Ginger-Derived Extracellular Vesicles: A Natural Solution for Alopecia.

BACKGROUND: Ginger (Zingiber officinale (L.) Rosc), as an edible plant-derived nanoparticle, offers several advantages, such as a high return rate, low budget, no ethical barriers, and good for health. Ginger-Derived Extracellular Vesicles (GDEVs) are nanoscale vesicles isolated from ginger. METHODS: In this study, GDEVs were used to treat the alopecia mouse model, and its main active components and potential mechanism of action were investigated. The LC-MS/MS analysis of GDEVs revealed the presence of 1299 chemical compounds, among which auxiliary components were identified. Interestingly, the crux of the analysis lies in the discovery of 13 specific ingredients that play a pivotal role in hair proliferation. The aim of this study was to investigate the protective effect of GDEVs on hair loss. These advantages make ginger-derived nanoparticles a promising solution to overcome technical limitations associated with mammalian nanoparticles. This study elucidates the mechanism of action of GDEVs in the treatment of alopecia. However, the active ingredients and mechanism of action of GDEVs in the treatment of hair loss are unknown. RESULTS: GDEVs were isolated from ginger using the differential centrifugal method. Network pharmacological analysis of the GDEVs revealed that the anti-hair loss effect of GDEVs on alopecia was closely linked to its ability to reduce inflammation and promote the proliferation of hair follicle stem cells. Subsequently, it was applied to the balding areas of hair-loss mice using a brush. The results demonstrated that the application of GDEVs led to a rapid recovery of the balding areas and promoted the growth of healthier hair. CONCLUSION: This experiment reported that GDEVs can effectively suppress the inflammatory activity in the alopecia model mice.

High specific surface area carbon aerogel derived from starch for methylene blue adsorption and supercapacitors.

Starch based carbon aerogel has attracted significant attention due to the wide source, environmental friendliness and low price of raw materials. Here, starch based carbon aerogel was fabricated by graft reaction and cross-linking reaction of starch. The network structure of starch hydrogel was optimized through graft and cross-linking reaction. After freeze drying and high temperature carbonization, the obtained carbon aerogel that carbonized at 800 °C showed a specific surface area of 1508 m2·g-1 without activation which is far higher than that of other unactivated carbon aerogels. The starch based carbon aerogel carbonized at 800 °C exhibited superior methylene blue adsorption ability with a maximum adsorption capacity of 963.5 mg·g-1 as a result of its rich surface functional groups, high specific surface area, and reasonable pore size distribution. Furthermore, the carbon aerogel carbonized at 700 °C exhibited excellent electrochemical performance with a specific capacitance of 180.1 F·g-1 at a current density of 1 A·g-1as electrode materials for supercapacitors. Overall, this work provides a new method to prepare high performance starch based carbon aerogel.

Analysis of the therapeutic effect of synchronous integrated intensity modulated radiotherapy combined with chemotherapy in stage IIIc of cervical cancer.

Objective: To explore the Therapeutic effect of synchronous Integrated intensity modulated radiotherapy combined with chemotherapy in stage IIIc of Cervical Cancer. Methods: A total of 58 patients with stage IIIC cervical cancer (KPS ≥ 80) were analyzed in this study. They were admitted to our hospital between August 2017 and August 2022. Synchronous integrated boost intensity-modulated radiotherapy (SIB-IMRT) and sequential boost intensity-modulated radiotherapy (LCB-IMRT) were used to treat pelvic and/or para-aortic metastatic lymph nodes, with 30 cases in the SIB group and 28 cases in the LCB group. Comparison of short-term and long-term efficacy. Comparison of recurrence and metastasis rates, radiation dose to organs at risk and incidence of adverse drug reactions. Result: 30 patients were treated with simultaneous integrated boost intensity-modulated radiotherapy (SIB-IMRT), and 28 patients were treated with sequential boost intensity-modulated radiotherapy (LCB-IMRT). At the completion of radiotherapy and 3 months after radiotherapy, there was no significant difference in clinical efficacy observed between the two treatment groups. The median overall survival (OS), progression-free survival (PFS), and disease-free survival (DMR) in the SIB-IMRT group were significantly higher compared to the LCB-IMRT group. The SIB-IMRT group demonstrated significantly lower rates compared to the LCB-IMRT group. Furthermore, within 3 years and 5 years, the rates of lymph node recurrence, cervical and vaginal local recurrence, and distant metastasis within the radiotherapy field were significantly lower in the SIB-IMRT group compared to the LCB-IMRT group. There were no significant differences observed between the two groups in terms of the maximum dose to the small intestine (Dmax), dose received by 2cc of the small intestine (D2cc), maximum dose to the rectum (Dmax), and dose received by 1cc of the bladder (D1cc). The incidence of bone marrow toxicity in the SIB-IMRT group was significantly lower compared to the LCB-IMRT group. Moreover, the occurrence of grade III and IV bone marrow toxicity was also significantly lower in the SIB-IMRT group compared to the LCB-IMRT group. Conclusion: The study has concluded that there is no significant differences in in terms of bladder associated adverse events and gastrointestinal toxicity in both Simultaneous Integrated Boost Intensity-Modulated Radiotherapy and Layered Conical Beam Intensity-Modulated Radiation Therapy.

