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BackgroundThe adenosine–adenosine receptor pathway plays important roles in the immune system and inflammation. Four adenosine receptors (i.e., A1R, A2AR, A2BR, and A3R) have been identified. However, the roles of these receptors were different in the disease progress and even play opposite roles in the same disease. This study aims to investigate the roles of A1R/A2AR/A2BR/A3R activation in liver fibrosis.MethodsIntraperitoneal injection of CCl4 into C57BL/6 mice was used to induce liver fibrosis in the models. Adenosine receptor agonists CCPA, CGS21680, BAY 60-6583, and namodenoson were used for A1R/A2AR/A2BR/A3R activation, respectively. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were used to evaluate the liver function. Hematoxylin and eosin (H&E) staining was used to investigate the pathological damage. Masson staining and Sirius Red staining were performed to evaluate the degree of collagen deposition. CCK8 and scratch assays were used to investigate the proliferation and migration ability of hepatic stellate cells (HSCs).ResultsBy using liver fibrosis mouse models, we observed that the A1R and A2AR agonists aggravated liver fibrosis, characterized by increasing ALT and AST levels, more serious liver pathological damage, and collagen deposition. However, the A2BR and A3R agonists alleviated liver fibrosis. Moreover, the A1R and A2AR agonist treatment promotes the proliferation and migration of HSC line LX2, while A2BR and A3R agonist treatment inhibited LX2 proliferation and migration. Consistently, A1R and A2AR agonist treatment elevated the expression of α-SMA and Col1α1 in LX2, whereas A2BR and A3R agonist treatment inhibited the expression of α-SMA and Col1α1 in LX2 cells. Additionally, 5′-N-ethyl-carboxamidoadenosine (NECA), a metabolically stable adenosine analog, alleviated liver fibrosis and inhibited LX2 cell activity, proliferation, and migration.ConclusionThis study demonstrated the different roles of A1R/A2AR/A2BR/A3R during liver fibrosis development via regulating the HSC activity and proliferation.

IntroductionInsomnia is a common comorbidity symptom in major depressive disorder (MDD) patients. Abnormal brain activities have been observed in both MDD and insomnia patients, however, the central pathological mechanisms underlying the co-occurrence of insomnia in MDD patients are still unclear. This study aimed to explore the differences of spontaneous brain activity between MDD patients with and without insomnia, as well as patients with different level of insomnia.MethodsA total of 88 first-episode drug-naïve MDD patients including 44 with insomnia (22 with high insomnia and 22 with low insomnia) and 44 without insomnia, as well as 44 healthy controls (HC), were enrolled in this study. The level of depression and insomnia were evaluated by HAMD-17, adjusted HAMD-17 and its sleep disturbance subscale in all subjects. Resting-state functional and structural magnetic resonance imaging data were acquired from all participants and then were preprocessed by the software of DPASF. Regional homogeneity (ReHo) values of brain regions were calculated by the software of REST and were compared. Finally, receiver operating characteristic (ROC) curves were conducted to determine the values of abnormal brain regions for identifying MDD patients with insomnia and evaluating the severity of insomnia.ResultsAnalysis of variance showed that there were significant differences in ReHo values in the left middle frontal gyrus, left pallidum, right superior frontal gyrus, right medial superior frontal gyrus and right rectus gyrus among three groups. Compared with HC, MDD patients with insomnia showed increased ReHo values in the medial superior frontal gyrus, middle frontal gyrus, triangular inferior frontal gyrus, calcarine fissure and right medial superior frontal gyrus, medial orbital superior frontal gyrus, as well as decreased ReHo values in the left middle occipital gyrus, pallidum and right superior temporal gyrus, inferior temporal gyrus, middle cingulate gyrus, hippocampus, putamen. MDD patients without insomnia demonstrated increased ReHo values in the left middle frontal gyrus, orbital middle frontal gyrus, anterior cingulate gyrus and right triangular inferior frontal gyrus, as well as decreased ReHo values in the left rectus gyrus, postcentral gyrus and right rectus gyrus, fusiform gyrus, pallidum. In addition, MDD patients with insomnia had decreased ReHo values in the left insula when compared to those without insomnia. Moreover, MDD patients with high insomnia exhibited increased ReHo values in the right middle temporal gyrus, and decreased ReHo values in the left orbital superior frontal gyrus, lingual gyrus, right inferior parietal gyrus and postcentral gyrus compared to those with low insomnia. ROC analysis demonstrated that impaired brain region might be helpful for identifying MDD patients with insomnia and evaluating the severity of insomnia.ConclusionThese findings suggested that MDD patients with insomnia had wider abnormalities of brain activities in the prefrontal-limbic circuits including increased activities in the prefrontal cortex, which might be the compensatory mechanism underlying insomnia in MDD. In addition, decreased activity of left insula might be associated with the occurrence of insomnia in MDD patients and decreased activities of the frontal–parietal network might cause more serious insomnia related to MDD.

Polyphenols are a group of naturally occurring compounds that possess a range of biological properties capable of potentially mitigating or preventing the progression of age-related cognitive decline and Alzheimer’s disease (AD). AD is a chronic neurodegenerative disease known as one of the fast-growing diseases, especially in the elderly population. Moreover, as the primary etiology of dementia, it poses challenges for both familial and societal structures, while also imposing a significant economic strain. There is currently no pharmacological intervention that has demonstrated efficacy in treating AD. While polyphenols have exhibited potential in inhibiting the pathological hallmarks of AD, their limited bioavailability poses a significant challenge in their therapeutic application. Furthermore, in order to address the therapeutic constraints, several polymer nanoparticles are being explored as improved therapeutic delivery systems to optimize the pharmacokinetic characteristics of polyphenols. Polymer nanoparticles have demonstrated advantageous characteristics in facilitating the delivery of polyphenols across the blood–brain barrier, resulting in their efficient distribution within the brain. This review focuses on amyloid-related diseases and the role of polyphenols in them, in addition to discussing the anti-amyloid effects and applications of polyphenol-based polymer nanoparticles.

ObjectivesWilson disease (WD) is a rare autosomal recessive disorder caused by a mutation in the ATP7B gene. Neurological symptoms are one of the most common symptoms of WD. This study aims to construct a model that can predict the occurrence of neurological symptoms by combining clinical multidimensional indicators with machine learning methods.MethodsThe study population consisted of WD patients who received treatment at the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine from July 2021 to September 2023 and had a Leipzig score ≥ 4 points. Indicators such as general clinical information, imaging, blood and urine tests, and clinical scale measurements were collected from patients, and machine learning methods were employed to construct a prediction model for neurological symptoms. Additionally, the SHAP method was utilized to analyze clinical information to determine which indicators are associated with neurological symptoms.ResultsIn this study, 185 patients with WD (of whom 163 had neurological symptoms) were analyzed. It was found that using the eXtreme Gradient Boosting (XGB) to predict achieved good performance, with an MCC value of 0.556, ACC value of 0.929, AUROC value of 0.835, and AUPRC value of 0.975. Brainstem damage, blood creatinine (Cr), age, indirect bilirubin (IBIL), and ceruloplasmin (CP) were the top five important predictors. Meanwhile, the presence of brainstem damage and the higher the values of Cr, Age, and IBIL, the more likely neurological symptoms were to occur, while the lower the CP value, the more likely neurological symptoms were to occur.ConclusionsTo sum up, the prediction model constructed using machine learning methods to predict WD cirrhosis has high accuracy. The most important indicators in the prediction model were brainstem damage, Cr, age, IBIL, and CP. It provides assistance for clinical decision-making.

Our previous study highlighted the therapeutic potential of glutathione (GSH), an intracellular thiol tripeptide ubiquitous in mammalian tissues, in mitigating hepatic and cerebral damage. Building on this premise, we posited the hypothesis that GSH could be a promising candidate for treating acute hepatic encephalopathy (AHE). To verify this conjecture, we systematically investigated the feasibility of GSH as a therapeutic agent for AHE through comprehensive pharmacokinetic, pharmacodynamic, and mechanistic studies using a thioacetamide-induced AHE rat model. Our pharmacodynamic data demonstrated that oral GSH could significantly improve behavioral scores and reduce hepatic damage of AHE rats by regulating intrahepatic ALT, AST, inflammatory factors, and homeostasis of amino acids. Additionally, oral GSH demonstrated neuroprotective effects by alleviating the accumulation of intracerebral glutamine, down-regulating glutamine synthetase, and reducing taurine exposure. Pharmacokinetic studies suggested that AHE modeling led to significant decrease in hepatic and cerebral exposure of GSH and cysteine. However, oral GSH greatly enhanced the intrahepatic and intracortical GSH and CYS in AHE rats. Given the pivotal roles of CYS and GSH in maintaining redox homeostasis, we investigated the interplay between oxidative stress and pathogenesis/treatment of AHE. Our data revealed that GSH administration significantly relieved oxidative stress levels caused by AHE modeling via down-regulating the expression of NADPH oxidase 4 (NOX4) and NF-κB P65. Importantly, our findings further suggested that GSH administration significantly regulated the excessive endoplasmic reticulum (ER) stress caused by AHE modeling through the iNOS/ATF4/Ddit3 pathway. In summary, our study uncovered that exogenous GSH could stabilize intracerebral GSH and CYS levels to act on brain oxidative and ER stress, which have great significance for revealing the therapeutic effect of GSH on AHE and promoting its further development and clinical application.

