ABSTRACT
Ulcerative colitis (UC), a prevalent form of inflammatory bowel disease (IBD), presents a significant clinical challenge due to the lack of optimal therapeutic strategies. Emerging evidence suggests that fibroblast growth factor 20 (FGF20) may play a crucial role in mitigating UC symptoms, though the mechanistic underpinnings remain elusive. In this study, a mouse model of UC was established using dextran sodium sulfate (DSS) to investigate the potential role of FGF20. Our findings revealed a marked reduction in FGF20 expression in the serum and colonic tissues of DSS-treated mice. Furthermore, FGF20 knockout did not exacerbate colonic damage in these mice. Conversely, overexpression of FGF20 via adeno-associated virus (AAV) significantly alleviated UC-associated symptoms. This alleviation was evidenced by attenuated intestinal shortening, mitigated weight loss, increased colonic goblet cell density and crypt formation, reduced inflammation severity and inflammatory cell infiltration, and enhanced expression of tight junction and mucin proteins. Moreover, FGF20 significantly ameliorated the dysbiosis of gut microbiota in DSS-treated mice by increasing the abundance of beneficial bacteria and decreasing the abundance of harmful bacteria. The beneficial effects of FGF20 were notably attenuated following gut microbiota depletion with an antibiotic regimen. Fecal microbiota transplantation experiments further supported the critical role of gut microbiota in mediating the effects of FGF20 on DSS-treated mice. In conclusion, these findings highlight the potential involvement of gut microbiota in the therapeutic effects of FGF20 in UC.
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Pyridaben is a broad-spectrum, contact-killing acaricide that can be used to control a variety of harmful food and plant mites. Pyridaben displays cardiotoxicity and liver toxicity toward fish, but the effects on fish embryonic development have not been characterized. We exposed early zebrafish embryos to 20, 30, and 40⯵g/L concentrations of pyridaben. The exposure caused developmental abnormalities, including delayed embryonic shield formation, yolk sac resorption, decreases in body length, reduced pigmentation, and delays in hatching. Pyridaben caused a significant increase in the transcription level of the endoderm marker foxa2, but the transcription levels of the ectoderm development marker foxb1a and the mesoderm development marker snaila were not significantly altered. The transcription levels of the genes SOX17 in early embryos were significantly reduced. After exposure to pyridaben, catalase (CAT) activity and glutathione (GSH) content were increased, and cyclin D1, that is involved in early embryonic development, was abnormally expressed. This study shows that pyridaben causes anomalous development in zebrafish embryos by interfering with the cell cycle order of early embryonic development and inducing excessive oxidative stress. Colivelin, an agonist of the STAT3 signaling pathway, acted as a salvage drug to restore the cell cycle order during embryonic development following exposure to pyridaben. Thus, the toxic effects may be caused by pyridaben's regulation of the STAT3 signaling pathway.
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Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized inflammatory imbalance, intestinal epithelial mucosal damage, and dysbiosis of the gut microbiota. Polygonatum cyrtonema polysaccharides (PCPs) can regulate gut microbiota and inflammation. Here, the different doses of PCPs were administered to dextran sodium sulfate-induced UC mice, and the effects of the whole PCPs were compared with those of the fractionated fractions PCP-1 (19.9 kDa) and PCP-2 (71.6 and 4.2 kDa). Additionally, an antibiotic cocktail was administered to UC mice to deplete the gut microbiota, and PCPs were subsequently administered to elucidate the potential role of the gut microbiota in these mice. The results revealed that PCP treatment significantly optimized the lost weight and shortened colon, restored the balance of inflammation, mitigated oxidative stress, and restored intestinal epithelial mucosal damage. And, the PCPs exhibited superior efficacy in ameliorating these symptoms compared with PCP-1 and PCP-2. However, depletion of the gut microbiota diminished the therapeutic effects of PCPs in UC mice. Furthermore, fecal transplantation from PCP-treated UC mice to new UC-afflicted mice produced therapeutic effects similar to PCP treatment. So, PCPs significantly ameliorated the symptoms, inflammation, oxidative stress, and intestinal mucosal damage in UC mice, and gut microbiota partially mediated these effects.
