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BACKGROUND: Paragonimiasis is a typical food-borne zoonotic disease. Hosts acquire Paragonimus infection through the ingestion of raw or undercooked crayfish and crab. The clinical manifestations of the disease are varied, and it is often misdiagnosed or missed. The diagnosis of paragonimiasis should be considered comprehensively. Praziquantel is the first choice for treatment, and albendazole can be used in combination with repeated courses in severe cases. CASE SUMMARY: We report a case of liver paragonimiasis that was misdiagnosed as an abscess. The patient presented with fatigue and poor appetite for 2 months, and was diagnosed with liver abscess in the local hospital. After 6 months, the patient visited our hospital because of recurrent abdominal pain and was diagnosed with liver paragonimiasis based on epidemiological history, clinical presentations, and laboratory findings. He was treated with praziquantel (25 mg/kg) three times a day for 3 days; however, the symptoms still presented after treatment. He was treated with oral praziquantel and albendazole for one further course. Follow-up suggested that the treatment was effective and the symptoms improved. CONCLUSION: The combination of albendazole and praziquantel may improve the therapeutic efficacy of paragonimiasis.
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BACKGROUND: With the profound changes in the global climate, the issue of grassland degradation is becoming increasingly prominent. Grassland degradation poses a severe threat to the carbon cycle and carbon storage within grassland ecosystems. Additionally, it will adversely affect the sustainability of food production. The grassland ecosystem in the northwest region of Liaoning Province, China, is particularly vulnerable due to factors such as erosion from the northern Horqin Sandy Land, persistent arid climate, and issues related to overgrazing and mismanagement of grassland. The degradation issue is especially pronounced in this ecological environment. However, previous research on the carbon density of degraded grasslands in Northeast China has predominantly focused on Inner Mongolia, neglecting the impact on the grasslands in the northwest of Liaoning Province. Therefore, this experiment aims to assess the influence of grassland degradation intensity on the vegetation and soil carbon density in the northwest of Liaoning Province. The objective is to investigate the changes in grassland vegetation and soil carbon density resulting from different degrees of grassland degradation. METHODOLOGY: This study focuses on the carbon density of grasslands at different degrees of degradation in the northwest of Liaoning Province, exploring the variations in vegetation and soil carbon density under different levels of degradation. This experiment employed field sampling techniques to establish 100 × 100 m plots in grasslands exhibiting varying degrees of degradation. Six replications of 100 × 100 m plots per degradation intensity were sampled. Vegetation and soil samples were collected for analysis of carbon density. RESULTS: The results indicate that in the context of grassland degradation, there is a significant reduction in vegetation carbon density. Furthermore, it was found that root carbon density is the primary contributor to vegetation carbon density. In comparison to mildly degraded grasslands, moderately and severely degraded grasslands experience a reduction in vegetation carbon density by 25.6% and 52.6%, respectively. However, with regard to the impact of grassland degradation on soil carbon density, it was observed that while grassland degradation leads to a slight decrease in soil carbon density, there is no significant change in soil carbon density in the short term under the influence of grassland degradation. CONCLUSIONS: Therefore, grassland degradation has exerted a negative impact on aboveground vegetation carbon density, reducing the carbon storage of above-ground vegetation in grasslands. However, there was no significant effect on grassland soil carbon density.
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Carbon , Grassland , Soil , Soil/chemistry , Carbon/metabolism , China , Conservation of Natural Resources , Poaceae/metabolism , EcosystemABSTRACT
Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.