Gynostemma pentaphyllum (Thunb.) Makino is an important producer of dammarene-type triterpenoid saponins. These saponins (gypenosides) exhibit diverse pharmacological benefits such as anticancer, antidiabetic, and immunomodulatory effects, and have major potential in the pharmaceutical and health care industries. Here, we employed single-cell RNA sequencing (scRNA-seq) to profile the transcriptomes of more than 50,000 cells derived from G. pentaphyllum shoot apexes and leaves. Following cell clustering and annotation, we identified five major cell types in shoot apexes and four in leaves. Each cell type displayed substantial transcriptomic heterogeneity both within and between tissues. Examining gene expression patterns across various cell types revealed that gypenoside biosynthesis predominantly occurred in mesophyll cells, with heightened activity observed in shoot apexes compared to leaves. Furthermore, we explored the impact of transposable elements (TEs) on G. pentaphyllum transcriptomic landscapes. Our findings the highlighted the unbalanced expression of certain TE families across different cell types in shoot apexes and leaves, marking the first investigation of TE expression at the single-cell level in plants. Additionally, we observed dynamic expression of genes involved in gypenoside biosynthesis and specific TE families during epidermal and vascular cell development. The involvement of TE expression in regulating cell differentiation and gypenoside biosynthesis warrant further exploration. Overall, this study not only provides new insights into the spatiotemporal organization of gypenoside biosynthesis and TE activity in G. pentaphyllum shoot apexes and leaves but also offers valuable cellular and genetic resources for a deeper understanding of developmental and physiological processes at single-cell resolution in this species.

Microorganisms, especially rare microbial species, are crucial in estuarine ecosystems for driving biogeochemical processes and preserving biodiversity. However, the understanding of the links between ecosystem multifunctionality (EMF) and the diversity of rare bacterial taxa in estuary ecosystems remains limited. Employing high-throughput sequencing and a variety of statistical methods, we assessed the diversities and assembly process of abundant and rare bacterioplankton and their contributions to EMF in a subtropical estuary. Taxonomic analysis revealed Proteobacteria as the predominant phylum among both abundant and rare bacterial taxa. Notably, rare taxa demonstrated significantly higher taxonomic diversity and a larger species pool than abundant taxa. Additionally, our findings highlighted that deterministic assembly processes predominantly shape microbial communities, with heterogeneous selection exerting a stronger influence on rare taxa. Further analysis reveals that rare bacterial beta-diversity significantly impacts to EMF, whereas alpha diversity did not. The partial least squares path modeling (PLS-PM) analysis demonstrated that the beta diversity of abundant and rare taxa, as the main biotic factor, directly affected EMF, while temperature and total organic carbon (TOC) were additional key factors to determine the relationship between beta diversity and EMF. These findings advance our understanding of the distribution features and ecological knowledge of the abundant and rare taxa in EMF in subtropical estuaries, and provide a reference for exploring the multifunctionality of different biospheres in aquatic environments.

Food-borne Campylobacter jejuni infections constitute serious threats to human health worldwide. Since antibiotic treatment is usually not indicated in infected immune-competent patients, antibiotic-independent treatment approaches are needed to tackle campylobacteriosis. To address this, we orally applied carvacrol, deferoxamine, deoxycholate, and 2-fucosyl-lactose either alone or all in combination to human microbiota-associated IL-10−/− mice from day 2 until day 6 following oral C. jejuni infection. Neither treatment regimen affected C. jejuni loads in the colon, whereas carvacrol lowered the pathogen numbers in the ileum on day 6 post-infection (p.i.). The carvacrol and combination treatment regimens resulted in alleviated diarrheal symptoms, less distinct histopathological and apoptotic epithelial cell responses in the colon, as well as diminished numbers of colonic neutrophils and T lymphocytes on day 6 p.i., whereas the latter cells were also decreased upon deferoxamine, deoxycholate, or 2-fucosyl-lactose application. Remarkably, the carvacrol, deferoxamine, and combination treatment regimens dampened ex-vivo IFN-γ secretion in the colon, the kidneys, and even in the serum to basal concentrations on day 6 p.i. In conclusion, carvacrol alone and its combination with deferoxamine, deoxycholate, and 2-fucosyl-lactose constitute promising antibiotics-independent treatment options to fight acute campylobacteriosis.

The rates of twin pregnancies and cesarean section have increased in recent years, and both of them are at high risks of postpartum hemorrhage (PPH). However, few studies have concentrated on the risks of PPH in twin pregnancies and cesarean deliveries. In this study, we aimed to identify the risk factors for PPH among twin-pregnant women with cesarean section. This was a retrospective observational study including 1,649 women with twin pregnancies delivered by cesarean section from 2016 to 2022 in the Second Affiliated Hospital of Wenzhou Medical University, China. The eligible women were divided into PPH group (n = 116) and non-PPH group (n = 1,533) according to the blood loss after delivery within 24 h. The baseline maternal and perinatal characteristics were compared between the two groups. Logistic regression analysis was conducted to identify the potential risk factors for PPH. We found nulliparity, assisted reproductive technology (ART) usage, preeclampsia or HELLP syndrome, placenta previa, placenta accreta and general anesthesia were more common in PPH group than non-PPH group (P < 0.05). Women in PPH group had higher maternal body mass index at delivery and higher combined birthweight of the twins than non-PPH group, but had lower parity (P < 0.05). Seven independent risk factors for PPH were identified after logistic regression analysis: ART usage (OR 2.354 95% CI 1.357–4.083, P = 0.002), preeclampsia or HELLP syndrome (OR 2.605, 95% CI 1.471–4.616, P = 0.001), placenta previa (OR 7.325, 95% CI 3.651–14.697, P < 0.001), placenta accreta (OR 6.296, 95% CI 1.316–30.12, P = 0.021), thrombocytopenia (OR 1.636, 95% CI 1.056–2.535, P = 0.027), general anesthesia (OR 2.394, 95% CI 1.223–4.686, P = 0.011), and combined birthweight (OR 1.00032, 95% CI 1.00005–1.00059, P = 0.020). Collectively, in women with twin pregnancies delivered by cesarean section, the use of ART, preeclampsia or HELLP syndrome, placenta previa, placenta accreta, thrombocytopenia, general anesthesia and the combined birthweight were identified as independent risk factors for PPH. More attention should be paid to women with these risk factors.

IntroductionAutism spectrum disorder (ASD) is a multifaceted developmental condition that commonly appears during early childhood. The etiology of ASD remains multifactorial and not yet fully understood. The identification of biomarkers may provide insights into the underlying mechanisms and pathophysiology of the disorder. The present study aimed to explore the causes of ASD by investigating the key biomedical markers, trace elements, and microbiota factors between children with autism spectrum disorder (ASD) and control subjects.MethodsMedline, PubMed, ProQuest, EMBASE, Cochrane Library, PsycINFO, Web of Science, and EMBSCO databases have been searched for publications from 2012 to 2023 with no language restrictions using the population, intervention, control, and outcome (PICO) approach. Keywords including “autism spectrum disorder,” “oxytocin,” “GABA,” “Serotonin,” “CRP,” “IL-6,” “Fe,” “Zn,” “Cu,” and “gut microbiota” were used for the search. The Joanna Briggs Institute (JBI) critical appraisal checklist was used to assess the article quality, and a random model was used to assess the mean difference and standardized difference between ASD and the control group in all biomedical markers, trace elements, and microbiota factors.ResultsFrom 76,217 records, 43 studies met the inclusion and exclusion criteria and were included in this meta-analysis. The pooled analyses showed that children with ASD had significantly lower levels of oxytocin (mean differences, MD = −45.691, 95% confidence interval, CI: −61.667, −29.717), iron (MD = −3.203, 95% CI: −4.891, −1.514), and zinc (MD = −6.707, 95% CI: −12.691, −0.722), lower relative abundance of Bifidobacterium (MD = −1.321, 95% CI: −2.403, −0.238) and Parabacteroides (MD = −0.081, 95% CI: −0.148, −0.013), higher levels of c-reactive protein, CRP (MD = 0.401, 95% CI: 0.036, 0.772), and GABA (MD = 0.115, 95% CI: 0.045, 0.186), and higher relative abundance of Bacteroides (MD = 1.386, 95% CI: 0.717, 2.055) and Clostridium (MD = 0.281, 95% CI: 0.035, 0.526) when compared with controls. The results of the overall analyses were stable after performing the sensitivity analyses. Additionally, no substantial publication bias was observed among the studies.InterpretationChildren with ASD have significantly higher levels of CRP and GABA, lower levels of oxytocin, iron, and zinc, lower relative abundance of Bifidobacterium and Parabacteroides, and higher relative abundance of Faecalibacterium, Bacteroides, and Clostridium when compared with controls. These results suggest that these indicators may be a potential biomarker panel for the diagnosis or determining therapeutic targets of ASD. Furthermore, large, sample-based, and randomized controlled trials are needed to confirm these results.

The principal benefit of employing percutaneous vertebroplasty (PVP) for managing osteoporotic vertebral compression fractures lies in its capacity to facilitate early mobilization in elderly patients, thereby effectively avoiding the potential catastrophic complications associated with prolonged bedridden states. However, bone cement leakage, as the most common complication of PVP, may have fatal consequences. Here, we report a case involving an 85-year-old male patient with L1 vertebral compression fracture who underwent PVP at our hospital and was discharged on the same day of the surgical intervention. Subsequently, the patient experienced symptoms of chest tightness and palpitations. Cardiac ultrasound examination revealed pericardial effusion, while pulmonary computed tomographic angiography (CTA) demonstrated a strip high-density shadow in the right ventricular area. Finally, it was determined that the perforation of the right ventricular wall was caused by bone cement embolism. Through this comprehensive case report, we aim to deepen the understanding of orthopedic doctors on the importance of preventing bone cement leakage.