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The KRASG12D mutation was believed to be locked in a GTP-bound form, rendering it fully active. However, recent studies have indicated that the presence of mutant KRAS alone is insufficient; it requires additional activation through inflammatory stimuli to effectively drive the development of pancreatic ductal adenocarcinoma (PDAC). It remains unclear to what extent RAS activation occurs during the development of PDAC in the context of inflammation. Here, in a mouse model with the concurrent expression of KrasG12D/+ and inflammation mediator IKK2 in pancreatic acinar cells, we showed that, compared to KRASG12D alone, the cooperative interaction between KRASG12D and IKK2 rapidly elevated both the protein level and activity of KRASG12D and NRAS in a short term. This high level was sustained throughout the rest phase of PDAC development. These results suggest that inflammation not only rapidly augments the activity but also the protein abundance, leading to an enhanced total amount of GTP-bound RAS (KRASG12D and NRAS) in the early stage. Notably, while KRASG12D could be further activated by IKK2, not all KRASG12D proteins were in the GTP-bound state. Overall, our findings suggest that although KRASG12D is not fully active in the context of inflammation, concurrent increases in both the protein level and activity of KRASG12D as well as NRAS at the early stage by inflammation contribute to the rise in total GTP-bound RAS.
Subject(s)
Carcinoma, Pancreatic Ductal , Pancreatic Neoplasms , Mice , Animals , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , ras Proteins/metabolism , Pancreatic Neoplasms/pathology , Carcinoma, Pancreatic Ductal/pathology , Mutation , Inflammation/genetics , Guanosine TriphosphateABSTRACT
The EGFR-RAS-ERK pathway is one of the most important signaling cascades in cell survival, growth, and proliferation. Aberrant activation of this pathway is a common mechanism in various cancers. Here, we report that CDK2 is a novel regulator of the ERK pathway via USP37 deubiquitinase (DUB). Mechanistically, CDK2 phosphorylates USP37, which is required for USP37 DUB activity. Further, USP37 deubiquitinates and stabilizes ERK1/2, thereby enhancing cancer cell proliferation. Thus, CDK2 is able to promote cell proliferation by activating USP37 and, in turn, stabilizing ERK1/2. Importantly, combined CDK1/2 and EGFR inhibitors have a synergetic anticancer effect through the downregulation of ERK1/2 stability and activity. Indeed, our patient-derived xenograft (PDX) results suggest that targeting both ERK1/2 stability and activity kills cancer cells more efficiently even at lower doses of these two inhibitors, which may reduce their associated side effects and indicate a potential new combination strategy for cancer therapy.
Subject(s)
MAP Kinase Signaling System , Neoplasms , Signal Transduction , Humans , Cell Proliferation , Cell Survival , Cyclin-Dependent Kinase 2/antagonists & inhibitors , ErbB Receptors/antagonists & inhibitors , Animals , Neoplasms/drug therapyABSTRACT
BACKGROUND AND PURPOSE: Oat ß-glucan could ameliorate epidermal hyperplasia and accelerate epidermal barrier repair. Dectin-1 is one of the receptors of ß-glucan and many biological functions of ß-glucan are mediated by Dectin-1. Dectin-1 promotes wound healing through regulating the proliferation and migration of skin cells. Thus, this study aimed to investigate the role of oat ß-glucan and Dectin-1 in epidermal barrier repair. EXPERIMENTAL APPROACH: To investigate the role of Dectin-1 in the epidermal barrier, indicators associated with the recovery of a damaged epidermal barrier, including histopathological changes, keratinization, proliferation, apoptosis, differentiation, cell-cell junctions and lipid content were compared between WT and Dectin-1-/- mice. Further, the effect of oat ß-glucan on the disruption of the epidermal barrier was also compared between WT and Dectin-1-/- mice. KEY RESULTS: Dectin-1 deficiency resulted in delayed recovery and marked keratinization, as well as abnormal levels of keratinocyte differentiation, cell-cell junctions and lipid synthesis during the restoration of the epidermal barrier. Oat ß-glucan significantly reduces epidermal hyperplasia, promotes epidermal differentiation, increases cell-cell junction expression, promotes lipid synthesis and ultimately accelerates the recovery of damaged epidermal barriers via Dectin-1. Oat ß-glucan could promote CaS receptor expression and activate the PPAR-γ signalling pathway via Dectin-1. CONCLUSION AND IMPLICATIONS: Oat ß-glucan promote the recovery of damaged epidermal barriers through promoting epidermal differentiation, increasing the expression of cell-cell junctions and lipid synthesis through Dectin-1. Dectin-1 deficiency delay the recovery of epidermal barriers, which indicated that Dectin-1 may be a potential target in epidermal barrier repair.