Subject(s)
Fatty Liver , Insulin Resistance , Interferon-gamma , Interleukin-12 , Liver , Macrophages , Mice, Knockout , Obesity , Signal Transduction , Animals , Interferon-gamma/metabolism , Interleukin-12/metabolism , Male , Obesity/metabolism , Mice , Fatty Liver/metabolism , Fatty Liver/pathology , Macrophages/metabolism , Liver/metabolism , Liver/pathology , Mice, Inbred C57BL , Diet, High-Fat/adverse effects , Receptors, Interferon/metabolism , Receptors, Interferon/genetics , Interferon gamma Receptor , Liver Cirrhosis/metabolism , Liver Cirrhosis/pathology , Liver Cirrhosis/geneticsABSTRACT
BACKGROUND: Xiaoyaosan (XYS), a traditional Chinese medicine formulation, has been used in the treatment of depression. However, no studies have yet identified the active compounds responsible for its antidepressant effects in the brain. STUDY DESIGN: We investigated the antidepressants effects of XYS and identified 18ß-glycyrrhetinic acid (18ß-GA) as the primary compound present in the brain following XYS injection. Furthermore, we explored the molecular mechanisms underlying the antidepressant-like effects of both XYS and 18ß-GA. METHODS: To investigate the antidepressant-like effects of XYS and elucidate the associated molecular mechanisms, we employed various methodologies, including cell cultures, the chronic social defeat stress (CSDS) model, behavioral tests, immunoprecipitation, quantitative PCR (qPCR) assays, Western blotting assays, luciferase assays, chromatin immunoprecipitation (ChIP) assays, immunofluorescence staining, and dendritic spine analysis. RESULTS: We identified 18ß-GA as the primary compound in the brain following XYS injection. In vitro, 18ß-GA was found to bind with ERK (extracellular signal-regulated kinase), subsequently activating ERK kinase activity toward both c-Jun and cAMP response element binding protein (CREB). Moreover, 18ß-GA activated brain-derived neurotrophic factor (BDNF) transcription by stimulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2), c-Jun, and CREB, while also inhibiting methyl CpG binding protein 2 (MeCP2) both in vitro and in vivo. Chronic intraperitoneal (i.p.) administration of 18ß-GA exhibited prophylactic antidepressant-like effects in a CSDS model, primarily by activating BDNF transcription in the medial prefrontal cortex (mPFC). Interestingly, a single i.p. injection of 18ß-GA produced rapid and sustained antidepressant-like effects in CSDS-susceptible mice by engaging the BDNF-tropomyosin receptor kinase B (TrkB) signaling pathway in the mPFC. CONCLUSION: These findings suggest that the activation of BDNF transcription in the mPFC underlies the antidepressant-like effects of 18ß-GA, a key component of XYS in the brain.
Subject(s)
Antidepressive Agents , Brain-Derived Neurotrophic Factor , Disease Models, Animal , Drugs, Chinese Herbal , Glycyrrhetinic Acid , Mice, Inbred C57BL , Social Defeat , Stress, Psychological , Animals , Brain-Derived Neurotrophic Factor/metabolism , Glycyrrhetinic Acid/pharmacology , Glycyrrhetinic Acid/analogs & derivatives , Antidepressive Agents/pharmacology , Male , Drugs, Chinese Herbal/pharmacology , Mice , Stress, Psychological/drug therapy , Depression/drug therapy , NF-E2-Related Factor 2/metabolism , Receptor, trkB/metabolism , Brain/drug effects , Brain/metabolismABSTRACT
Background: Palliative care can enhance quality of life during a terminal hospitalization. Despite advances in diagnostic and treatment tools, blood cancers lag behind solid malignancies in palliative use. It is not clear what factors affect palliative care use in blood cancer. Methods: We used the 2016 to 2019 National Inpatient Sample to identify demographic and socioeconomic factors associated with receiving palliative care among patients over age 18 with any malignant hematological diagnosis during a terminal hospitalization lasting at least 3 days, excluding those receiving a stem cell transplant. Results: Palliative care use was documented 54% of the time among 49,720 weighted cases (9944 distinct individual hospitalizations), approximately evenly distributed across the years 2016-2019. Palliative care use was lowest in 2016 (51%) and highest in 2018 (58%), and increased with age, reaching 58% for those 80 years and older. Men and women were similarly likely to receive care. Patients of Hispanic ethnicity and African Americans received less palliative care (47% and 49%, respectively), as did those insured by Medicaid (48%), and those admitted to small or rural hospitals (52% and 47%, respectively). Charges for hospitalizations with palliative care were 19% lower than for those without it. Conclusions: This study highlights disparities in palliative care use among blood-cancer patients who died in the hospital. It seems likely that many of the 46% who did not receive palliative care could have benefitted from it. Interventions are likely needed to achieve equitable access to ideal levels of palliative care services in late-stage blood cancer.
