori has prompted the search for alternative treatment options. Photodynamic therapy has emerged as a potential alternative therapy, thus offering the advantage of avoiding some of the side effects associated with antibiotics and effectively targeting drug-resistant strains. In the postantibiotic era, photodynamic therapy (PDT) has shown promise as a novel treatment for H. pylori infection. This review focused on elucidating the mechanism of photodynamic therapy in the treatment of H. pylori. Additionally, we present an overview of the current research on photodynamic therapy by examining both standalone photodynamic therapy and combination therapies for H. pylori infection treatment. Furthermore, the safety profile of photodynamic therapy was also evaluated. Finally, we discuss the challenges and prospects associated with this innovative technology, with an aim to provide new insights and methodologies for the treatment of H. pylori infection.

Knowledge and Practices of Helicobacter pylori Infection Management Among Physicians in Gansu Province, China: A Cross-Sectional Study.

BACKGROUND AND AIMS: Physicians' knowledge and practices regarding the diagnosis, treatment, and follow-up of Helicobacter pylori (H. pylori) infection can impact the effectiveness of eradication therapy. This study aimed to investigate the current state of knowledge and practices concerning H. pylori infection management among physicians in Gansu Province, northwest China. MATERIALS AND METHODS: From October to November 2023, 557 physicians from 14 cities and prefectures in Gansu Province participated in this multicenter cross-sectional study and completed a survey questionnaire. RESULTS: A total of 519 valid questionnaires were collected. 43.2% of the physicians supported H. pylori screening for high-risk populations or individuals with H. pylori-related diseases. The awareness of target screening populations varied among these physicians, ranging from 69.6% to 98.2%. Most physicians preferred the urea breath test (UBT) as the method for diagnosing H. pylori infection (98.3%) and for follow-up after eradication therapy (98.5%). 89.6% of the physicians preferred bismuth-containing quadruple therapy for initial eradication, with amoxicillin and clarithromycin being the most commonly used antibiotic combination (56.3%). In addition, 84.6% of the physicians indicated that they would inquire about the antibiotic usage history for most patients before treatment, 93.8% would ask patients about their previous eradication history, and 94.2% would inform patients about treatment-related considerations. However, only 43.5%, 27.7%, and 29.7% of the physicians were aware of the high resistance rates of H. pylori to clarithromycin, levofloxacin, and metronidazole, respectively, in Gansu Province. Subgroup analysis revealed that the performance of gastroenterologists, nongastroenterologists, and physicians from different levels of hospitals differed in the diagnosis, treatment, and follow-up of H. pylori infection. CONCLUSIONS: Knowledge and practices regarding H. pylori infection management among physicians in Gansu Province, China, need further improvement. Strengthening targeted continuing education to increase the overall management level of H. pylori infection is recommended.

Assessment of the quality, diagnosis, and therapeutic recommendations of clinical practice guidelines on patients with Helicobacter pylori infection: A systematic review.

We conducted this study to systematically review and assess the current clinical practice guidelines (CPGs) related to the diagnosis and treatment of Helicobacter pylori (H. pylori) infection. The aim was to evaluate the quality of these included CPGs and provide clinicians with a convenient and comprehensive reference for updating their own CPGs. We searched four databases to identify eligible CPGs focusing on H. pylori diagnosis and treatment recommendations. The results were presented using evidence mappings. Quality and clinical applicability were assessed comprehensively using AGREE-II and AGREE-REX. Statistical tests, specifically Bonferroni tests, were employed to compare the quality between evidence-based guidelines and consensus. A total of 30 eligible CPGs were included, comprising 17 consensuses and 13 guidelines. The quality showed no statistical significance between consensuses and guidelines, mainly within the moderate to low range. Notably, recommendations across CPGs exhibited inconsistency. Nevertheless, concerning diagnosis, the urea breath test emerged as the most frequently recommended method for testing H. pylori. Regarding treatment, bismuth quadruple therapy stood out as the predominantly recommended eradication strategy, with high-dose dual therapy being a newly recommended option. Our findings suggest the need for specific organizations to update their CPGs on H. pylori or refer to recently published CPGs. Specifically, CPGs for pediatric cases require improvement and updating, while a notable absence of CPGs for the elderly was observed. Furthermore, there is a pressing need to improve the overall quality of CPGs related to H. pylori. Regarding recommendations, additional evidence is essential to elucidate the relationship between H. pylori infection and other diseases and refine test indications. Clinicians are encouraged to consider bismuth quadruple or high-dose dual therapy, incorporating locally sensitive antibiotics, as empirical radical therapy. .