WITHDRAWN: Investigating the ERG a-wave and Retinal Diseases with Rod Equivalent Circuit Model Based on the APD.

This article has been withdrawn: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been withdrawn at the request of the Editor and Publisher, after being inadvertently published due to an editorial error. This error bears no reflection on the article or its authors. The Publisher apologizes for any inconvenience this may cause.

Noninvasive serum markers for predicting significant liver histopathology in HBeAg-negative chronic HBV-infected patients with normal alanine aminotransferase.

This study is to explore the proportion of significant liver histopathology in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV)-infected patients with normal alanine aminotransferase (ALT) and investigate noninvasive indicators for predicting significant liver histopathology. A total of 201 HBeAg-negative chronic HBV-infected patients with normal ALT who underwent liver biopsy were involved in this study. Significant liver histological changes were defined as necroinflammation grade ≥2 (G ≥ 2) and/or fibrosis stage ≥2 (S ≥ 2). The results showed that 42.3% (85/201) and 45.8% (92/201) of the HBeAg-negative patients with normal ALT have significant liver necroinflammation (G ≥ 2) and fibrosis (S ≥ 2), respectively. High normal ALT (>22 U/L), high level of serum HBV DNA (>3.42 log IU/mL), and low level of prealbumin (PA) (<170 mg/L) were independent predictors for significant liver necroinflammation, and the predictive value of the combined indicators was 0.750 (P < 0.001), while high normal ALT (>24 U/L) and high level of FIB-4 (>1.53) were independent predictors for significant liver fibrosis, and the predictive value of the combined indicators was 0.740 (P < 0.001). In conclusion, more than 40% of HBeAg-negative patients with normal ALT have significant liver histopathology and require immediate antiviral treatment. ALT, PA, HBV DNA, and FIB-4 can independently predict significant liver inflammation and fibrosis for HBeAg-negative patients with normal ALT. Lowering the treatment threshold of ALT may benefit the HBeAg-negative chronic HBV-infected patients. IMPORTANCE: Hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV)-infected patients with normal alanine aminotransferase (ALT) were supposed to have a low risk of progression to cirrhosis or hepatocellular carcinoma, and it was recommended to regularly follow up or undergo liver biopsy to assess liver histopathology according to the major international guidelines. However, this study indicates that a considerable number of HBeAg-negative chronic HBV-infected patients with normal ALT have significant liver histopathology and require immediate antiviral treatment. Besides, several clinical commonly used noninvasive indicators were found that can be used to predict significant liver histopathology; thereby liver biopsy might be avoided for HBeAg-negative chronic HBV-infected patients with normal ALT.

Transfer of inflammatory mitochondria via extracellular vesicles from M1 macrophages induces ferroptosis of pancreatic beta cells in acute pancreatitis.

Extracellular vesicles (EVs) exert a significant influence not only on the pathogenesis of diseases but also on their therapeutic interventions, contingent upon the variances observed in their originating cells. Mitochondria can be transported between cells via EVs to promote pathological changes. In this study, we found that EVs derived from M1 macrophages (M1-EVs), which encapsulate inflammatory mitochondria, can penetrate pancreatic beta cells. Inflammatory mitochondria fuse with the mitochondria of pancreatic beta cells, resulting in lipid peroxidation and mitochondrial disruption. Furthermore, fragments of mitochondrial DNA (mtDNA) are released into the cytosol, activating the STING pathway and ultimately inducing apoptosis. The potential of adipose-derived stem cell (ADSC)-released EVs in suppressing M1 macrophage reactions shows promise. Subsequently, ADSC-EVs were utilized and modified with an F4/80 antibody to specifically target macrophages, aiming to treat ferroptosis of pancreatic beta cells in vivo. In summary, our data further demonstrate that EVs secreted from M1 phenotype macrophages play major roles in beta cell ferroptosis, and the modified ADSC-EVs exhibit considerable potential for development as a vehicle for targeted delivery to macrophages.

The objectively measured walking speed and risk of hypertension in Chinese older adults: a prospective cohort study.