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BACKGROUND AND AIMS: Fibrosis is the common end point for all forms of chronic liver injury, and the progression of fibrosis leads to the development of end-stage liver disease. Activation of HSCs and their transdifferentiation into myofibroblasts results in the accumulation of extracellular matrix proteins that form the fibrotic scar. Long noncoding RNAs regulate the activity of HSCs and provide targets for fibrotic therapies. APPROACH AND RESULTS: We identified long noncoding RNA TILAM located near COL1A1 , expressed in HSCs, and induced with liver fibrosis in humans and mice. Loss-of-function studies in human HSCs and human liver organoids revealed that TILAM regulates the expression of COL1A1 and other extracellular matrix genes. To determine the role of TILAM in vivo, we annotated the mouse ortholog ( Tilam ), generated Tilam- deficient green fluorescent protein-reporter mice, and challenged these mice in 2 different models of liver fibrosis. Single-cell data and analysis of single-data and analysis of Tilam-deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Tilam -deficient reporter mice revealed that Tilam is induced in murine HSCs with the development of fibrosis in vivo. Furthermore, loss of Tilam expression attenuated the development of fibrosis in the setting of in vivo liver injury. Finally, we found that TILAM interacts with promyelocytic leukemia nuclear body scaffold protein to regulate a feedback loop by which TGF-ß2 reinforces TILAM expression and nuclear localization of promyelocytic leukemia nuclear body scaffold protein to promote the fibrotic activity of HSCs. CONCLUSIONS: TILAM is activated in HSCs with liver injury and interacts with promyelocytic leukemia nuclear body scaffold protein to drive the development of fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end-stage liver disease.
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INTRODUCTION: Gastric cancer has the highest incidence and mortality in Eastern Asia. The efficacy and safety of ramucirumab (RAM) monotherapy or in combination with paclitaxel (PTX) for patients with unresectable advanced or metastatic gastric/gastroesophageal junction adenocarcinoma (G/GEA) have been established in clinical trials. To assess the effectiveness and safety of RAM or RAM-based therapy as a second-line treatment in real-world clinical practice in Eastern Asia and to pave the way for future research, a systematic literature review (SLR) was conducted. METHODS: Studies published between January 2014 and December 2021 were identified in PubMed, Embase, Cochrane Library, CNKI, Wanfang, and CBM databases. RESULTS: This SLR included 23 studies from Japan and South Korea, of which 22 were retrospective and 11 were full-text articles. Most studies investigated RAM + PTX (range of median overall survival [mOS] 7.4-12.2 months; median progression-free survival [mPFS] 3.35-7.0 months). Data were limited for RAM, RAM + albumin-bound paclitaxel, and RAM + taxane. RAM + PTX was associated with longer survival (mOS 9.3-12.2 months vs. 5.2-9.7 months; mPFS 4.1-5.1 months vs. 3.0-4.1 months) than PTX. Patients with prior anti-programmed cell death 1 (anti-PD-1) exposure experienced longer mPFS (4.8 vs. 3.4 months) from RAM + taxane than those without prior anti-PD-1 exposure. Few patients (3.3-6.3%) discontinued RAM or RAM-based therapy because of adverse events (AEs). Hematological toxicities were most frequently occurring AEs and no new safety signals were identified compared to clinical trials. CONCLUSION: RAM + PTX as a second-line treatment is effective and associated with an acceptable toxicity profile in patients with advanced or metastatic G/GEA in real-world settings of Japan and South Korea. More studies are recommended to further evaluate effectiveness and safety of RAM or RAM-based therapy, especially after anti-PD-1 therapy, in a wider Eastern Asian population. TRIAL REGISTRATION: INPLASY registration number INPLASY2022120023.