GCdiscrimination: identification of gastric cancer based on a milliliter of blood.

Gastric cancer (GC) continues to be one of the major causes of cancer deaths worldwide. Meanwhile, liquid biopsies have received extensive attention in the screening and detection of cancer along with better understanding and clinical practice of biomarkers. In this work, 58 routine blood biochemical indices were tentatively used as integrated markers, which further expanded the scope of liquid biopsies and a discrimination system for GC consisting of 17 top-ranked indices, elaborated by random forest method was constructed to assist in preliminary assessment prior to histological and gastroscopic diagnosis based on the test data of a total of 2951 samples. The selected indices are composed of eight routine blood indices (MO%, IG#, IG%, EO%, P-LCR, RDW-SD, HCT and RDW-CV) and nine blood biochemical indices (TP, AMY, GLO, CK, CHO, CK-MB, TG, ALB and γ-GGT). The system presented a robust classification performance, which can quickly distinguish GC from other stomach diseases, different cancers and healthy people with sensitivity, specificity, total accuracy and area under the curve of 0.9067, 0.9216, 0.9138 and 0.9720 for the cross-validation set, respectively. Besides, this system can not only provide an innovative strategy to facilitate rapid and real-time GC identification, but also reveal the remote correlation between GC and these routine blood biochemical parameters, which helped to unravel the hidden association of these parameters with GC and serve as the basis for subsequent studies of the clinical value in prevention program and surveillance management for GC. The identification system, called GC discrimination, is now available online at http://lishuyan.lzu.edu.cn/GC/.

ULBP2 is a biomarker related to prognosis and immunity in colon cancer.

The study aimed to determine whether ULBP2 was associated with prognosis and immune infiltration in colon cancer (CC) and provided important molecular basis in order to early non-invasive diagnosis and immunotherapy of CC. Using The Cancer Genome Atlas database (TCGA) and ImmPort database, we extracted messenger RNA (mRNA) data of CC and immune-related genes, then we used "limma" package, "survival" package, and Venn overlap analysis to obtain the differentially expressed mRNA (DEmRNA) associated with prognosis and immunity of CC patients. "pROC" package was used to analyze receiver operating characteristics (ROC) of target gene. We used chi-square test and two-class logistics model to identify clinicopathological parameters that correlated with target gene expression. In order to determine the effects of target gene expression and clinicopathological parameters on survival, univariate and multivariate cox regression analyses were performed. We analyzed the related functions and signaling pathways of target gene by enrichment analysis. Finally, the correlation between target gene and tumor immune infiltrating was explored by ssGSEA and spearman correlation analysis. Results showed that ULBP2 was a target gene associated with immunity and prognosis in CC patients. CC patients with higher ULBP2 expression had poor outcomes. In terms of ROC, ULBP2 had an area under the curve (AUC) of 0.984. ULBP2 was associated with T stage, N stage, and pathologic stage of CC patients, and served as an independent predictor of overall survival in CC patients. Functional enrichment analysis revealed ULBP2 was obviously enriched in pathways connected with carcinogenesis and immunosuppression. The expression of ULBP2 was significantly associated with tumor immune cells and immune checkpoints according to ssGSEA and spearman correlation analysis. To conclude, our study suggested that ULBP2 was associated with tumor immunity, and might be a biomarker associated with the diagnosis and prognosis of CC patients, and a potential target of CC immunotherapy.

Constructed the ceRNA network and predicted a FEZF1-AS1/miR-92b-3p/ZIC5 axis in colon cancer.

The purpose of this study was to identify the role of FEZF1-AS1 in colon cancer and predicted the underlying mechanism. We extracted sequencing data of colon cancer patients from The Cancer Genome Atlas database, identified the differential expression of long noncoding RNA, microRNA, and messenger RNA, constructed a competitive endogenous RNA network, and then analyzed prognosis. Then, we used the enrichment analysis databases for functional analysis. Finally, we studied the FEZF1-AS1/miR-92b-3p/ZIC5 axis. We detected the expression of FEZF1-AS1, miR-92b-3p, and ZIC5 via quantitative reverse transcription-PCR, transfected colon cancer cell RKO with lentivirus and conducted FEZF1-AS1 knockdown, and performed cancer-related functional assays. It indicated that many RNA in the competitive endogenous RNA network, such as ZIC5, were predicted to be related to overall survival of colon cancer patients, and enrichment analysis showed cancer-related signaling pathways, such as PI3K/AKT signaling pathway. The expression of FEZF1-AS1 and ZIC5 was significantly higher and that of miR-92b-3p was lower in the colon cancer than in the normal colon tissues. FEZF1-AS1 promoted the migration, proliferation, as well as invasion of RKO. According to the prediction, FEZF1-AS1 and ZIC5 might competitively bind to miR-92b-3p, leading to the weakening of the inhibitory impact of miR-92b-3p on ZIC5 and increasing expression of ZIC5, thus further activating the PI3K/AKT signaling pathway, which led to the occurrence and development of colon cancer. The study suggested that FEZF1-AS1 might be an effective diagnosis biomarker for colon cancer.