Gliomas, the most prevalent primary tumors in the central nervous system, are marked by their immunosuppressive properties and consequent poor patient prognosis. Current evidence emphasizes the pivotal role of the tumor microenvironment in the progression of gliomas, largely attributed to tumor-associated macrophages (brain-resident microglia and bone marrow-derived macrophages) that create a tumor microenvironment conducive to the growth and invasion of tumor cells. Yet, distinguishing between these two cell subgroups remains a challenge. Thus, our review starts by analyzing the heterogeneity between these two cell subsets, then places emphasis on elucidating the complex interactions between microglia and glioma cells. Finally, we conclude with a summary of current attempts at immunotherapy that target microglia. However, given that independent research on microglia is still in its initial stages and has many shortcomings at the present time, we express our related concerns and hope that further research will be carried out to address these issues in the future.

Ischemic stroke (IS) is the second leading cause of death and disability in the world. Pyroptosis, a form of programmed cell death initiated by caspases, participates in the occurrence and development of IS. Because it can increase cell membrane permeability, mediate the release of inflammatory factors, and aggravate inflammation, inhibiting this process can significantly reduce the pathological injury of IS. The nucleotide binding oligomerization domain-like receptor family pyrin domain protein 3 (NLRP3) is a multiprotein complex whose activation is the core link of pyroptosis. In recent years, studies have reported that traditional Chinese medicine (TCM) could regulate pyroptosis mediated by NLRP3 inflammasome through multi-channel and multi-target networks and thus exert the effect against IS. This article reviews 107 papers published in recent years in PubMed, Chinese National Knowledge Infrastructure (CNKI), and WanFang Data in recent years. It has found that the activation factors of NLRP3 inflammasome include ROS, mitochondrial dysfunction, K+, Ca2+, lysosome rupture, and trans-Golgi breakdown. TLR4/NF-κB/NLRP3, ROS/TXNIP/NLRP3, AMPK/Nrf2/NLRP3, DRP1/NLRP3, TAK1/JNK/NLRP3 signaling pathways regulate the initiation and assembly of the NLRP3 inflammasome, subsequently induce pyroptosis, affecting the occurrence and development of IS. TCM can affect the above signaling pathways and regulate the pyroptosis mediated by NLRP3 inflammasome, so as to play a protective role against IS, which provides a new entry point for discussing the pathological mechanism of IS and a theoretical basis for developing TCM treasure house.

Potato is one of the world’s most important food crops, with a time-consuming breeding process. In this study, we performed a genome-wide association (GWAS) analysis of the two important traits of potato tuber shape and eye depth, using the tetraploid potato genome (2n=4x=48) as a reference. A total of 370 potatoes were divided into three subgroups based on the principal component analysis and evolutionary tree analysis. The genetic diversity within subgroups is low (5.18×10-5, 4.36×10-5 and 4.24×10-5). Genome-wide linkage disequilibrium (LD) analysis showed that their LD is about 60 Kb. GWAS analysis identified that 146 significant single nucleotide polymorphism (SNP) loci at Chr01A1:34.44−35.25 Mb and Chr02A1:28.35−28.54 Mb regions are significantly associated with potato tuber shape, and that three candidate genes that might be related to potato tuber traits, PLATZ transcription factor, UTP-glucose-1-phosphate uridylyltransferase and FAR1 DNA-binding domain, are in the association region of Chr02A1. GWAS analysis identified 53 significant SNP loci at Chr05A2: 49.644-50.146 Mb and Chr06A2: 25.866-26.384 Mb regions with robust associations with potato tuber eye depth. Hydrolase and methyltransferases are present in the association region of Chr05A2, and three CYPs are present in the association region of Chr06A2. Our findings suggested that these genes are closely associated with potato tuber shape and eye depth. Our study identified molecular markers and candidate genes for improving tetraploid potato tuber shape and eye depth and provided ideas and insights for tetraploid potato breeding.

IntroductionThe food-borne Gram-negative bacterial pathogen Campylobacter jejuni may cause the acute enterocolitis syndrome campylobacteriosis in infected humans. Given that human C. jejuni infections are rising globally which hold also true for resistance rates against antibiotic compounds such as macrolides and fluoroquinolones frequently prescribed for the treatment of severe infectious enteritis, novel antibiotics-independent therapeutic strategies are needed. Distinct organic acids are well known for their health-beneficial including anti-microbial and immunomodulatory properties. In our present study, we investigated potential pathogen-lowering and anti-inflammatory effects of benzoic acid, butyric acid, caprylic acid, and sorbic acid either alone or in combination during acute murine campylobacteriosis.MethodsTherefore, secondary abiotic IL-10–/– mice were perorally infected with C. jejuni strain 81–176 and subjected to a 4-day-course of respective organic acid treatment.Results and discussionOn day 6 post-infection, mice from the combination cohort displayed slightly lower pathogen loads in the duodenum, but neither in the stomach, ileum nor large intestine. Remarkably, the clinical outcome of C. jejuni induced acute enterocolitis was significantly improved after combined organic acid treatment when compared to the placebo control group. In support, the combinatory organic acid treatment dampened both, macroscopic and microscopic inflammatory sequelae of C. jejuni infection as indicated by less colonic shrinkage and less pronounced histopathological including apoptotic epithelial cell changes in the colon on day 6 post-infection. Furthermore, mice from the combination as compared to placebo cohort exhibited lower numbers of innate and adaptive immune cells such as neutrophilic granulocytes, macrophages, monocytes, and T lymphocytes in their colonic mucosa and lamina propria, respectively, which also held true for pro-inflammatory cytokine secretion in the large intestines and mesenteric lymph nodes. Notably, the anti-inflammatory effects were not restricted to the intestinal tract, but could also be observed systemically given pro-inflammatory mediator concentrations in C. jejuni infected mice from the combination organic acid treatment that were comparable to basal values. In conclusion, our in vivo study provides first evidence that an oral application of distinct organic acids in combination exhibits pronounced anti-inflammatory effects and hence, constitutes a promising novel antibiotics-independent therapeutic strategy in the combat of acute campylobacteriosis.

Recent large datasets measuring the gene expression of millions of possible gene promoter sequences provide a resource to design and train optimized deep neural network architectures to predict expression from sequences. High predictive performance due to the modeling of dependencies within and between regulatory sequences is an enabler for biological discoveries in gene regulation through model interpretation techniques. To understand the regulatory code that delineates gene expression, we have designed a novel deep-learning model (CRMnet) to predict gene expression in Saccharomyces cerevisiae. Our model outperforms the current benchmark models and achieves a Pearson correlation coefficient of 0.971 and a mean squared error of 3.200. Interpretation of informative genomic regions determined from model saliency maps, and overlapping the saliency maps with known yeast motifs, supports that our model can successfully locate the binding sites of transcription factors that actively modulate gene expression. We compare our model's training times on a large compute cluster with GPUs and Google TPUs to indicate practical training times on similar datasets.

Introduction: Hyperlipidemia is a common metabolic disorder with presence of excess fat or lipids in the blood, may induce liver injury, oxidative stress and inflammatory. Xuezhiping capsule (XZP) is a famous Chinese patent medicine clinically used for anti-hyperlipidemia. However, the regulation mechanism of XZP on hyperlipidemia has not been elucidated so far.Methods: This study aimed to explore the effects of XZP on hypolipidemic, antioxidant and anti-inflammatory effects, and the potential mechanism by a combination of untargeted metabolomics and 16S rRNA sequencing.Results: The results indicated that XZP reduced the level of total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), increased the level of high density liptein cholesterol (HDL-C), alleviated excessive accumulation of lipid droplets in liver. Biochemical indexes of liver function including gamma glutamyl transferase (GGT) and glutamic oxaloacetic transaminase (GOT) in liver were remarkably decreased. Meanwhile, XZP increased the level of oxidative stress biochemical indexes including superoxide dismutase (SOD) and glutathione (GSH). In addition, XZP increased the level of peroxisome proliferators-activated receptors α (PPARα), acetyl CoA carboxylase 1 (ACOX1) and cholesterol 7-alpha hydroxylase (CYP7A1) in liver, and improved lipid metabolism in serum, liver and fecal lipid metabolism. XZP increased diversity index and the ratio of Firmicutes and Bacteroidetes, regulated seventeen genera, and illustrated strong correlations with liver lipid metabolism and phenotypic indicators.Discussion: These findings suggest that XZP reduced blood lipid and liver lipid, protected liver function, anti inflammation and anti-oxidation, ameliorate lipid metabolic disorders by modulating alpha linolenic acid and linoleic acid metabolism, bile acid metabolism, arachidonic acid metabolism, and regulated gut microbiota composition of high-fat diet (HFD) hamsters.