Subject(s)
Cell Differentiation , Epidermis , Lectins, C-Type , Up-Regulation , beta-Glucans , Animals , Lectins, C-Type/metabolism , beta-Glucans/pharmacology , Epidermis/metabolism , Epidermis/drug effects , Cell Differentiation/drug effects , Mice , Up-Regulation/drug effects , Mice, Knockout , Mice, Inbred C57BL , Intercellular Junctions/drug effects , Intercellular Junctions/metabolism , Male , Wound Healing/drug effects , Keratinocytes/drug effects , Keratinocytes/metabolism , Lipid Metabolism/drug effectsABSTRACT
PURPOSE: Nurses play an important role in ensuring patient rehabilitation and are involved in all aspects of multidimensional rehabilitation. Therefore, strengthening rehabilitation nursing education is vital to ascertain high-quality rehabilitation and optimum outcomes. This study examined the effectiveness of a new teaching reform-a modified Six-Sigma-based training program-against a conventional educational program on rehabilitation specialist nurses' core competencies, post-training performance, and satisfaction. METHODS: A quasi-randomized controlled trial was conducted to assess the effectiveness of the modified training program. We recruited 56 learners from the 2020 training course at the Hunan Rehabilitation Specialist Nurse Training Base as the control group. Sixty learners from the base's 2021 training course were recruited as the intervention group. Data were collected in a consistent manner from both groups after the training program was implemented. RESULTS: Those who underwent the modified training program showed better improvement in all core competencies than those who underwent the conventional training program (p < .05); the scores for theoretical knowledge, clinical nursing lectures, reviews, and nursing case management improved significantly following the teaching reform (p < 0.05). Further, overall satisfaction as well as base management and theoretical teaching satisfaction improved significantly (p < .05). CONCLUSION: The modified training program strengthens rehabilitation nurses' base management abilities; enhances their core competencies; expands their interest in and breadth, depth, and practicability of theoretical courses; and updates the teaching methods.
Subject(s)
Nurse Specialists , Nursing Care , Humans , Educational Status , KnowledgeABSTRACT
Ferroptosis is an important pathological process in acute kidney injury (AKI) which could lead to chronic kidney disease (CKD) and end-stage renal disease (ESRD). As an active ingredient of Chinese medicine Tripterygium wilfordii, celastrol has been reported to alleviate inflammation and preclinical studies have confirmed its anticancer effect. In the present study, we investigated the renal protective effects of celastrol against cisplatin induced AKI. Mice were administrated cisplatin by intraperitoneal injection and we found that celastrol reduced serum levels of BUN and creatinine, inhibited renal dysfunction, inflammation and oxidative stress. In addition, renal iron accumulation and ferroptosis were significantly reduced by celastrol treatment. Further mechanistic analyses suggested that Nrf2 is essential for celastrol upregulated GPX4 to alleviate ferroptosis and reduction of LDH release, intracellular iron accumulation and lipid peroxidation. These findings expand the potential uses of celastrol for treatment of various kinds of AKI associated with ferroptosis.