Association of aberrant brain network dynamics with gut microbial composition uncovers disrupted brain-gut-microbiome interactions in irritable bowel syndrome: Preliminary findings.

BACKGROUND AND PURPOSE: Growing evidence suggests that abnormalities in brain-gut-microbiome (BGM) interactions are involved in the pathogenesis of irritable bowel syndrome (IBS). Our study aimed to explore alterations in dynamic functional connectivity (DFC), the gut microbiome and the bidirectional interaction in the BGM. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI), fecal samples and clinical chacteristics were collected from 33 IBS patients and 32 healthy controls. We performed a systematic DFC analysis on rs-fMRI. The gut microbiome was analyzed by 16S rRNA gene sequencing. Associations between DFC characteristics and microbial alterations were explored. RESULTS: In the DFC analysis, four dynamic functional states were identified. IBS patients exhibited increased mean dwell and fraction time in State 4, and reduced transitions from State 3 to State 1. Aberrant temporal properties in State 4 were only evident when choosing a short window (36 s or 44 s). Decreased functional connectivity (FC) variability was found in State 1 and State 3 in IBS patients, two of which (independent component [IC]51-IC91, IC46-IC11) showed significant correlations with clinical characteristics. Additionally, we identified nine significantly differential abundances in microbial composition. We also found that IBS-related microbiota were associated with aberrant FC variability, although these exploratory results were obtained at an uncorrected threshold of significance. CONCLUSIONS: Although future studies are needed to confirm our results, the findings not only provide a new insight into the dysconnectivity hypothesis in IBS from a dynamic perspective, but also establish a possible link between DFC and the gut microbiome, which lays the foundation for future research on disrupted BGM interactions.

High-dose amoxicillin-proton pump inhibitor dual therapy as first-line treatment for Helicobacter pylori infection in Northwest China: A prospective, randomised controlled trial.

AIMS: We aimed to assess the eradication efficacy and factors that influencing it of high-dose dual therapy (HDDT) in Gansu region, Northwest China. METHODS: A total of 216 treatment-naive patients with Helicobacter pylori infection were randomly assigned to two groups for the 14-day eradication treatment: the HDDT group (amoxicillin 750 mg q.i.d. and esomeprazole 40 mg t.i.d.) and the amoxicillin and clarithromycin-containing bismuth quadruple therapy group (ACBQT: esomeprazole 20 mg, bismuth potassium citrate 2 g, amoxicillin 1 g, and clarithromycin 500 mg; b.i.d.). The eradication rates, adverse effects and patient compliance of these two groups were compared. Eradication efficacy was determined by 13 C urea breath test (13 C UBT) 4-8 weeks after finishing treatment. Antibiotic resistance was determined by the Epsilometer testing (E-test) method. RESULTS: The eradication rates for the HDDT and ACBQT groups were 71.0% and 74.7% (P = .552) by per-protocol analysis, and 65.7% and 68.5% (P = .664) by intention-to-treat analysis. The overall adverse event rates in the HDDT and ACBQT groups were 2.0% and 43.4% (P < .001), respectively. The resistance rates to amoxicillin, clarithromycin, tetracycline, levofloxacin and metronidazole were 15.2%, 42.0%, 5.4%, 35.7% and 83.0%, respectively. Amoxicillin resistance and delta over baseline (DOB) of 13 C UBT ≥ 20 before treatment significantly reduced the eradication rate in 112 participants with H. pylori cultured. CONCLUSION: The HDDT as first-line treatment for H. pylori was unsatisfactory in Gansu. Amoxicillin resistance and DOB of 13 C UBT ≥ 20 before treatment were significantly correlated with H. pylori eradication failure.

Colloidal bismuth pectin-containing quadruple therapy as the first-line treatment of Helicobacter pylori infection: A multicenter, randomized, double-blind, non-inferiority clinical trial.