Introduction: Epimedium, a traditional Chinese medicine (TCM) commonly used in ancient and modern China, is one of the traditional Chinese medicines clinically used to treat kidney yang deficiency syndrome (KYDS). There are differences in the efficacy of Epimedium before and after processing, and the effect of warming the kidney and enhancing yang is significantly enhanced after heating with suet oil. However, the active compounds, corresponding targets, metabolic pathways, and synergistic mechanism of frying Epimedium in suet oil to promote yang, remain unclear.Methods: Herein, a strategy based on comprehensive GC-TOF/MS metabolomics and network pharmacology analysis was used to construct an “active compounds-targets-metabolic pathways” network to identify the active compounds, targets and metabolic pathways involved. Subsequently, the targets in kidney tissue were further validated by real-time quantitative polymerase chain reaction (RT-qPCR). Histopathological analysis with physical and biochemical parameters were performed.Results: Fifteen biomarkers from urine and plasma, involving five known metabolic pathways related to kidney yang deficiency were screened. The network pharmacology results showed 37 active compounds (13 from Epimedium and 24 from suet oil), 159 targets, and 267 pathways with significant correlation. Importantly, integrated metabolomics and network pharmacologic analysis revealed 13 active compounds (nine from Epimedium and four from suet oil), 7 corresponding targets (ALDH2, ARG2, GSTA3, GSTM1, GSTM2, HPGDS, and NOS2), two metabolic pathways (glutathione metabolism, arginine and proline metabolism), and two biomarkers (Ornithine and 5-Oxoproline) associated with improved kidney yang deficiency by Epimedium fried with suet oil.Discussion: These finds may elucidate the underlying mechanism of yang enhancement via kidney warming effects. Our study indicated that the mechanism of action mainly involved oxidative stress and amino acid metabolism. Here, we demonstrated the novel strategies of integrating metabolomics and network pharmacology in exploring of the mechanisms of traditional Chinese medicines.

Background/ObjectiveThe efficacy of transcranial magnetic stimulation (TMS) on Parkinson’s disease (PD) varies across the stimulation targets. This study aims to estimate the effect of different TMS targets on motor symptoms in PD.MethodsA Bayesian hierarchical model was built to assess the effects across different TMS targets, and the rank probabilities and the surface under the cumulative ranking curve (SUCRA) values were calculated to determine the ranks of each target. The primary outcome was the Unified Parkinson’s Disease Rating Scale part-III. Inconsistency between direct and indirect comparisons was assessed using the node-splitting method.ResultsThirty-six trials with 1,122 subjects were included for analysis. The pair-wise meta-analysis results showed that TMS could significantly improve motor symptoms in PD patients. Network meta-analysis results showed that the high-frequency stimulation over bilateral M1, bilateral DLPFC, and M1+DLPFC could significantly reduce the UPDRS-III scores compared with sham conditions. The high-frequency stimulation over both M1 and DLPFC had a more significant effect when compared with other parameters, and ranked first with the highest SCURA value. There was no significant inconsistency between direct and indirect comparisons.ConclusionConsidering all settings reported in our research, high-frequency stimulation over bilateral M1 or bilateral DLPFC has a moderate beneficial effect on the improvement of motor symptoms in PD (high confidence rating). High-frequency stimulation over M1+DLPFC has a prominent beneficial effect and appears to be the most effective TMS parameter setting for ameliorating motor symptoms of PD patients (high confidence rating).

Hyperactivation of Bruton’s tyrosine kinase (BTK) or interleukin-2-inducible T cell kinase (ITK) has been attributed to the pathogenesis of B-cell lymphoma or T-cell leukemia, respectively, which suggests that Bruton’s tyrosine kinase and interleukin-2-inducible T cell kinase are critical targets for the treatment of hematological malignancies. We identified a novel third-generation epidermal growth factor receptor (EGFR) inhibitor, ASK120067 (limertinib) in our previous research, which has been applied as a new drug application against non-small cell lung cancer in China. In this work, we found that ASK120067 displayed potent in vitro inhibitory efficacy against Bruton’s tyrosine kinase protein and interleukin-2-inducible T cell kinase protein via covalent binding. In cell-based assays, ASK120067 dose-dependently suppressed Bruton’s tyrosine kinase phosphorylation and exhibited anti-proliferation potency by inducing apoptosis in numerous B-lymphoma cells. Meanwhile, it caused growth arrest and induced the apoptosis of T-cell leukemia cells by attenuating interleukin-2-inducible T cell kinase activation. Oral administration of ASK120067 led to significant tumor regression in B-cell lymphoma and T-cell leukemia xenograft models by weakening Bruton’s tyrosine kinase and interleukin-2-inducible T cell kinase signaling, respectively. Taken together, our studies demonstrated that ASK120067 exerted preclinical anti-tumor activities against B-/T-cell malignancy by targeting BTK/ITK.

AimsTo compare efficacy and safety of the levonorgestrel-releasing intrauterine system (LNG-IUS) with systemic medication or blank control in the treatment of dysmenorrhea.MethodsPubMed, EMBASE, the China National Knowledge Infrastructure (CNKI) and Wanfang Data were searched to collect randomized controlled trials (RCTs) comparing LNG-IUS with systemic medication or blank control among women diagnosed with primary dysmenorrhea or secondary dysmenorrhea (adenomyosis or endometriosis) from inception to 2020.04. Der Simonian-Laird random-effect model was used to pool data.ResultsSeventy-one RCTs (6551 patients) were included. Overall bias risk was medium. Sixty-two articles enrolled patients with adenomyosis; LNG-IUS significantly reduced the visual analogue scale (VAS) score compared with the systemic medication group among adenomyosis women at 3 months (standardized mean difference (SMD) = −0.81, 95% confidence interval (CI) −1.22 to −0.40); 6 months (SMD = −1.25, 95%CI: −1.58 to −0.92); 9 months (SMD = −1.23, 95%CI: −1.63 to −0.83); 12 months (SMD = −1.66, 95%CI: −2.14 to −1.18). No difference was found in the incidence of irregular vaginal bleeding (16 RCTs; RR = 0.91, 95%CI: 0.62−1.33, P = 0.63, I2 = 4%) and other adverse outcomes. Sensitivity analysis regarding randomization methods was robust. Nine RCTs enrolled endometriosis women. Pooling results showed no significant difference between LNG-IUS and systemic medication treatment in terms of VAS at 6 months (SMD = −0.27, 95% CI: −0.97–0.43). Moreover, LNG-IUS was associated with higher risk of irregular vaginal bleeding (26.8% vs. 0).ConclusionsLNG-IUS was associated with a reduced severity of dysmenorrhea compared with systemic medication; it was also beneficial for better control of menstrual blood loss and fewer adverse outcomes. Owing to small sample sizes, further well-designed RCTs are warranted to confirm these findings and long-term effects of LNG-IUS in the treatment of dysmenorrhea. Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42021228343.

The interaction between the gut microbiota and the host has been described experimentally by germ-free animals or by antibiotic-disturbed gut microbiota. Studies on germ-free mice have shown that gut microbiota is critical for bone growth and development in mice, emphasizing that microbiota dysbiosis may interfere with normal bone development processes. This study aimed to clarify the effect of antibiotic treatment on disturbed gut microbiota on bone development in mice and to investigate the effect of probiotic treatment on fracture healing in mice with dysbiosis. Our results showed that 4 weeks old female Kunming mice showed significantly lower abundance and diversity of the gut microbiota and significantly lower bone mineral density after 12 weeks of antibiotic treatment and significantly increased levels of RANKL and Ang II in serum (p

Traditional Chinese medicine (TCM) has attracted a great deal of attention in the treatment of cerebral ischemia is credited with the remarkable neuroprotective effects. However, the imperfect functional mechanism of TCM is a major obstacle to their application. Many studies have been conducted to illustrate the pathophysiology of post-ischemic cerebral ischemia by elucidating the neuronal cell death pathway. Meanwhile, a new type of cell death, ferroptosis, is gradually being recognized in various diseases and is becoming a new pathway of therapeutic intervention strategy to solve many health problems. Especially since ferroptosis has been found to be closely involved into the pathogenesis of cerebral ischemia, it has been considered as a key target in the treatment of cerebral ischemia. Therefore, this paper reviews the latest research findings about the treatment of cerebral ischemia with TCM focused on ferroptosis as a target. Also, in order to explores the possibility of a new approach to treat cerebral ischemia with TCM, we discusses the correlation between ferroptosis and other cell death pathways such as apoptosis and autophagy, which would provide references for the following researches.

Xylooligosaccharide (XOS) are functional oligosaccharides with prebiotic activities, which originate from lignocellulosic biomass and have attracted extensive attention from scholars in recent years. This paper summarizes the strategies used in the production of XOS, and introduces the raw materials, preparation methods, and purification technology of XOS. In addition, the biological characteristics and applications of XOS are also presented. The most commonly recommended XOS production strategy is the two-stage method of alkaline pre-treatment and enzymatic hydrolysis; and further purification by membrane filtration to achieve the high yield of XOS is required for prebiotic function. At the same time, new strategies and technologies such as the hydrothermal and steam explosion have been used as pre-treatment methods combined with enzymatic hydrolysis to prepare XOS. XOS have many critical physiological activities, especially in regulating blood glucose, reducing blood lipid, and improving the structure of host intestinal flora.

Fowl adenovirus serotype 4 (FAdV-4) is recognized as a pathogen that causes hydropericardium syndrome. Irrespective of the pathway used by the virus to invade the chicken, the pathological characteristics of the disease include degeneration and necrosis of hepatocytes, formation of intranuclear inclusions, as well as inflammatory cell infiltration. Liver dysfunction constitutes one of the critical factors leading to death. Therefore, it is vital to investigate the virus-mediated severe pathological liver damage to further understand the pathogenesis of FAdV-4. Here, proteomics, a tandem mass tag (TMT)-based approach to directly analyze protein expression, was used to determine the protein expression during FAdV-4 proliferation in leghorn male hepatoma (LMH) cells. We identified 177 differentially expressed proteins associated with various biological processes and pathways. The functional enrichment analysis revealed that FAdV-4 could downregulate some signaling pathways in LMH cells, including NOD-like receptor signaling, RIG-I-like receptor signaling, NF-κB signaling, TNF signaling pathway, and Notch signaling, FoxO signaling, PI3K-Akt signaling, and autophagy. The results of proteomics screening suggested an association between FAdV-4 infection and Notch signaling in LMH in vitro, indicating that Notch signaling regulated the expression of inflammatory cytokines and interferons but not viral replication in LMH cells. These data contributed to the understanding of the immunopathogenesis and inflammopathogenesis of FAdV-4 infection and also provided valuable information for the further analysis of the molecular mechanisms underlying viral pathogenesis.