Subject(s)
Acute Kidney Injury , Ferroptosis , Animals , Mice , NF-E2-Related Factor 2 , Cisplatin , Acute Kidney Injury/chemically induced , Acute Kidney Injury/drug therapy , Inflammation , IronABSTRACT
Background: Thin endometrium is a reproductive disorder that affects embryo implantation. There are several therapies available for this disease, however they are not so effective. Fibroblast growth factor 1 (FGF1) is a member of fibroblast growth factor superfamily (FGFs), and it has been demonstrated that FGF1 expression was altered in samples collected from patients with thin endometrium. However, it is unclear if FGF1 could improve thin endometrium. The aim of this study was to investigate whether FGF1 have a therapeutic effect on thin endometrium. Methods: A model of thin endometrium induced by ethanol was constructed to investigate the effect and mechanism of action of FGF1 in thin endometrium. In the characterization experiments, 6-8 weeks female rats (n = 40) were divided into four groups: i) Control group; ii) Sham group; iii) Injured group; (iv) FGF1 therapy group. Endometrial tissues would be removed after three sexuel cycles after molding. Morphology and histology of the endometrium were evaluated by visual and hematoxylin and eosin staining. Masson staining and expression of α-SMA in endometrium showed the degree of endometrial fibrosis. Western blotting (PCNAãvWF and Vim) and immunohistochemistry (CK19 and MUC-1) demonstrated the effect of FGF1 on cell proliferation and angiogenesis. Moreover, immunohistochemistry (ER and PR) was used to explore the function of endometrium. The remaining rats (n = 36) were divided into three groups: i) Injured group; ii) FGF1 therapy group; and iii) 3-methyladenine. Western blotting (p38ãp-p38ãPI3K ãSQSTM1/p62ãbeclin-1 and LC3) was used to explore the mechanisms of FGF1. Results: In FGF1 therapy group, the morphology and histology of endometrium improved compared with the model group. Masson staining and the expression level of α-SMA showed that FGF1 could decrease the fibrotic area of endometrium. Besides, changes in ER and PR expression in the endometrium suggested that FGF1 could restore endometrium-related functions. Western blotting and immunohistochemistry revealed that PCNA, vWF, Vim, CK19 and MUC-1 were significantly increased after FGF1 treatment compared with the thin endometrium. In addition, Western blotting showed that p38, p-p38, PI3K, SQSTM1/p62, beclin-1 and LC3 levels were higher in FGF1 group than in the injured group. Conclusion: FGF1 application cured the thin endometrium caused by ethanol through autophagy mechanism.
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Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, inflammation, and fibrosis, as well as gut dysbiosis. Fibroblast growth factor 21 (FGF21), which regulates glucose and lipid metabolism, has been proven to have a good effect on NAFLD. However, the modulating process between FGF21 and gut microbiota remains unclear in treating NAFLD. Here, the fecal microbiota composition of 30 patients with NAFLD who had undergone liver biopsy and 29 matched healthy participants were studied, together with the fecal bile acid (BA) profile. Treatment with FGF21 was given in methionine-choline-deficient (MCD) diet-induced NAFLD model C57BL/6 mice. An antibiotic cocktail and fecal microbiota transplantation were used to further confirm the benefits of FGF21 that were partially attributable to the change in gut microbiota. Patients with NAFLD had higher serum FGF21 levels and dysregulated fecal microbiota compositions and fecal BA profiles. In NAFLD mice, FGF21 significantly reduced steatohepatitis and collagen deposition in vivo and restored intestinal structure. FGF21 treatment also changed gut microbiota composition and regulated dysbiosis in BA metabolism. After treatment with an antibiotic cocktail, FGF21 partially alleviated hepatic and intestinal damage in NAFLD mice. Furthermore, fecal microbiota transplantation from FGF21-treated mice showed benefits similar to FGF21 therapy. The improvement using FGF21 in MCD diet-induced NAFLD mice is partially mediated via gut microbiota and BA. Gut microbiota-regulated BA metabolism may be a potential target of FGF21 in improving NAFLD.
Subject(s)
Gastrointestinal Microbiome , Non-alcoholic Fatty Liver Disease , Animals , Mice , Bile Acids and Salts/metabolism , Choline/metabolism , Diet , Dysbiosis/drug therapy , Dysbiosis/metabolism , Gastrointestinal Microbiome/physiology , Liver/metabolism , Methionine/metabolism , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/metabolismABSTRACT