BACKGROUND: Bismuth-containing quadruple therapy is an effective regimen for Helicobacter pylori (H. pylori) treatment. No head-to-head comparison trials have been conducted to evaluate the efficacy of colloidal bismuth pectin (CBP) in quadruple therapy for eradicating H. pylori. We aimed to compare the efficacy and safety of CBP quadruple therapy and bismuth potassium citrate (BPC) quadruple therapy for 14 days in the first-line treatment of H. pylori. METHODS: In this multicenter, randomized, double-blind, non-inferiority clinical trial, H. pylori-infected subjects without eradication history were randomized to receive amoxicillin 1 g twice daily, tetracycline 500 mg three time daily, esomeprazole 20 mg twice daily in combination with CBP 200 mg three time daily or BPC 240 mg twice daily for 14 days. 13 C-urea breath tests were used to access the eradication rate at least 4 weeks after treatment. RESULTS: Between April 2021 and July 2022, 406 patients were assessed for eligibility and 339 subjects were randomized. The cure rates (primary outcome) of CBP and BPC quadruple therapy were 90.5% and 92.3% (p = 0.56) by intention-to-treat analysis, respectively, and 96.1% and 96.2% (p = 1.00) by per-protocol analysis, respectively. CBP quadruple therapy was non-inferior to BPC quadruple therapy in the intention-to-treat and per-protocol analysis (p < 0.025). The frequency of adverse events and compliance were not different among the two groups (p > 0.05). CONCLUSIONS: Both CBP and BPC quadruple therapy for 14 days provide high efficacy, good compliance, and safety in the first-line treatment of H. pylori in China.

Eradication rates of Helicobacter pylori in treatment-naive patients following 14-day vonoprazan-amoxicillin dual therapy: A multicenter randomized controlled trial in China.

BACKGROUND: Potassium-competitive acid blockers (P-CAB) are recommended for the treatment of Helicobacter pylori infections, but dual therapy of P-CAB with amoxicillin has been poorly studied. The current study compared the efficacy, adverse reactions, compliance, and effects on gut microbiota of 14-day vonoprazan-amoxicillin (VA) dual therapy with esomeprazole, bismuth potassium citrate, amoxicillin, and metronidazole (EBAM) quadruple therapy in treatment-naive patients with H. pylori. MATERIALS AND METHODS: This was a multicenter, open-label, randomized, and controlled, non-inferiority study. Patients (n = 194) enrolled from six centers were randomly divided into either the VA or EBAM group. H. pylori eradication was determined using 13 C urea breath tests (UBT) 4-6 weeks post-treatment. Fecal samples were collected, and gut microbial populations were analyzed by 16S rDNA and metagenomic sequencing technology. RESULTS: Eradication rates of H. pylori in the VA and EBAM groups were 88.7% and 91.8%, respectively, according to intention-to-treat (ITT) analysis; 95.6% and 96.7% with per-protocol (PP) analysis; and 94.5% and 96.7% with modified ITT (mITT) analysis (all p > 0.05). The incidence of adverse reactions in the VA group was significantly lower compared to the EBAM group, and compliance within both groups was good. There was no difference in α-diversity or microbial composition in the VA and EBAM groups at one-month post-treatment compared to baseline, except for a markedly reduced abundance of Bacteroides in the EBAM group. CONCLUSION: VA therapy achieved excellent eradication rates with low adverse reactions, good compliance, and little impact on gut microbiota. VA therapy should be recommended as a first-line treatment against H. pylori.

Discoidin domain receptor 1(DDR1) promote intestinal barrier disruption in Ulcerative Colitis through tight junction proteins degradation and epithelium apoptosis.