DNA damage repair (DDR) is critical in maintaining normal cellular function and genome integrity and is associated with cancer risk, progression, and therapeutic response. However, there is still a lack of a thorough understanding of the effects of DDR genes’ expression level in cancer progression and therapeutic resistance. Therefore, we defined a tumor-related DDR score (TR-DDR score), utilizing the expression levels of 20 genes, to quantify the tumor signature of DNA damage repair pathways in tumors and explore the possible function and mechanism for the score among different cancers. The TR-DDR score has remarkably predictive power for tumor tissues. It is a more accurate indicator for the response of chemotherapy or immunotherapy combined with the tumor-infiltrating lymphocyte (TIL) and G2M checkpoint score than the pre-existing predictors (CD8 or PD-L1). This study points out that the TR-DDR score generally has positive correlations with patients of advanced-stage, genome-instability, and cell proliferation signature, while negative correlations with inflammatory response, apoptosis, and p53 pathway signature. In the context of tumor immune response, the TR-DDR score strongly positively correlates with the number of T cells (CD4+ activated memory cells, CD8+ cells, T regs, Tfh) and macrophages M1 polarization. In addition, by difference analysis and correlation analysis, COL2A1, MAGEA4, FCRL4, and ZIC1 are screened out as the potential modulating factors for the TR-DDR score. In summary, we light on a new biomarker for DNA damage repair pathways and explore its possible mechanism to guide therapeutic strategies and drug response prediction.

Background: Danhong injection is widely used for treating ischemic stroke in China. However, its effects on ischemic stroke patients when given along with Western medicines (i.e., the add-on effect) were not well-established.Methods: We searched PubMed, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and three Chinese databases from inception to 20 July 2020 to identify randomized controlled trials (RCTs) that assessed the effects of Danhong injection as add-on therapy in patients with ischemic stroke. Pairs of trained reviewers independently screened for eligible studies, assessed risk of bias, and extracted the data. The outcomes were the National Institutes of Health Stroke Scale Score (NIHSS), Barthel index, activities of daily living (ADL), total cholesterol, and homocysteine (Hcy).Results: Sixty-seven RCTs of 6594 patients with varying risk of bias were included. Compared with Western medicine alone, the addition of Danhong injection to Western medicine significantly lowered the NIHSS score (45 RCTs with 4565 patients; MD −4.21, 95% CI −4.96 to −3.46), total cholesterol (10 trials with 1019 patients; MD −1.14 mmol/L, 95% CI −1.57 to −0.72), and Hcy (four trials with 392 patients; MD −3.54 μmol/L, 95% CI −4.38 to −2.07). The addition of Danhong also increased the Barthel index (14 trials with 1270 patients; MD 8.71, 95% CI 3.68–13.74) and ADL (12 trials with 1114 patients; MD 14.48, 95% CI 9.04–19.92) scores. Subgroup analyses showed differential effects in the average cerebral blood flow rate by mean age of patients (

Recently, there are many researches on signature molecules of periodontitis derived from different periodontal tissues to determine the disease occurrence and development, and deepen the understanding of this complex disease. Among them, a variety of omics techniques have been utilized to analyze periodontitis pathology and progression. However, few accurate signature molecules are known and available. Herein, we aimed to screened and identified signature molecules suitable for distinguishing periodontitis patients using machine learning models by integrated analysis of TMT proteomics and transcriptomics with the purpose of finding novel prediction or diagnosis targets. Differential protein profiles, functional enrichment analysis, and protein–protein interaction network analysis were conducted based on TMT proteomics of 15 gingival tissues from healthy and periodontitis patients. DEPs correlating with periodontitis were screened using LASSO regression. We constructed a new diagnostic model using an artificial neural network (ANN) and verified its efficacy based on periodontitis transcriptomics datasets (GSE10334 and GSE16134). Western blotting validated expression levels of hub DEPs. TMT proteomics revealed 5658 proteins and 115 DEPs, and the 115 DEPs are closely related to inflammation and immune activity. Nine hub DEPs were screened by LASSO, and the ANN model distinguished healthy from periodontitis patients. The model showed satisfactory classification ability for both training (AUC=0.972) and validation (AUC=0.881) cohorts by ROC analysis. Expression levels of the 9 hub DEPs were validated and consistent with TMT proteomics quantitation. Our work reveals that nine hub DEPs in gingival tissues are closely related to the occurrence and progression of periodontitis and are potential signature molecules involved in periodontitis.

In this study, we screened adjuvants for an inactivated vaccine against Erysipelothrix rhusiopathiae (E. rhusiopathiae). Inactivated cells of E. rhusiopathiae strain HG-1 were prepared as the antigen in five adjuvanted inactivated vaccines, including a mineral-oil-adjuvanted vaccine (Oli vaccine), aluminum-hydroxide-gel-adjuvanted vaccine (Alh vaccine), ISA201-biphasic-oil-emulsion-adjuvanted vaccine (ISA201 vaccine), GEL02-water-soluble-polymer-adjuvanted vaccine (GEL vaccine), and IMS1313-water-soluble-nanoparticle-adjuvanted vaccine (IMS1313 vaccine). The safety test results of subcutaneous inoculation in mice showed that Oli vaccine had the most severe side effects, with a combined score of 35, followed by the ISA201 vaccine (25 points), Alh vaccine (20 points), GEL vaccine (10 points), and IMS1313 vaccine (10 points). A dose of 1.5LD50 of strain HG-1 was used to challenge the mice intraperitoneally, 14 days after their second immunization. The protective efficacy of Oli vaccine and Alh vaccine was 100% (8/8), whereas that of the other three adjuvanted vaccines was 88% (7/8). Challenge with 2.5LD50 of strain HG-1 resulted in a 100% survival rate, demonstrating the 100% protective efficacy of the Oli vaccine, followed by the GEL vaccine (71%, 5/7), IMS1313 vaccine (57%, 4/7), ISA201 vaccine (43%, 3/7), and Alh vaccine (29%, 2/7). Challenge with 4LD50 of strain HG-1 showed 100% (7/7) protective efficacy of the Oli vaccine and 71% (5/7) protective efficacy of the GEL vaccine, whereas the protective efficacy of other three adjuvanted vaccine was 14% (1/7). The Alh and GEL vaccines were selected for comparative tests in piglets, and both caused minor side effects. A second immunization with these two adjuvanted vaccines conferred 60 and 100% protective efficacy, respectively, after the piglets were challenged via an ear vein with 8LD100 of strain HG-1. After challenge with 16LD100 of strain HG-1, the Alh and GEL vaccines showed 40% and 100% protective efficacy, respectively. Our results suggested that GEL is the optimal adjuvant for an inactivated vaccine against E. rhusiopathiae.

Natural transformation is a mechanism by which a particular bacterial species takes up foreign DNA and integrates it into its genome. The swine pathogen Glaesserella parasuis (G. parasuis) is a naturally transformable bacterium. The regulation of competence, however, is not fully understood. In this study, the natural transformability of 99 strains was investigated. Only 44% of the strains were transformable under laboratory conditions. Through a high-resolution melting curve and phylogenetic analysis, we found that genetic differences in the core regulator of natural transformation, the tfoX gene, leads to two distinct natural transformation phenotypes. In the absence of the tfoX gene, the highly transformable strain SC1401 lost its natural transformability. In addition, when the SC1401 tfoX gene was replaced by the tfoX of SH0165, which has no natural transformability, competence was also lost. These results suggest that TfoX is a core regulator of natural transformation in G. parasuis, and that differences in tfoX can be used as a molecular indicator of natural transformability. Transcriptomic and proteomic analyses of the SC1401 wildtype strain, and a tfoX gene deletion strain showed that differential gene expression and protein synthesis is mainly centered on pathways related to glucose metabolism. The results suggest that tfoX may mediate natural transformation by regulating the metabolism of carbon sources. Our study provides evidence that tfoX plays an important role in the natural transformation of G. parasuis.

Wheat germ, a byproduct of wheat industrial processing, contains 30% protein and is a comprehensive source of plant-based protein. But a large amount of wheat germs are disposed of as waste every year. Wheat germ protein can be hydrolyzed into polypeptides with antioxidant, antihypertensive, anti-tumor, bacteriostatic and other activities. At present, researches on the hydrolysis of wheat germ protein and the preparation of bioactive peptides from wheat germ protein have attracted increasing attentions. However, the traditional protein hydrolysis method, protease hydrolysis, can no longer meet the market's needs for efficient production. Various auxiliary means, such as ultrasound, microwave and membrane separation, were applied to boost the yield and biological activity of wheat germ peptides by enzymatic hydrolysis. Under ultrasound and microwave, the protein structure may expand to increase the binding sites between enzyme and substrate and promote hydrolysis efficiency. Membrane separation is applied to separate products from enzymatic hydrolysate to reduce the inhibitory effect of the product on the hydrolysis reaction. The paper reviewed the hydrolysis methods of wheat germ protein and summarized the biological activity of wheat germ peptides to provide references for further study of wheat germ peptides.