Subject(s)
Adenocarcinoma , Antibodies, Monoclonal, Humanized , Esophageal Neoplasms , Esophagogastric Junction , Paclitaxel , Ramucirumab , Stomach Neoplasms , Humans , Stomach Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Adenocarcinoma/drug therapy , Adenocarcinoma/secondary , Esophagogastric Junction/pathology , Republic of Korea , Esophageal Neoplasms/drug therapy , Paclitaxel/therapeutic use , Paclitaxel/adverse effects , Paclitaxel/administration & dosage , Japan , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Treatment OutcomeABSTRACT
Ulcerative colitis (UC) is a refractory inflammatory disease with imbalances in intestinal mucosal homeostasis. Cuproptosis serves as newly identified programmed cell death (PCD) form involved in UC. In the study, UC-related datasets were extracted from the Gene Expression Omnibus (GEO) database. A comparison of UC patients and healthy controls identified 11 differentially expressed cuproptosis-related genes (DE-CRGs), where FDX1, LIAS, and DLAT were differentially expressed in UC groups from the mouse models and clinical samples, with their expression correlating with disease severity. By comprehending weighted gene co-expression network analysis (WGCNA) and differential expression analysis, the key genes common to the module genes relevant to different cuproptosis-related clusters and differentially expressed genes (DEGs) both in different clusters and patients with and without UC were identified using several bioinformatic analysis. Furthermore, the mRNA levels of four characteristic genes with diagnostic potential demonstrated significant decrease in both mouse models and clinical UC samples. Our discoveries offer a theoretical foundation for cuproptosis effect in UC.
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OBJECTIVES: Silk fiber is difficult to degrade in vivo, which limits its application in tissue engineering materials such as artificial nerves. Therefore, in this study aim to promote its degradation in vivo by chemical treating silk fibers in vitro. MATERIALS AND METHODS: Sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), scanning electron microscopy (SEM) observations, mechanical test, Fourier transform infrared spectroscopy (FT-IR) measurements were used to investigate the degradation effect of chemicals (hydrochloric acid, phosphoric acid, acetic acid, sodium hydroxide, calcium hydroxide, sodium bicarbonate, and calcium chloride) on silk fiber in vitro. Immunofluorescence staining and transcriptome analysis were used to investigate the effect of inflammatory factors on the degradation of chemically treated silk fiber in rats. RESULTS: (1) Silks were separated into finer fibers in each group. (2) FT-IR absorption peaks of amides I, II, and III overlap in each group. (3) Silk degradation degree in each group was higher than that in an untreated group. The calcium chloride-treated group was completely degraded. (4) Fibronectin, collagen I, collagen III, integrin α and CD68 were immunofluorescence positive in all vegetation section. (5) There were no significant differences in the expressions of collagen I, collagen III, and fibronectin in the vegetations formed on the 14th day of subcutaneous implantation, while integrin α, CD68, TNF-α, IL-1b, and IL-23 express at higher levels with IL-10 at lower levels. CONCLUSIONS: All chemicals could completely degrade silk; however, their degradation products were not the same. The chemicals change the mechanical properties of silk by separating it into finer fibers, which increase the contact surface area between the silk and tissue fluid, accelerating the degradation of monofilaments in vivo by promoting inflammation and macrophage activity through the increased and decreased expressions of pro- and anti-inflammatory factors, respectively.
Subject(s)
Fibroins , Silk , Rats , Animals , Silk/chemistry , Fibronectins , Fibroins/chemistry , Spectroscopy, Fourier Transform Infrared , Calcium Chloride , Collagen/chemistry , Collagen Type I , IntegrinsABSTRACT
Viral infections present significant challenges to human health, underscoring the importance of understanding the immune response for effective therapeutic strategies. Immune cell activation leads to dynamic changes in gene expression. Numerous studies have demonstrated the crucial role of long noncoding RNAs (lncRNAs) in immune activation and disease processes, including viral infections. This review provides a comprehensive overview of lncRNAs expressed in immune cells, including CD8 T cells, CD4 T cells, B cells, monocytes, macrophages, dendritic cells, and granulocytes, during both acute and chronic viral infections. LncRNA-mediated gene regulation encompasses various mechanisms, including the modulation of viral replication, the establishment of latency, activation of interferon pathways and other critical signaling pathways, regulation of immune exhaustion and aging, and control of cytokine and chemokine production, as well as the modulation of interferon-stimulated genes. By highlighting specific lncRNAs in different immune cell types, this review enhances our understanding of immune responses to viral infections from a lncRNA perspective and suggests potential avenues for exploring lncRNAs as therapeutic targets against viral diseases.