BACKGROUND: Fibroblast growth factor 21 (FGF21), primarily secreted by the pancreas, liver, and adipose tissues, plays a pivotal role in regulating glucose and lipid metabolism. Acute pancreatitis (AP) is a common inflammatory disease with specific clinical manifestations. Many patients with diabetes present with concurrent inflammatory symptoms. Diabetes exacerbates intestinal permeability and intestinal inflammation, thus leading to the progression to AP. Our previous study indicated that FGF21 significantly attenuated susceptibility to AP in mice. AIM: To investigate the potential protective role of FGF21 against AP in diabetic mice. METHODS: In the present study, a mouse model of AP was established in diabetic (db)/db diabetic mice through ceruletide injections. Thereafter, the protective effects of recombinant FGF21 protein against AP were evaluated, with an emphasis on examining serum amylase (AMS) levels and pancreatic and intestinal inflammatory cytokines [interleukin (IL)-6, tumor necrosis factor-alpha (TNF-), and intestinal IL-1ß]. Additionally, the impact of this treatment on the histopathologic changes of the pancreas and small intestinal was examined to elucidate the role of FGF21 in diabetic mice with AP. An antibiotic (Abx) cocktail was administered in combination with FGF21 therapy to investigate whether the effect of FGF21 on AP in diabetic mice with AP was mediated through the modulation of the gut microbiota. Subsequently, the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt), a bioinformatics software package, was used to predict different pathways between the groups and to explore the potential mechanisms by which the gut microbiota influenced the protective effect of FGF21. RESULTS: The results indicated that FGF21 notably diminished the levels of serum AMS (944.5 ± 15.9 vs 1732 ± 83.9, P < 0.01) and inflammatory factors including IL-6 (0.2400 ± 0.55 vs 1.233 ± 0.053, P < 0.01), TNF- (0.7067 ± 0.22 vs 1.433 ± 0.051, P < 0.01), and IL-1ß (1.377 ± 0.069 vs 0.3328 ± 0.02542, P < 0.01) in diabetic mice with AP. Moreover, notable signs of recovery were observed in the pancreatic structure of the mice. The histologic evidence of inflammation in the small intestine, including edema and villous damage, was significantly alleviated. FGF21 also significantly altered the composition of the gut microbiota, reestablishing the Bacteroidetes/Firmicutes ratio. Upon treatment with an Abx cocktail to deplete the gut microbiota, the FGF21 + Abx group showed lower levels of serum AMS (0.9328 ± 0.075 vs 0.2249 ± 0.023, P < 0.01) and inflammatory factors (1.083 ± 0.12 vs 0.2799 ± 0.032, p < 0.01) than the FGF21 group. Furthermore, the FGF21 + Abx group exhibited diminished injury to the pancreatic and small intestinal tissues, accompanied by a significant decrease in blood glucose levels (17.50 ± 1.1 vs 9.817 ± 0.69 mmol/L, P < 0.001). These findings underscored the superior protective effects of the combination therapy involving an Abx cocktail with FGF21 over the FGF21 treatment alone in diabetic mice with AP. The gut microbiota composition across different groups was further characterized, and a differential expression analysis of gene functions was undertaken using the PICRUSt2 prediction method. These findings suggested that FGF21 could potentially confer therapeutic effects on diabetic mice with AP by modulating the sulfate reduction I pathway and the superpathway of n-acetylceramide degradation in the gut microbiota. CONCLUSION: This study reveals the potential of FGF21 in improving pancreatic and intestinal damage recovery, reducing blood glucose levels, and reshaping gut microbiota composition in diabetic mice with AP. Notably, the protective effects of FGF21 are augmented when combined with the Abx cocktail.
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Background: Ferroptosis is a newly discovered form of regulated cell death with distinct properties and recognizing functions involved in physical conditions or various diseases, including cancers. However, the relationship between gliomas and ferroptosis-related lncRNAs (FRLs) remains unclear. Methods: We collected a total of 1850 samples from The Cancer Genome Atlas (TCGA) and Genotype Tissue Expression (GTEX) databases, including 698 tumor and 1,152 normal samples. A list of ferroptosis-related genes was downloaded from the Ferrdb website. Differentially expressed FRLs (DEFRLS) were analyzed using the "limma" package in R software. Subsequently, prognosis-related FRLs were obtained by univariate Cox analysis. Finally, a prognostic model based on the 3 FRLs was constructed using Cox regression analysis with the least absolute shrinkage and selection operator (LASSO) algorithm. The prognostic power of the model was assessed using receiver operating characteristic (ROC) curve analysis and Kaplan-Meier (K-M) survival curve analysis. In addition, we further explored the relationship of the immune landscape and somatic mutations to prognostic model characteristics. Finally, we validated the function of LINC01426 in vitro. Results: We successfully constructed a 3-FRLs signature and classified glioma patients into high-risk and low-risk groups based on the risk score calculated from this signature. Compared with traditional clinicopathological features [age, sex, grade, isocitrate dehydrogenase (IDH) status], the prognostic accuracy of this model is more stable and stronger. Additionally, the model had stable predictive power for overall survival over a 5-year period. In addition, we found significant differences between the two groups in cellular immunity, the numbers of many immune cells, including NK cells, CD4+, CD8+ T-cells, and macrophages, and the expression of many immune-related genes. Finally, the two groups were also significantly different at the level of somatic mutations, especially in glioma prognosis-related genes such as IDH1 and ATRX, with lower mutation rates in the high-risk group leading to poorer prognosis. Finally, we found that the ferroptosis process of glioma cells was inhibited after knocking down the expression of LINC01426. Conclusion: The proposed 3-FRL signature is a promising biomarker for predicting prognostic features in glioma patients.