BackgroundLoss of masticatory function consequent to tooth loss has been associated with changes in food choices and insufficient nutritional intake. To date, interventions based on dental prostheses alone did not significantly improve nutrient intake. Pilot studies have shown positive impacts of interventions combining implant-supported fixed dental prosthesis with brief dietary advice. The relative contribution and the potential synergy of the components of such interventions need to be determined as it has major public health implications for the community-dwelling aging population that continues to disproportionately suffer from tooth loss and its consequences.ObjectiveTo assess the effect of rehabilitation of masticatory function with fixed implant supported dentures and nutrition education in older subjects with terminal dentition (stage IV periodontitis) or full edentulism.MethodsA 2 × 2 factorial randomized controlled trial with 16-month follow-up of eligible adults (≥60 years) with loss of masticatory function consequent to full arch edentulism or terminal dentition (n = 120) will be conducted to test whether the rehabilitation of masticatory function with fixed implant supported dentures, nutrition education and/or their combination improves intake of fresh fruits and vegetables for aging subjects. The study has been designed to detect changes in fresh fruits and fresh vegetables intake at 4 months using the 24-h dietary recall method. Changes in protein as percentage of total energy, nutritional biomarkers, plasma metabolomics, oral and gut microbiome, quality of life and masticatory function will also be assessed.DiscussionWe hypothesize that receiving rehabilitation of masticatory function with fixed implant dentures together with nutrition education is the most effective intervention for improving nutrient intake in aging community-dwelling subjects with extensive tooth loss. The results of this study will assist in designing better treatment regimens, guide medical care for individual subjects, and inform public health and policy.Clinical Trials RegistrationNCT05334407.

ObjectiveAdenosine deaminase (ADA) plays an important role in immune response, which includes two isoenzymes: ADA1 and ADA2. This study aims to explore the roles of ADA1 and ADA2 in cancers.MethodsHuman Protein Atlas (HPA) and Gene Expression Profiling Interactive Analysis (GEPIA2) databases were used to analyze the mRNA expression of ADA1 and ADA2 in human normal cells and tumor tissues. The enzyme assay was used to detect the ADA1 and ADA2 activities in serum from cancer patients. The Kaplan–Meier (KM) plotter was used to analyze the prognostic value of ADA1 and ADA2. TIMER2.0 was used to explore how ADA1 and ADA2 correlate with immune infiltration and immune checkpoints. cBioPortal database was used to investigate the mutations of ADA1 and ADA2. LinkedOmics was used to screen the ADA1 and ADA2 expression-related genes.ResultsADA1 was significantly increased in several tumor tissues, including cholangiocarcinoma (CHOL), lymphoid neoplasm diffuse large B-cell lymphoma (DLBC), head and neck squamous cell carcinoma (HNSC), kidney renal clear cell carcinoma (KIRC), ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), thymoma (THYM), and uterine carcinosarcoma (UCS). ADA2 expression was significantly increased in esophageal carcinoma (ESCA), glioblastoma multiforme (GBM), acute myeloid leukemia (LAML), OV, PAAD, skin cutaneous melanoma (SKCM), and stomach adenocarcinoma (STAD). There were no significant changes in serum ADA1 activities in most cancers, while serum ADA2 activities were increased in most cancers. For prognosis, high ADA1 expression was associated with the poor survival in several cancers, including esophageal squamous cell carcinoma (ESCC), HNSC, KIRC, kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), and uterine corpus endometrial carcinoma (UCEC). However, high ADA2 expression showed a favorable prognosis in breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), HNSC, KIRC, KIRP, LUAD, OV, PAAD, sarcoma, and THYM. ADA1 showed a moderate positive correlation with multiple infiltrating immune cells in most cancers. ADA2 was positively correlated with B cells, CD8 T cells, monocytes/macrophages, and dendritic cells (DCs) and was strongly negatively correlated with myeloid-derived suppressor cells. Function analysis showed that ADA1 expression-related genes were mainly enriched in cell division biological progression. However, ADA2-related genes were mainly associated with immune response.ConclusionAs isoenzymes, ADA1 and ADA2 showed opposite prognostic values and different correlative patterns with immune infiltrating. These data demonstrated the distinct roles of ADA1 and ADA2 in cancer. ADA2 might act as a protective factor in cancer.

BackgroundEarly diagnosis and effective intervention are the keys to delaying the progression of Alzheimer’s Disease (AD). Therefore, we aimed to identify new biomarkers for the early diagnosis of AD through bioinformatic analysis and elucidate the possible underlying mechanisms.Methods and ResultsGSE1297, GSE63063, and GSE110226 datasets from the GEO database were used to screen the highly differentially expressed genes. We identified a potential biomarker, Platelet activating factor receptor (PTAFR), significantly upregulated in the brain tissue, peripheral blood, and cerebrospinal fluid of AD patients. Furthermore, PTAFR levels in the plasma and brain tissues of APP/PS1 mice were significantly elevated. Simultaneously, PTAFR could mediate the inflammatory responses to exaggerate the microenvironment, particularly mediated by the microglia through the IL10-STAT3 pathway. In addition, PTAFR was a putative target of anti-AD compounds, including EGCG, donepezil, curcumin, memantine, and Huperzine A.ConclusionPTAFR was a potential biomarker for early AD diagnosis and treatment which correlated with the microglia-mediated microenvironment. It is an important putative target for the development of a novel strategy for clinical treatment and drug discovery for AD.

Mitochondria release many damage-associated molecular patterns (DAMPs) when cells are damaged or stressed, with mitochondrial DNA (mtDNA) being. MtDNA activates innate immune responses and induces inflammation through the TLR-9, NLRP3 inflammasome, and cGAS-STING signaling pathways. Released inflammatory factors cause damage to intestinal barrier function. Many bacteria and endotoxins migrate to the circulatory system and lymphatic system, leading to systemic inflammatory response syndrome (SIRS) and even damaging the function of multiple organs throughout the body. This process may ultimately lead to multiple organ dysfunction syndrome (MODS). Recent studies have shown that various factors, such as the release of mtDNA and the massive infiltration of inflammatory factors, can cause intestinal ischemia/reperfusion (I/R) injury. This destroys intestinal barrier function, induces an inflammatory storm, leads to SIRS, increases the vulnerability of organs, and develops into MODS. Mitophagy eliminates dysfunctional mitochondria to maintain cellular homeostasis. This review discusses mtDNA release during the pathogenesis of intestinal I/R and summarizes methods for the prevention or treatment of intestinal I/R. We also discuss the effects of inflammation and increased intestinal barrier permeability on drugs.

Klebsiella pneumoniae exhibits extensive phenotypic and genetic diversity. Higher plasmid loads in the cell were supposed to play an key role in its genome diversity. Although some plasmids are widely distributed in Kp populations, they are poorly recognized. A plasmid named p2 in strain Kp1604 was predicted to be an intact prophage like Salmonella phage SSU5. However, our study showed that p2 was specifically packaged into membrane vesicles (MVs) rather than phage particles triggered by mitomycin C and subinhibitory concentrations of antibiotics. p2-minus mutant Kp1604Δp2 did not affect MV production. Compared with Kp1604, the capacity of plasmid uptake and the amount of phage burst of Kp1604Δp2 were improved. Moreover, virulence of Kp1604Δp2 also increased. Our results indicated that p2 could contribute to the host defense against the invasion of transferable DNA elements at the cost of reduced virulence. Further study on the mechanism will help us understand how it provides adaptive phenotypes to host evolution.

Shading stress strongly limits the effective growth of plants. Understanding how plant morphogenesis and physiological adaptation are generated in response to the reduced low light conditions is important for food crop development. In this study, two mung bean (Vigna radiata L.) cultivars, namely, Xilv 1 and Yulv 1, were grown in the field to explore the effects of shading stress on their growth. The results of morphology, physiology, and biochemistry analyses showed that the shading stress significantly weakened the leaf photosynthetic capacity as measured by the decreased net photosynthetic rate, stomatal conductance, and transpiration rate and increased intercellular CO2 concentration. These responses resulted in plant morphological characteristics that increased the light energy absorption in low light conditions. Such variations occurred due to the leaf anatomical structure with destroyed palisade tissues and spongy tissues. Under shading stress, Yulv 1 showed higher physiological metabolic intensity than Xilv 1, which was related to changes in chlorophyll (Chl), such as Chl a and b, and Chl a/b ratio. Compared with normal light conditions, the Chl fluorescence values, photosynthetic assimilation substances, and enzyme activities in mung bean plants under shading stress were reduced to different extent. In addition, the relative expression levels of VrGA2ox, VrGA20ox1, VrGA3ox1, VrROT3, and VrBZR1, which are related to endogenous hormone in mung bean leaves, were upregulated by shading stress, further leading to the improvements in the concentrations of auxin, gibberellins (GAs), and brassinolide (BR). Combined with the morphological, physiological, and molecular responses, Yulv 1 has stronger tolerance and ecological adaptability to shading stress than Xilv 1. Therefore, our study provides insights into the agronomic traits and gene expressions of mung bean cultivars to enhance their adaptability to the shading stress.