Subject(s)
RNA, Long Noncoding , Virus Diseases , Humans , RNA, Long Noncoding/genetics , Immunity, Innate , Virus Diseases/genetics , Interferons , CytokinesABSTRACT
Background & Aims: Fibrosis is the common endpoint for all forms of chronic liver injury, and progression of fibrosis leads to the development of end-stage liver disease. Activation of hepatic stellate cells (HSCs) and their transdifferentiation to myofibroblasts results in the accumulation of extracellular matrix (ECM) proteins that form the fibrotic scar. Long noncoding (lnc) RNAs regulate the activity of HSCs and may provide targets for fibrotic therapies. Methods: We identified lncRNA TILAM as expressed near COL1A1 in human HSCs and performed loss-of-function studies in human HSCs and liver organoids. Transcriptomic analyses of HSCs isolated from mice defined the murine ortholog of TILAM . We then generated Tilam -deficient GFP reporter mice and quantified fibrotic responses to carbon tetrachloride (CCl 4 ) and choline-deficient L-amino acid defined high fat diet (CDA-HFD). Co-precipitation studies, mass spectrometry, and gene expression analyses identified protein partners of TILAM . Results: TILAM is conserved between human and mouse HSCs and regulates expression of ECM proteins, including collagen. Tilam is selectively induced in HSCs during the development of fibrosis in vivo . In both male and female mice, loss of Tilam results in reduced fibrosis in the setting of CCl 4 and CDA-HFD injury models. TILAM interacts with promyelocytic leukemia protein (PML) to stabilize PML protein levels and promote the fibrotic activity of HSCs. Conclusion: TILAM is activated in HSCs and interacts with PML to drive the development of liver fibrosis. Depletion of TILAM may serve as a therapeutic approach to combat the development of end stage liver disease.
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Long noncoding RNAs (lncRNAs) play critical regulatory roles in human development and disease. Although there are over 100,000 samples with available RNA sequencing (RNA-seq) data, many lncRNAs have yet to be annotated. The conventional approach to identifying novel lncRNAs from RNA-seq data is to find transcripts without coding potential but this approach has a false discovery rate of 30-75%. Other existing methods either identify only multi-exon lncRNAs, missing single-exon lncRNAs, or require transcriptional initiation profiling data (such as H3K4me3 ChIP-seq data), which is unavailable for many samples with RNA-seq data. Because of these limitations, current methods cannot accurately identify novel lncRNAs from existing RNA-seq data. To address this problem, we have developed software, Flnc, to accurately identify both novel and annotated full-length lncRNAs, including single-exon lncRNAs, directly from RNA-seq data without requiring transcriptional initiation profiles. Flnc integrates machine learning models built by incorporating four types of features: transcript length, promoter signature, multiple exons, and genomic location. Flnc achieves state-of-the-art prediction power with an AUROC score over 0.92. Flnc significantly improves the prediction accuracy from less than 50% using the conventional approach to over 85%. Flnc is available via GitHub platform.
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Some studies show that athlete students are more likely to engage in health-risk behaviors with negative health consequences, while others suggest that they lead a healthier life than their non-athlete peers. Given these inconsistent results, this study aims to compare health behaviors, depression, and perceived health status between athlete and non-athlete students, and explore the associations between health behaviors and health outcomes. An online questionnaire survey including Heath Habits Scale for five health-risk behaviors and five health-promoting behaviors, Patient Health Questionnaire-9 (PHQ-9), and 5-point scale for perceived health status was conducted in Beijing Sports University in March 2021. Data from 372 athlete students and 252 non-athlete students aging from 18 to 22 were included in this study. Chi-squared tests and t-tests were used to determine differences between athlete and non-athlete samples, and logistic regression analyses were conducted to examine the associations of health behaviors with depression and perceived health status. The significance level was p < 0.05. The results show that compared with non-athlete students, athlete students perform better in health habits (10.01 vs. 8.27), report lower proportion of depression (44.6% vs. 54.4%) and higher proportion of good health (77.2% vs. 55.6%). Health behaviors, such as getting adequate sleeping, participating in vigorous physical activity, overeating, and smoking, were significantly associated with health outcomes of athlete students. The findings may contribute to the better understanding of health behaviors in athlete students and warrant continued attention on mental health and health habits in this population.