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This study aimed to analyze the effect of carbon fiber nanotube tracheotomy (CFNT) under swallowing training (ST) combined with bronchofiberoscope alveolar lavage (BAL), so as to provide theoretical guidance for the clinical treatment of pulmonary infection. 40 patients with pulmonary infection were selected as the research objects, and the effects of ST combined with BAL were analyzed after CFNT. The patients were randomly divided into four groups: a control group (group A) and three observation groups (groups B, C, and D), with 10 cases in each group. Patients in group A received conventional treatment, patients in group B received conventional treatment + ST, patients in group C received conventional treatment + BAL, and patients in group D received conventional treatment + ST + BAL. The effect of ST + BAL was analyzed after CFNT. The results showed that compared with the group A, the number of lung infections and infection rates in groups C and D was reduced (P < 0.05); the use time and per capita cost of antibiotics in group A were much higher than those in the groups C and D (P < 0.05); and in group B and D, the number of successful extubation of tracheal catheters and the success rate were greatly increased (P < 0.05) and the average time of intubation was dramatically shortened (P < 0.05). The scores of the water swallow test (WST) in groups B and D were much lower than the score of group A (P < 0.05), and the scores for swallowing ability and swallowing dysfunction scores were much different from those of the group A (P < 0.05). In summary, after a CFNT, the lung infection and swallowing function of patients were effectively improved after ST + BAL.
Subject(s)
Deglutition Disorders , Nanotubes, Carbon , Carbon Fiber , Deglutition , Deglutition Disorders/therapy , Humans , Therapeutic Irrigation , TracheotomyABSTRACT
Pentachloronitrobenzene (PCNB) is an organochlorine protective fungicide mainly used as a soil and seed fungicide. Currently, there are few reports on the toxicity of PCNB to zebrafish embryo. Here, we evaluated the toxicity of PCNB in aquatic vertebrates using a zebrafish model. Exposure of zebrafish embryos to PCNB at concentrations of 0.25 mg/L, 0.5 mg/L, and 0.75 mg/L from 6 hpf to 72 hpf resulted in abnormal embryonic development, including cardiac malformation, pericardial edema, decreased heart rate, decreased blood flow velocity, deposition at yolk sac, shortened body length, and increased distance between venous sinus and arterial bulb (SV-BA). The expression of genes related to cardiac development was disordered. However, due to the unstable embryo status in the 0.75 mg/L exposure concentration group, the effect of PCNB on the expression levels of cardiac-related genes was not concentration-dependent. We found that PCNB increased reactive oxygen species stress levels in zebrafish, increased malondialdehyde (MDA) content and catalase (CAT) activity, and decreased superoxide dismutase (SOD) activity. The increased level of oxidative stress reduced the proliferation ability of zebrafish cardiomyocytes, and the expressions of zebrafish proliferation-related genes such as cdk-2, cdk-6, ccnd1, and ccne1 were significantly down-regulated. Astaxanthin (AST) attenuates PCNB-induced reduction in zebrafish cardiomyocyte proliferation by reducing oxidative stress levels. Our study shows that PCNB can cause severe oxidative stress in zebrafish, thereby reducing the proliferative capacity of cardiomyocytes, resulting in zebrafish cardiotoxicity.
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Following injury, tissue autonomously initiates a complex repair process, resulting in either partial recovery or regeneration of tissue architecture and function in most organisms. Both the repair and regeneration processes are highly coordinated by a hierarchy of interplay among signal transduction pathways initiated by different growth factors, cytokines and other signaling molecules under normal conditions. However, under chronic traumatic or pathological conditions, the reparative or regenerative process of most tissues in different organs can lose control to different extents, leading to random, incomplete or even flawed cell and tissue reconstitution and thus often partial restoration of the original structure and function, accompanied by the development of fibrosis, scarring or even pathogenesis that could cause organ failure and death of the organism. Ample evidence suggests that the various combinatorial fibroblast growth factor (FGF) and receptor signal transduction systems play prominent roles in injury repair and the remodeling of adult tissues in addition to embryonic development and regulation of metabolic homeostasis. In this review, we attempt to provide a brief update on our current understanding of the roles, the underlying mechanisms and clinical application of FGFs in tissue injury repair.