BackgroundThe prevalence of thyroid carcinoma (TC) and Hashimoto’s thyroiditis (HT) has been increasing dramatically over the past decades. We investigated the relationship between HT and TC.MethodsWe followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines for carrying out and reporting this meta-analysis. The literature from January 1, 2010 to December 31, 2020, regardless of region and publication type, was searched comprehensively in PubMed, Embase, Web of Science, and Cochrane Library databases. After careful selection and data extraction, the pooled odds ratio of various clinical characteristics in 39 studies were calculated. Publication bias was analyzed using funnel plots.ResultsMeta-analysis of 39 original research articles showed HT to be a risk factor of TC (pooled odds ratio = 1.71; 95% confidence interval, 1.57–1.80; p < 0.00001) and papillary thyroid carcinoma (1.67, 1.51–1.85,

Higenamine, a natural product with multiple targets in heart diseases, is originally derived from Aconitum, which has been traditionally used in China for the treatment of heart disease, including heart failure, arrhythmia, bradycardia, cardiac ischemia/reperfusion injury, cardiac fibrosis, etc. This study is aimed to clarify the role of higenamine in heart diseases. Higenamine has effects on improving energy metabolism of cardiomyocytes, anti-cardiac fibroblast activation, anti-oxidative stress and anti-apoptosis. Accumulating evidence from various studies has shown that higenamine exerts a wide range of cardiovascular pharmacological effects in vivo and in vitro, including alleviating heart failure, reducing cardiac ischemia/reperfusion injury, attenuating pathological cardiac fibrosis and dysfunction. In addition, several clinical studies have reported that higenamine could continuously increase the heart rate levels of healthy volunteers as well as patients with heart disease, but there are variable effects on systolic blood pressure and diastolic blood pressure. Moreover, the heart protection and therapeutic effects of higenamine on heart disease are related to regulating LKB1/AMPKα/Sirt1, mediating the β2-AR/PI3K/AKT cascade, induction of heme oxygenase-1, suppressing TGF-β1/Smad signaling, and targeting ASK1/MAPK (ERK, P38)/NF-kB signaling pathway. However, the interventional effects of higenamine on heart disease and its underlying mechanisms based on experimental studies have not yet been systematically reviewed. This paper reviewed the potential pharmacological mechanisms of higenamine on the prevention, treatment, and diagnosis of heart disease and clarified its clinical applications. The literature shows that higenamine may have a potent effect on complex heart diseases, and proves the profound medicinal value of higenamine in heart disease.

Alzheimer's disease (AD) remains a medical and social challenge worldwide. Magnesium (Mg) is one of the most frequently evaluated essential minerals with diverse biological functions in human body. However, the association between circulating Mg levels and AD remains controversial. We conducted a meta-analysis of 21 studies published between 1991 and 2021 to determine whether the Mg levels in the blood and cerebrospinal fluid (CSF) are abnormal in AD. Literatures were searched in PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang Data without language limitations. A pooled subject sample including 1,112 AD patients and 1,001 healthy controls (HCs) was available to assess Mg levels in serum and plasma; 284 AD patients and 117 HCs were included for Mg levels in CSF. It was found that serum and plasma levels of Mg were significantly reduced in AD patients compared with HCs (standardized mean difference [SMD] = −0.89; 95% confidence interval [CI] [−1.36, −0.43]; P = 0.000). There was statistically non-significant for Mg level in CSF between AD and HCs, whereas a decreased tendency were detected (SMD = −0.16; 95% CI [−0.50, 0.18]; P = 0.364). .In addition, when we analyzed the Mg levels of serum, plasma and CSF together, the circulating Mg levels in AD patients was significantly lower (SMD = −0.74, 95% CI [−1.13; −0.35]; P = 0.000). These results indicate that Mg deficiency may be a risk factor of AD and Mg supplementation may be a potentially valuable adjunctive treatment for AD.Systematic Review Registration:www.crd.york.ac.uk/PROSPERO/, registration number CRD42021254557.

Mutated JAK3 has been considered a promising target for cancer therapy. Activating mutations of JAK3 are observed in 3.9%–10% of acute myeloid leukemia (AML) patients, but it is unclear whether AML cells are sensitive to JAK3 inhibitors, and no disease-related human AML cell model has been reported. We have identified U937 as the first human AML cell line expressing the JAK3M511I activated mutation and confirmed that JAK3 inhibitors sensitively suppress the proliferation of U937 AML cells.

Background: Balanced chromosomal aberrations, especially balanced translocations, can cause infertility, recurrent miscarriage or having chromosomally defective offspring. Preimplantation genetic testing for structural rearrangement (PGT-SR) has been widely implemented to improve the clinical outcomes by selecting euploid embryos for transfer, whereas embryos with balanced translocation karyotype were difficult to be distinguished by routine genetic techniques from those with a normal karyotype.Method: In this present study, we developed a clinically applicable method for reciprocal translocation carriers to reduce the risk of pregnancy loss. In the preclinical phase, we identified reciprocal translocation breakpoints in blood of translocation carriers by long-read Oxford Nanopore sequencing, followed by junction-spanning polymerase chain reaction (PCR) and Sanger sequencing. In the clinical phase of embryo diagnosis, aneuploidies and unbalanced translocations were screened by comprehensive chromosomal screening (CCS) with single nucleotide polymorphism (SNP) microarray, carrier embryos were diagnosed by junction-spanning PCR and family haplotype linkage analysis of the breakpoints region. Amniocentesis and cytogenetic analysis of fetuses in the second trimester were performed after embryo transfer to conform the results diagnosed by the presented method.Results: All the accurate reciprocal translocation breakpoints were effectively identified by Nanopore sequencing and confirmed by Sanger sequencing. Twelve embryos were biopsied and detected, the results of junction-spanning PCR and haplotype linkage analysis were consistent. In total, 12 biopsied blastocysts diagnosed to be euploid, in which 6 were aneuploid or unbalanced, three blastocysts were identified to be balanced translocation carriers and three to be normal karyotypes. Two euploid embryos were subsequently transferred back to patients and late prenatal karyotype analysis of amniotic fluid cells was performed. The outcomes diagnosed by the current approach were totally consistent with the fetal karyotypes.Conclusions: In summary, these investigations in our study illustrated that chromosomal reciprocal translocations in embryos can be accurately diagnosed. Long-read Nanopore sequencing and breakpoint analysis contributes to precisely evaluate the genetic risk of disrupted genes, and provides a way of selecting embryos with normal karyotype, especially for couples those without a reference.

The use of local anesthetics during surgical treatment of cancer patients is an important part of perioperative analgesia. In recent years, it has been showed that local anesthetics can directly or indirectly affect the progression of tumors. In vitro and in vivo studies have demonstrated that local anesthetics reduced cancer recurrence. The etiology of this effect is likely multifactorial. Numerous mechanisms were proposed based on the local anesthetic used and the type of cancer. Mechanisms center on NaV1.5 channels, Ras homolog gene family member A, cell cycle, endothelial growth factor receptor, calcium Influx, microRNA and mitochondrial, in combination with hyperthermia and transient receptor potential melastatin 7 channels. Local anesthetics significantly decrease the proliferation of cancers, including ovarian, breast, prostate, thyroid, colon, glioma, and histiocytic lymphoma cell cancers, by activating cell death signaling and decreasing survival pathways. We also summarized clinical evidence and randomized trial data to confirm that local anesthetics inhibited tumor progression.

To investigate the expression levels and prognostic value of CD73 in lung cancer. And moreover, to identify the effect and potential mechanism of CD73 on lung cancer cells proliferation and migration. CD73 expression levels in lung cancer were analyzed base on GEPIA2 and GEO database. GEPIA2 and Kaplan-Meier Plotter (KM Plotter) was used to analyzed the correlation between CD73 expression and prognosis. GEO dataset were analyzed via GEO2R. CD73 overexpression cell model was construction via recombinant lentivirus transfection into A549 and NCI-H520 cells. CCK8 assay were used to investigate cells proliferation. Migration and invasion ability were evaluated by scratch and transwell methods. Base on GEPIA2, GSE32683, GSE116959 and GSE37745 dataset, we found that CD73 expression were significant higher in tumor tissues of lung adenocarcinoma (LUAD) compared with that in non-tumor normal tissues and in lung squamous cell carcinoma (LUSC), while there were no significant difference of CD73 expression between LUSC and normal control tissues. Interestingly, a high CD73 level predict poor overall survival (OS) of LUSC. However, GEPIA2 and KM plotter showed the opposite conclusion of prognostic value of CD73 in LUAD. By using cell experiments, we found that CD73 overexpression promoted proliferation and migration of LUAD A549 cells. However, there was no significant effect of CD73 overexpression on LUSC NCI-H520 cells. Furthermore, CD73 overexpression facilitates epithelial to mesenchymal transition (EMT) progression of A549 cells. In conclusion, our results indicated that CD73 expression were increased in LUAD and might be an poor prognostic marker for LUSC patients. CD73 play an important role in LUAD cells proliferation and migration. These data allowed to support CD73 as a therapeutic target for LUAD.