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Objective: Increasing evidence shows a close relationship between gut microbiota and major depressive disorder (MDD), but the specific mechanisms remain unknown. This study was conducted to explore differential gut microbiota compositions related to the severity of MDD. Methods: Healthy controls (HC) (n = 131) and MDD patients (n = 130) were included. MDD patients with Hamilton Depression Rating Scale (HDRS) score <25 and ≥25 were assigned into moderate (n = 72) and severe (n = 58) MDD groups, respectively. Univariate and multivariate analyses were used to analyze the gut microbiota compositions at the genus level. Results: Thirty-six and 27 differential genera were identified in moderate and severe MDD patients, respectively. The differential genera in moderate and severe MDD patients mainly belonged to three (Firmicutes, Actinobacteriota, and Bacteroidota) and two phyla (Firmicutes and Bacteroidota), respectively. One specific covarying network from phylum Actinobacteriota was identified in moderate MDD patients. In addition, five genera (Collinsella, Eggerthella, Alistipes, Faecalibacterium, and Flavonifractor) from the shared differential genera by two MDD groups had a fair efficacy in diagnosing MDD from HC (AUC = 0.786). Conclusions: Our results were helpful for further exploring the role of gut microbiota in the pathogenesis of depression and developing objective diagnostic methods for MDD.
Subject(s)
Depressive Disorder, Major , Gastrointestinal Microbiome , Bacteria , Depressive Disorder, Major/microbiology , HumansABSTRACT
Backgrounds: Many pieces of evidence demonstrated that there were close relationships between gut microbiota and depression. However, the specific molecular mechanisms were still unknown. Here, using targeted metabolomics, this study was conducted to explore the relationships between microbial metabolites in feces and neurotransmitters in prefrontal cortex of depressed mice. Methods: Chronic unpredictable mild stress (CUMS) model of depression was built in this study. Targeted liquid chromatography-mass spectrometry analysis was used to detect the microbial metabolites in feces and neurotransmitters in prefrontal cortex of mice. Both univariate and multivariate statistical analyses were applied to identify the differential microbial metabolites and neurotransmitters and explore relationships between them. Results: Ninety-eight differential microbial metabolites (mainly belonged to amino acids, fatty acids, and bile acids) and 11 differential neurotransmitters (belonged to tryptophan pathway, GABAergic pathway, and catecholaminergic pathway) were identified. Five affected amino acid-related metabolic pathways were found in depressed mice. The 19 differential microbial metabolites and 10 differential neurotransmitters were found to be significantly correlated with depressive-like behaviors. The two differential neurotransmitters (tyrosine and glutamate) and differential microbial metabolites belonged to amino acids had greater contributions to the overall correlations between microbial metabolites and neurotransmitters. In addition, the significantly decreased L-tyrosine as microbial metabolites and tyrosine as neurotransmitter had the significantly positive correlation (r = 0.681, p = 0.0009). Conclusions: These results indicated that CUMS-induced disturbances of microbial metabolites (especially amino acids) might affect the levels of neurotransmitters in prefrontal cortex and then caused the onset of depression. Our findings could broaden the understanding of how gut microbiota was involved in the onset of depression.