BACKGROUND AND AIMS: Discoidin domain receptor 1 (DDR1) encodes a receptor tyrosine kinase involved in multiple physiological and pathological processes. DDR1 is expressed in the intestinal epithelium, but its role in Ulcerative Colitis (UC) is poorly understand. This study aimed to identify the function of DDR1 in maintaining the homeostasis of UC. METHODS: The DDR1 expression level in non-inflamed and inflamed colon samples from IBD patients were assessed. DDR1 knock-out (DDR1-/-) and wild-type (WT) mice were administered dextran sulfate sodium (DSS) to induce colitis and assessed based on colitis symptoms. In addition, intestinal epithelial barrier injury was induced by TNF-α and IFN-γ incubation to cell monolayers transfected with PCDH-DDR1 or pLKO.1-sh-DDR1-1 plasmids. The effect of DDR1 in regulating barrier integrity, tight junctions (TJ) protein status, and cell apoptosis was investigated in vivo and in vitro. Furthermore, the activation of the NF-κB p65-MLCK-p-MLC2 pathway was also investigated. RESULTS: Decreased DDR1 expression levels were observed at the inflamed sites compared with the non-inflamed. DDR1-/- mice had alleviated intestinal mucosal barrier injuries, upregulated TJ proteins, decreased epithelium apoptosis from DSS-induced colitis, and reduced proinflammatory cytokines production in the colon. These findings were further confirmed in vitro. DDR1 over-expression aggravated the TNF-α/IFN-γ-induced TJ disruption, while DDR1 shRNA prevented TJ damage even in the presence of JSH-23. DDR1 dependently destroyed the intestinal barrier via the NF-κB p65-MLCK-p-MLC2 pathway. CONCLUSION: Our findings revealed that DDR1 regulated the intestinal barrier in colitis by modulating TJ proteins expression and epithelium apoptosis, making it a potential target of UC.

Diagnosis and treatment of Helicobacter pylori infection by physicians in China: A nationwide cross-sectional study.

BACKGROUND: To investigate the current state of knowledge and practice of Helicobacter pylori (H. pylori) infection management in China. MATERIALS AND METHODS: This nationwide, multicenter, cross-sectional questionnaire survey was conducted between March and April 2021 with respect to the diagnosis and treatment of H. pylori infection in 31 provinces, encompassing over 1000 hospitals in mainland China. General physician information, diagnostic and detection status, eradication treatment, reexamination and follow-up after treatment, and basic knowledge of physicians were collected and compared with the Fifth Chinese National Consensus Report on Management of H. pylori infection and the 2016 Maastricht V/Florence guidelines. The subgroup analysis was also performed. RESULTS: Of the 6873 questionnaire respondents, 48.8% were males, and 51.2% were females. Approximately, 26.5% of respondents indicated that their hospitals had dedicated clinics for managing H. pylori infection. Moreover, 88.0% of respondents prescribed a bismuth-containing quadruple regimen as the initial eradication treatment, and 92.7% deemed the gastric acid suppression critical. Furthermore, 91.0% of respondents routinely recommended a reexamination 1-2 months after eradication therapy, and 95.1% advised patients to stop PPI treatment at least 2 weeks before reexamination. The detail of following (the choice of target population/methods; the choice/availability of drugs/regimens, indications for eradication, factors influencing eradication efficacy/improvement methods and factors influencing adherence, management options/factors influencing relapse; the timing and methods, awareness of reinfection rates/prevention measures, and the approach to continuing education, awareness of guidelines, and acceptance of current core concepts of management) was also described. Subgroup analysis further revealed that significant differences were existed in being gastroenterologist or not, different education level, professional title, years of working, and provincial administrative regions. CONCLUSIONS: Chinese physicians' skills and knowledge about the diagnosis and treatment of H. pylori infection could be improved. More works on education are needed in future.

Discoidin domain receptor 1 may be involved in biological barrier homeostasis.

WHAT IS KNOWN AND OBJECTIVE: Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase involved in the pathological processes of several diseases, such as keloid formation, renal fibrosis, atherosclerosis, tumours, and inflammatory processes. The biological barrier is the first line of defence against pathogens, and its disruption is closely related to diseases. In this review, we attempt to elucidate the relationship between DDR1 and the biological barrier, explore the potential biological value of DDR1, and review the current research status and clinical potential of DDR1-selective inhibitors. METHODS: We conducted an extensive literature search on PubMed to collect studies on the relevance of DDR1 to biological barriers and DDR1-selective inhibitors. With these studies, we explored the relationship between DDR1 and biological barriers and briefly reviewed representative DDR1-selective inhibitors that have been reported in recent years. RESULTS AND DISCUSSION: First, the review of the potential mechanisms by which DDR1 regulates biological barriers, including the epithelial, vascular, glomerular filtration, blood-labyrinth, and blood-brain barriers. In the body, DDR1 dysfunction and aberrant expression may be involved in the homeostasis of the biological barrier. Secondly, the review of DDR1 inhibitors reported in recent years shows that DDR1-targeted inhibition is an attractive and promising pharmacological intervention. WHAT IS NEW AND CONCLUSIONS: This review shows that DDR1 is involved in various physiological and pathological processes and in the regulation of biological barrier homeostasis. However, studies on DDR1 and biological barriers are still scarce, and further studies are needed to elucidate their specific mechanisms. The development of targeted inhibitors provides a new direction and idea to study the mechanism of DDR1.