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Liver injury can lead to different hepatic diseases, which are the mainly causes of high global mortality and morbidity. Autophagy and Sirtuin type 1 (SIRT1) have been shown protective effects in response to liver injury. Previous studies have showed that Fibroblast growth factor 21 (FGF21) could alleviate acute liver injury (ALI), but the mechanism remains unclear. Here, we verified the relationship among FGF21, autophagy and SIRT1 in carbon tetrachloride (CCl4 )-induced ALI. We established CCl4 -induced ALI models in C57BL/6 mice and the L02 cell line. The results showed that FGF21 was robustly induced in response to stress during the development of ALI. After exogenous FGF21 treatment in ALI models, liver damage in ALI mice was significantly reduced, as well as serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Consistently, FGF21 also greatly reduced the levels of ALT, AST, pro-inflammatory cytokines interleukin 6 (IL6) and tumour necrosis factor-alpha (TNFα) in ALI cell lines. Mechanistically, exogenous FGF21 treatment efficiently upregulated the expression of autophagy marker microtubule-associated protein light chain-3 beta (LC3 II) and autophagy key molecule coiled-coil myosin-like BCL2-interacting protein (Beclin1), which was accompanied by alleviating hepatotoxicity in CCl4 -treated wild-type mice. Then, we examined how FGF21 induced autophagy expression and found that SIRT1 was also upregulated by FGF21 treatment. To further verify our results, we constructed an anti-SIRT1 lentit-RNAi to inhibit SIRT1 expression in mice and L02 cells, which reversed the protective effect of FGF21 on ALI. In summary, these results indicate that FGF21 alleviates ALI by enhancing SIRT1-mediated autophagy.
Subject(s)
Chemical and Drug Induced Liver Injury , Sirtuin 1 , Animals , Autophagy , Chemical and Drug Induced Liver Injury/pathology , Fibroblast Growth Factors , Liver/metabolism , Mice , Mice, Inbred C57BL , Sirtuin 1/genetics , Sirtuin 1/metabolismABSTRACT
Background Pulmonary rehabilitation is recommended for most patients with lung diseases. However, some previous studies have shown that pulmonary rehabilitation has no obvious effect on short-term lung function in patients with lung cancer. Objective The purpose of this study was to evaluate the effect of the ABCDEF pulmonary rehabilitation program on lung cancer patients who have undergone surgery. Design This was a randomized controlled trial with repeated measures. Settings The study was conducted in the Cardiothoracic Surgery Department of a 4000-bed comprising training and research hospital from 2019 to 2020. Participants A total of 90 patients who underwent thoracoscopic pneumonectomy were divided into two groups of 45, using a completely randomized model. Methods Patients in the experimental group participated in an ABCDEF program (Acapella positive vibration pressure training, breathing exercise, cycling training, dance in the square, education, and follow-up) after surgery. In contrast, the regular care provided to the control group focused on breathing and expectoration guidance. The study outcomes were the first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, 6 min walking distance, Borg score, incidence of postoperative complications, length of indwelling chest tube, and length of postoperative stay. Generalized estimating equation models were used to compare the changes in the outcomes between the groups over time. Results The ABCDEF pulmonary rehabilitation program for patients who underwent thoracoscopic pneumonectomy was found to be more effective in increasing lung function at 3 months after discharge (p<0.05). However, there was no statistically significant difference on the day of discharge (p>0.05). Exercise tolerance was different at both time points (p<0.05). The incidence of postoperative complications in the experimental group was lower than that in the control group (p<0.05). The length of postoperative stay in the experimental group was also shorter (p<0.05), however, the length of the indwelling chest tube was not significantly different between the intervention and control groups (p>0.05). Conclusions This study showed that the ABCDEF pulmonary rehabilitation program could effectively improve mid-term lung function and exercise tolerance in patients after thoracoscopic pneumonectomy, and reduce the incidence of postoperative complications along with the length of postoperative hospital stay.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/surgery , Humans , Lung/surgery , Lung Neoplasms/surgery , Postoperative Complications , ThoracoscopyABSTRACT