Subject(s)
Depression , Gastrointestinal Microbiome , Amino Acids , Animals , Depression/etiology , Depression/metabolism , Disease Models, Animal , Mice , Neurotransmitter Agents/analysis , Neurotransmitter Agents/metabolism , TyrosineABSTRACT
Aim: To evaluate the protective effect of axillary channel-assisted (ACA) transoral endoscopic thyroidectomy vestibular approach on mental nerve. Materials and Methods: From August 2018 to December 2020, 126 cases of thyroid micro-carcinoma patients who underwent endoscopic thyroidectomy were recruited retrospectively. Of those, 74 cases were performed with ACA trans-oral endoscopic thyroidectomy vestibular approach (ACA_TOETVA) (V and A group), 52 cases received standard TOETVA (V group). On postoperative day 1 (POD1), nylon monofilament test and numbness visual analogue scale score were conducted to evaluate the severity of numbness within the mental area, facial expression was tested to determine the motor function of lower mandible and the thickness of cutaneous and subcutaneous layers was measured with ultrasound. The other observation parameters including the time for operation and intraoperative blood loss were carefully collected. Results: On POD1, nylon monofilament test showed that scores in the V and A group (2.9 ± 0.3) were significantly higher than V group (1.7 ± 0.5), P < 0.01, u = 254. The completion percentage of facial expression in the V and A group was 90.5% (67/74) and significantly higher than in V group (21.2%, 11/52), P < 0.01, χ2 = 62.35. The thickness increment of cutaneous and subcutaneous layer was 2.2 ± 1.2 mm in the V and A group, which was significantly less than in the V group (4.0 ± 1.2 mm), P < 0.01, u = 605. Compared with V group, the operation time (113.4 ± 22.3 min vs. 127.7 ± 25.6 min, u = 1262) and intraoperative blood loss (43.5 ± 13.4 ml vs. 51.0 ± 14.1 ml, u = 1355) were also significantly less in the V and A group. Conclusions: The ACA transoral endoscopic thyroidectomy possesses the protective effect on mental nerve and motor function of lower mandible and facilitates the operative procedures of TOETVA.
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RATIONALE: There is accumulating evidence to support the idea that brain-derived neurotrophic factor (BDNF) is involved in stress resilience. However, the precise molecular mechanisms underlying resilience in major depressive disorder (MDD) remain unknown. OBJECTIVE: The objective of this study was to explore the role of methyl CpG binding protein 2 (MeCP2) and the BDNF/tropomyosin-receptor-kinase B (TrkB) signaling pathway in the stress resilience to chronic social defeat stress (CSDS) in mice. RESULTS: We found that the overexpression of MeCP2 inhibited BDNF transcription, resulting in BDNF mRNA and protein downregulation in neuro-2a cells. The overexpression of MeCP2 increased S80-MeCP2 and decreased S421-MeCP2, BDNF, the ratio of S133-cyclic AMP response element binding protein (CREB)/CREB and p-TrkB/TrkB expression in neuro-2a cells. In addition, using the CSDS mouse model, we found that MeCP2 mRNA levels were decreased in the medial prefrontal cortex (mPFC) of resilient mice and increased in the hippocampus of susceptible mice. BDNF exon IV promoter and BDNF mRNA levels were decreased in the mPFC and hippocampus of susceptible mice. Finally, MeCP2 and S80-MeCP2 protein levels were increased in the mPFC and hippocampus of susceptible mice, whereas the protein expression of S421-MeCP2 and BDNF, the ratio of S133-CREB/CREB, and the levels of p-TrkB/TrkB were decreased in susceptible mice. CONCLUSIONS: These data suggest that the overexpression of MeCP2 inhibits BDNF transcription in neuro-2a cells. The inhibition of MeCP2 expression and activation of the BDNF/TrkB signaling pathway may confer stress resilience in CSDS mice.