DDR1 promotes LoVo cell proliferation by regulating energy metabolism.

Cellular energy metabolism dysregulation is associated with colorectal cancer (CRC) development and progression. Discoidin domain receptor 1a (DDR1a), one of the five DDR1 isoforms, is closely related to cell proliferation, invasion, and apoptosis in various tumors. Whether it participates in cellular metabolic reprogramming and regulates CRC initiation and progression remains unclear. In this study, we compared the expression of DDR1 in CRC tissues and adjacent tissues from 126 postoperative CRC samples. Moreover, lentivirus-mediated DDR1a overexpression and knockdown were performed in LoVo cells, and cell viability and proliferation were determined by CCK-8 and BrdU assays, respectively. Oxygen consumption rate, extracellular acidification rate, and lactate production were used to determine the effect of DDR1a on metabolic reprogramming. Clinically, CRC patients with high DDR1 expression had poor differentiation and were at an advanced TNM stage. DDR1a promoted LoVo cell proliferation, mitochondrial function, and extracellular acidification. Moreover, DDR1a knockdown inhibited intracellular lactic acid production in LoVo cells, while a pyruvate kinase inhibitor (diamide, 200 µM) significantly reversed this progression. Taken together, our results reveal that DDR1 plays a crucial role in maintaining intracellular environment homeostasis through metabolic reprogramming.

Effect of dihydromyricetin on hepatic encephalopathy associated with acute hepatic failure in mice.

CONTEXT: Hepatic encephalopathy (HE) is a complex neuropsychiatric disease caused by liver failure. Dihydromyricetin (DMY) is a traditional medicine used to treat liver injury. OBJECTIVE: To investigate the effects of dihydromyricetin (DMY) on hepatic encephalopathy associated with acute hepatic failure mice models established by thioacetamide (TAA) exposure. MATERIALS AND METHODS: Female BALB/c mouse were randomly divided into control, DMY, TAA, and TAA + DMY groups (n = 8). The first two groups were intraperitoneally injected with saline or 5 mg/kg DMY, respectively. The last two groups were injected with 600 mg/kg TAA to establish HE models, and then the mice in the last group were treated with 5 mg/kg DMY. Neurological and cognition functions were evaluated 24 and 48 h after injection. Mice were sacrificed after which livers and brains were obtained for immunoblot and histopathological analysis, while blood was collected for the analysis of liver enzymes. RESULTS: In the TAA + DMY group, ALT and AST decreased to 145.31 ± 12.88 U/L and 309.51 ± 25.92 U/L, respectively, whereas ammonia and TBIL decreased to 415.67 ± 41.91 µmol/L and 3.31 ± 0.35 µmol/L, respectively. Moreover, MDA decreased to 10.74 ± 3.97 nmol/g, while SOD and GST increased to 398.69 ± 231.30 U/g and 41.37 ± 21.84 U/g, respectively. The neurological score decreased to 2.87 ± 0.63, and the number of GFAP-positive cells decreased to 41.10 ± 1.66. Furthermore, the protein levels of TNF-α, IL-6, and GABAA in the cortex decreased. CONCLUSIONS: We speculate that DMY can serve as a novel treatment for HE.

MicroRNA-125a suppresses intestinal mucosal inflammation through targeting ETS-1 in patients with inflammatory bowel diseases.

MicroRNA (miR)-125a is highly expressed in T cells and regulates the functions of Treg through the IL-6-STAT3 signaling pathway. However, the role of miR-125a in regulating immune responses in intestinal mucosa of patients with inflammatory bowel diseases (IBD) is still not understood. Here we showed that miR-125a expression was decreased in PBMC and inflamed intestinal mucosa from IBD patients compared with that in healthy controls. Transduction with LV-miR-125a into IBD CD4+ T cells could significantly inhibit proinflammatory cytokine production, including IFN-γ, TNF-α and IL-17A. RNA-seq analysis of miR-125a-/- CD4+ T cells revealed enhanced genes (e.g., Stat1, Stat3, RORγt, Irf4, Klf13) in T cell activation and effector pathways, while ETS-1 as its functional target promoted IBD CD4+ T cell differentiation into Th1 cells. Consistently, miR-125a-/- mice developed more severe colitis induced by TNBS compared with WT mice. Thus, our data suggest that miR-125a protects intestinal mucosa from inflammatory injury and that ETS-1 as its target participates in the pathogenesis of IBD.