This study aimed to investigate the efficacy and safety of a novel balloon catheter in dilation intervention for patients with cricopharyngeus achalasia after stroke. Thirty-four patients with cricopharyngeus achalasia after stroke received routine swallowing rehabilitation training and were randomly assigned to an experimental group (Exp, n = 17) that received dilation therapy using the novel balloon catheter once daily for 5 days per week or a control group (Con, n = 17) that received dilation therapy with a 14-Fr ordinary urinary catheter once daily for 5 days per week. The intervention duration, Eating Assessment Tool (EAT)-10 scores, and Functional Oral Intake Scale (FOIS) scores were recorded at baseline and each day during intervention. The time for a patient's FOIS score to be ≥ 3 as well as the recovery time for oral intake of water, liquid food, mushy food, and solid food were recorded or estimated. Complications were also recorded during intervention. The intervention duration was shorter in the Exp group than in the Con group (p = 0.005). The Exp group patients improved faster than the Con group patients, with a shorter recovery time for oral intake of liquid food (p = 0.002), mushy food (p = 0.001), and solid food (p = 0.001). At the time of intervention termination, EAT-10 scores were lower in the Exp group than in the Con group (p = 0.005). The Exp group had a similar incidence of complications as the Con group but with better tolerability (p = 0.028). Compared with the urinary catheter, the novel balloon catheter for dilation in patients with cricopharyngeus achalasia after stroke may lead to a better and more rapid recovery.
Subject(s)
Esophageal Achalasia , Pharyngeal Diseases , Stroke , Humans , Dilatation/adverse effects , Esophageal Achalasia/complications , Esophageal Achalasia/therapy , Esophageal Sphincter, Upper , Urinary Catheters , Treatment Outcome , Stroke/complicationsABSTRACT
Regeneration of a part of the diseased liver after surgical resection is mainly achieved by the proliferation of the remaining healthy liver cells. However, in case of extreme loss of liver cells or in the final stages of chronic liver disease, most liver cells are depleted or lose their ability to proliferate. Therefore, to foster liver regeneration, it is of great clinical and scientific significance to improve the survival and proliferation ability of residual hepatocytes. In this study, we conducted experiments on a zebrafish model of targeted ablation of liver cells to clarify the role of fibroblast growth factor 21 (FGF21). We found that FGF21 increased the regeneration area of the damaged liver and improved the survival rate of damaged liver cells by inhibiting cell apoptosis and reducing oxidative stress. Our results also showed that administration of FGF21 upregulated autophagy, and the beneficial effects of FGF21 were reversed by the well-known autophagy inhibitor chloroquine (CQ), indicating that FGF21-activated autophagy played a central role in the treatment. We further showed that the enhancement of autophagy induced by FGF21 was due to the activation of the AMPK-mTOR signaling pathway. Taken together, these data provide new evidence that FGF21 is an effective autophagy regulator that can significantly improve the survival of damaged livers.
ABSTRACT
Nitazoxanide (NTZ) is a broad-spectrum antiparasitic and antiviral drug (thiazole). However, although NTZ has been extensively used, there are no reports concerning its toxicology in vertebrates. This study used the zebrafish as a vertebrate model to evaluate the safety of NTZ and to analyse the related molecular mechanisms. The experimental results showed that zebrafish embryos exposed to NTZ had cardiac malformation and dysfunction. NTZ also significantly inhibited proliferation and promoted apoptosis in cardiomyocytes. Transcriptomic analysis used compared gene expression levels between zebrafish embryos in the NTZ treatment and the control groups identified 200 upregulated genes and 232 downregulated genes. Analysis by Kyoto encyclopaedia of genes and genomes (KEGG) and gene ontology (GO) showed that signal pathways on cardiomyocyte development were inhibited while the oxidative stress pathways were activated. Further experiments showed that NTZ increased the content of reactive oxygen species (ROS) in the hearts of zebrafish. Antioxidant gadofullerene nanoparticles (GFNPs) significantly alleviated the developmental toxicity to the heart, indicating that NTZ activated the oxidative stress response to cause embryonic cardiomyocyte injury in zebrafish. This study provides evidence that NTZ causes developmental abnormalities in the cardiovascular system of zebrafish.