Subject(s)
Brain-Derived Neurotrophic Factor , Depressive Disorder, Major , Methyl-CpG-Binding Protein 2 , Social Defeat , Animals , Brain-Derived Neurotrophic Factor/metabolism , Depressive Disorder, Major/metabolism , Hippocampus/metabolism , Methyl-CpG-Binding Protein 2/genetics , Methyl-CpG-Binding Protein 2/metabolism , Mice , RNA, Messenger/metabolism , Receptor, trkB/metabolism , Signal TransductionABSTRACT
MiRs are important players in cancer and primarily genetic/transcriptional means of regulating their gene expression are known. However, epigenetic changes modify gene expression significantly. Here, we evaluated genome-wide methylation changes focusing on miR genes from primary CRC and corresponding normal tissues. Differentially methylated CpGs spanning CpG islands, open seas, and north and south shore regions were evaluated, with the largest number of changes observed within open seas and islands. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed several of these miRs to act in important cancer-related pathways, including phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) and mitogen-activated protein kinase (MAPK) pathways. We found 18 miR genes to be significantly differentially methylated, with MIR124-2, MIR124-3, MIR129-2, MIR137, MIR34B, MIR34C, MIR548G, MIR762, and MIR9-3 hypermethylated and MIR1204, MIR17, MIR17HG, MIR18A, MIR19A, MIR19B1, MIR20A, MIR548F5, and MIR548I4 hypomethylated in CRC tumor compared with normal tissue, most of these miRs having been shown to regulate steps of metastasis. Generally, methylation changes were distributed evenly across all chromosomes with predominance for chromosomes 1/2 and protein-coding genes. Interestingly, chromosomes abundantly affected by methylation changes globally were rarely affected by methylation changes within miR genes. Our findings support additional mechanisms of methylation changes affecting (miR) genes that orchestrate CRC progression and metastasis.
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BACKGROUND: In the global phase 3 RAINBOW study, ramucirumab plus paclitaxel significantly improved overall survival compared with placebo plus paclitaxel in patients with advanced gastric or gastro-oesophageal junction (GEJ) adenocarcinoma. RAINBOW-Asia, a bridging study with similar design to RAINBOW, aimed to evaluate the efficacy and safety of ramucirumab plus paclitaxel for advanced gastric or GEJ adenocarcinoma in Asian, predominantly Chinese, patients. METHODS: RAINBOW-Asia was a randomised, double-blind, placebo-controlled, phase 3 trial done at 32 centres in China, Malaysia, the Philippines, and Thailand. Adult patients (≥18 years) with metastatic or locally advanced, unresectable gastric or GEJ adenocarcinoma who previously received fluoropyrimidine-platinum-based chemotherapy were randomly assigned with a centralised interactive web response system in a 2:1 ratio to receive ramucirumab 8 mg/kg or placebo intravenously on days 1 and 15 plus paclitaxel 80 mg/m2 intravenously on days 1, 8, and 15 of every 28-day cycle. Randomisation was stratified by Eastern Cooperative Oncology Group performance status and presence of peritoneal metastases. The co-primary endpoints were progression-free survival and overall survival. Efficacy analyses were done in the intention-to-treat population, and safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02898077, and has been completed. FINDINGS: Between March 2, 2017, and June 30, 2020, 440 patients were randomly assigned to receive ramucirumab plus paclitaxel (n=294) or placebo plus paclitaxel (n=146). Median progression-free survival was 4·14 months (95% CI 3·71-4·30) in the ramucirumab plus paclitaxel group compared with 3·15 months (2·83-4·14) in the placebo plus paclitaxel group (hazard ratio [HR] 0·765, 95% CI 0·613-0·955, p=0·0184). Median overall survival was 8·71 months (95% CI 7·98-9·49) in the ramucirumab plus paclitaxel group and 7·92 months (6·31-9·10) in the placebo plus paclitaxel group (HR 0·963, 95% CI 0·771-1·203, p=0·7426). The most common grade 3 or worse treatment-emergent adverse events were decreased neutrophil count (159 [54%] of 293 patients in the ramucirumab plus paclitaxel group vs 56 [39%] of 145 in the placebo plus paclitaxel group), decreased white blood cell count (127 [43%] vs 42 [29%]), anaemia (46 [16%] vs 24 [17%]), hypertension (21 [7%] vs nine [6%]), and febrile neutropenia (18 [6%] vs one [<1%]). INTERPRETATION: These findings, along with the results from RAINBOW, support the use of ramucirumab plus paclitaxel as second-line therapy in a predominantly Chinese population with advanced gastric or GEJ adenocarcinoma. FUNDING: Eli Lilly and Company, USA. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.