Background: The anesthetic characteristics of ultrasound-guided bi-level erector spinae plane block (ESPB) plus dexmedetomidine (Dex) remain unclear. We compared the efficacy and safety of ultrasound-guided bi-level ESPB plus different doses of Dex in patients undergoing video-assisted thoracic surgery (VATS).Methods: One-hundred eight patients undergoing VATS were randomized into three groups: R group (n = 38, 15 ml of 0.375% ropivacaine with 0.1 mg/kg dexamethasone), RD1 group (n = 38, 15 ml of 0.375% ropivacaine plus 0.5 μg/kg DEX with 0.1 mg/kg dexamethasone) and RD2 group (n = 38, 15 ml of 0.375% ropivacaine plus 1.0 μg/kg DEX with 0.1 mg/kg dexamethasone). The primary outcome was the pain 12 h after surgery. Secondary outcomes included the Prince Henry Hospital Pain Score; hemodynamics; consumption of sufentanil; anesthetized dermatomal distribution; recovery time; rescue analgesia; satisfaction scores of patients and surgeon; quick recovery index; adverse effects; the prevalence of chronic pain and quality of recovery.Results: The visual analog scale (VAS) and the Prince Henry pain score were significantly lower in both the RD1 and RD2 groups during the first 24 h after surgery (P < 0.05). Both VAS with coughing and the Prince Henry pain score were significantly lower in the RD2 group than in the RD1 group 8–24 h after surgery (P < 0.05). Both heart rate and mean arterial pressure were significantly different from T2 to T6 in the RD1 and RD2 groups (P < 0.05). The receipt of remifentanil, propofol, Dex, and recovery time was significantly reduced in the RD2 group (P < 0.05). The requirement for sufentanil during the 8–72 h after surgery, less rescue medication, and total press times were significantly lower in the RD2 group (P < 0.05). The time to the first dose of rescue ketorolac was significantly longer in the RD2 group (P < 0.05). Further, anal exhaust, removal of chest tubes, and ambulation were significantly shorter in the RD2 group (P < 0.05). The incidence of tachycardia, post-operative nausea and vomiting, and chronic pain was significantly reduced in the RD2 group, while the QoR-40 score was significantly higher in the RD2 group (P < 0.05).Conclusions: Pre-operative bi-level, single-injection ESPB plus 1 μg/kg DEX provided superior pain relief and long-term post-operative recovery for patients undergoing VATS.Clinical Trial Registration:http://www.chictr.org.cn/searchproj.aspx.

Coastal lagoons are among the most vulnerable and economically significant ecosystems on Earth. Songkhla Lake, connected with the Gulf of Thailand, is the second largest lake in Southeast Asia and supports the development of the fishery, transportation, and tourism industries in southern Thailand. With increasing anthropogenic disturbances, the lake is facing acute ecological problems and further research is needed. Here, we provide 55-year record of grain size, color reflectance, magnetic susceptibility, total organic carbon, total nitrogen, and trace element (As, Hg, Pb, Cr, Ni, Cu, and Zn) concentrations of sediment core SKL8-2 collected from Songkhla Lake. These records reveal a three-stage sedimentary and input history of trace metals under anthropogenic effects: 1) From 1964 to 1982, it was a natural terrigenous input period with a relative reduction environment when the channel connecting Songkhla Lake and the Gulf of Thailand was closed. 2) Trace metal concentrations, organic carbon content, b* value, and magnetic susceptibility changed abruptly in 1982. During 1982–2000, the sources of trace metals were more complex than during 1964–1982 and mainly came from urban wastewater, industrial effluent, and fishery discharge. 3) From 2000 to 2019, contamination signals of Pb, Hg, As, Zn, and Ni emerged in the first decade because of the rapid development and poor sewage treatment around nearby cities.

Background: Secreted protein acidic and rich in cysteine (SPARC) plays an important role in cancer development. The roles of SPARC in the liver hepatocellular carcinoma (LIHC) are unclear.Methods: GEPIA2 and UALCAN were used to analyze the SPARC mRNA expression levels in LIHC based on the TCGA database. The GEO database was used to verify the analysis results. Immunohistochemical (IHC) analysis was used to investigate the SPARC protein levels in LIHC tissues. The Kaplan–Meier (KM) plotter was used to analyze the correlation between SPARC and prognosis. The serum SPARC levels were measured by ELISA. CCK8 and murine xenograft models were used to investigate the effect of SPARC on the liver cancer growth in vitro and in vivo. SPARC-correlated genes were screened by LinkedOmics.Results: Based on the TCGA and GEO databases, the analysis showed that the SPARC mRNA expression levels were increased in tumor tissues and peripheral blood mononuclear cell (PBMC) from LIHC compared to normal controls. The IHC analysis showed an increased level of SPARC in LIHC tissues compared to adjacent non-tumor tissues. However, we found that the serum SPARC levels were lower in LIHC than those in healthy controls. The KM plotter showed that there was no significant correlation between the SPARC mRNA levels and overall survival. However, in sorafenib-treated LIHC patients, the high SPARC expression predicts favorable prognosis. Furthermore, the endogenous SPARC overexpression promotes liver cancer cell proliferation in vitro and tumor growth in vivo, while there was no significant effect of exogenous SPARC treatment on liver cancer cell proliferation. Function enrichment analysis of SPARC-correlated genes indicated a critical role of interaction with an extracellular matrix in SPARC-promoting cancer cell proliferation.Conclusion: SPARC mRNAs were increased in LIHC tumor tissues, and SPARC overexpression may promote the liver cancer growth. Further studies are needed to clarify the potential prognostic value of SPARC, both in tissues and in circulation.

BackgroundThe severities of human adenovirus (HAdV) infection are diverse in different areas of Tibet, China, where a large altitude span emerges. Serious consequences may be caused by medical staff if the clinical stages and immunological conditions of patients in high-altitude areas are misjudged. However, the clinical symptoms, immunological characteristics, and environmental factors of HAdV infection patients at different altitude areas have not been well described.MethodsIn this retrospective, multicenter cohort study, we analyzed the data of patients who were confirmed HAdV infection by PCR tests in the General Hospital of Tibet Military Command or CDC (the Center for Disease Control and Prevention) of Tibet Military Command from January 1, 2019, to December 31, 2020. Demographic, clinical, laboratory, radiological, and epidemiological data were collected from medical records system and compared among different altitude areas. The inflammatory cytokines as well as the subsets of monocytes and regulatory T cells of patients were also obtained and analyzed in this study.ResultsSix hundred eighty-six patients had been identified by laboratory-confirmed HAdV infection, including the low-altitude group (n = 62), medium-altitude group (n = 206), high-altitude group (n = 230), and ultra-high-altitude group (n = 188). Referring to the environmental factors regression analysis, altitude and relative humidity were tightly associated with the number of infected patients (P < 0.01). A higher incidence rate of general pneumonia (45.7%) or severe pneumonia (8.0%) occurred in the ultra-high-altitude group (P < 0.05). The incubation period, serial interval, course of the disease, and PCR-positive duration were prolonged to various extents compared with the low-altitude group (P < 0.05). Different from those in low-altitude areas, the levels of IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, TNF-α, TNF-β, and VEGF in the plasma of the ultra-high-altitude group were increased (P < 0.05), while the proportion of non-classical monocytes and regulatory T cells was decreased (P < 0.05).ConclusionsThe findings of this research indicated that patients with HAdV infection in high-altitude areas had severe clinical symptoms and a prolonged course of disease. During clinical works, much more attention should be paid to observe the changes in their immunological conditions. Quarantine of patients in high-altitude areas should be appropriately extended to block virus shedding.

The mitochondria play a significant role in many cellular processes and are recognized as one of the most important therapeutic targets in cancer. Direct long-term imaging of the mitochondria is very crucial for treating cancer. However, the development of a red-emitting mitochondrial probe with a large Stokes shift and photostability remains highly challenging. Fluorescent metal complexes with superior physicochemical property have emerged as new fluorescent nanomaterials due to their increasing advantages in bioimaging. Herein, a luminescent pitaya-type nanostructure based on rhein-magnesium(II) (Rh-Mg) coordination polymer nanodots was used as a fluorescent nanoprobe to selectively image the mitochondria benefiting from the introduction of triphenylphosphine. The as-prepared Rh-Mg nanodot-based nanoprobe showed red emission peaking at 620 nm, a large Stokes shift (100 nm), and excellent photostability as compared with commercial mitochondrial probes. Due to these extraordinary features, this fluorescent nanoprobe was successfully used for mitochondrial targeting imaging of live cancer cell line Neuro-2a (mouse neuroblastoma) and BV2 microglial cells. Therefore, our results pave a new way for the design of fluorescent nanoprobes for imaging mitochondria in cancer cell.

BackgroundDysregulated microRNAs (miRNAs) are common in human cancer and are involved in the proliferation, promotion, and metastasis of tumor cells. Therefore, this study aimed to evaluate the expression and biological function of miR-1236-3p in colon cancer.MethodsThis study screened the miRNA in normal and colon cancer tissues through array analysis. In addition, quantitative Reverse Transcription–Polymerase Chain Reaction (qRT-PCR) analysis was performed to validate the expression of miR-1236-3p in normal and tumor tissues from colon cancer patients and cancer cell lines. Online predicting algorithms and luciferase reporter assays were also employed to confirm Doublecortin Like Kinase 3 (DCLK3) was the target for miR-1236-3p. Moreover, the impact of miR-1236-3p on the progression of colon cancer was evaluated in vitro and in vivo. Western blotting and qRT-PCR were also performed to investigate the interactions between miR-1236-3p and DCLK3.ResultsMiR-1236-3p was significantly downregulated in colon cancer tissues and its expression was associated with the TNM stage and metastasis of colon. In addition, the in vitro and in vivo experiments showed that miR-1236-3p significantly promoted cancer cell apoptosis and inhibited the proliferation, invasion, and migration of cancer cells. The results also showed that miR-1236-3p hindered Epithelial–mesenchymal Transition (EMT) by targeting DCLK3. Moreover, the expression of DCLK3 mediated the effects of miR-1236-3p on the progression of cancer.ConclusionsMiR-1236-3p functions as a tumor suppressor in colon cancer by targeting DCLK3 and is therefore a promising therapeutic target for colon cancer.