This study aims to investigate the longitudinal association between objectively measured walking speed and hypertension and to explore the potential effect modification of obesity on this association in Chinese older adults. The data from the Chinese Health and Retirement Prospective Cohort Study (CHARLS) during 2011-2015 was used. Walking speed was assessed by measuring the participants' usual gait in a 2.5 m course, and it was divided into four groups according to the quartiles (Q1, Q2, Q3, and Q4). A total of 2733 participants ≥60 years old were eligible for the analyses. After a follow-up of 4 years, 26.9% occurred hypertension. An inverse association was observed between walking speed and the risk of hypertension. There was an interaction between body mass index (BMI) and walking speed for the hypertension risk (P = 0.010). the association of walking speed with hypertension was stronger in overweight and obese participants (Q2, OR: 0.54, 95%CI = 0.34-0.85, P = 0.009; Q3, OR: 0.69, 95%CI = 0.44-1.08, P = 0.106; Q4, OR: 0.62, 95%CI = 0.39-0.98, P = 0.039). However, this association was not significant among lean ones. A similar trend was observed for systolic and diastolic blood pressure. In conclusion, higher walking speed was longitudinally associated with a lower risk of hypertension in Chinese older adults, especially among overweight and obese participants.

Methionine enkephalin inhibited cervical cancer migration as well as invasion and activated CD11b+ NCR1+ NKs of tumor microenvironment.

This study was to study the role of methionine enkephalin (menk) in cell invasion and migration as well as NK cells activation of tumor microenvironment in cervical cancer. The results showed that menk inhibited cervical cancer migration and invasion. In addition, we found menk affected epithelial to mesenchymal transition (EMT) related indicators, with increasing E-cadherin level, decreasing N-cadherin and vimentin level. Through in vivo mouse model, we found that menk IFNγ and NKP46 expression was upregulated in tumor tissues by menk compared with controls, while LAG3 expression was inhibited by menk, besides, there was an upregulation of CD11b+ NCR1+ NKs of tumor microenvironment in cervical cancer. Therefore, we concluded that menk inhibited cancer migration and invasion via affecting EMT related indicators and activated CD11b+ NCR1+ NKs of tumor microenvironment in cervical cancer, laying a theoretical foundation for the further clinical treatment of menk.

Corrigendum: miR-212/132-enriched extracellular vesicles promote differentiation of induced pluripotent stem cells into pancreatic beta cells.

[This corrects the article DOI: 10.3389/fcell.2021.673231.].

Effects of lower-extremity explosive strength on youth judo athletes adopting different types of power-based resistance training.

Objective: The present study compared the effects of two different resistance types (pneumatic resistance and free weight) of 6-week squat training on the performance for young female judo athletes in linear speed and vertical jump by utilizing the maximum power of each set of squats in each training session as the monitoring vehicle. Monitoring data were used to assess the effects and trends of the two resistance types on 70% 1RM weight-bearing during the 6-week intervention training. Methods: In a 6 weeks squat training (2 reps/week with a constant load), 23 adolescent female judo athletes (Age span: 13-16 years, 14.58 ± 0.96) were randomly selected and then divided into the traditional barbell (FW) group (n = 12) and the pneumatic resistance (PN) (n = 11) group according to different resistance types (free weight and pneumatic resistance), with 10 in FW group and 9 in PN group actually completed the study. Before and after training, the 30-m Sprint time (T-30M), vertical jump height and relative power (countermovement jump, static-squat jump, and drop jump), reactive strength index (DJ-RSI), and maximal strength were assessed. One-Way ANOVA was used to examine the pre-test differences of groups (FW and PN). A 2-factor mixed-model analysis of variance was used to examine the independent effects of group (FW and PN) and time (pre and post) on each dependent measure. Scheffe post hoc comparisons were used to examine the differences. Pre- and post-experimental differences between the two groups were analyzed using independent samples t-tests and magnitude-based inferences (MBI) derived from their p values, and effect statistics were applied to compare the pre- and post-changes exhibited by each group to identify the potential beneficiary groups. Results: The PN group outperformed the FW group in terms of maximal power output per training session (822.5 ± 55.22 vs. 927.42 ± 48.15, conventional vs. pneumatic, p < 0.001, effect size = -2.02). After 6 weeks of training, the FW group showed significant increases in vertical jump height and relative strength (CMJ, SJ, DJ), with no significant gains observed in T-30 and maximal strength. The PN group showed significant improvements in maximal strength; however, no significant improvements were observed in the other tests. In addition, there was no significant difference in DJ-RSI between the two groups before and after training. Discussion: At 70% weight bearing, free weight resistance appears to be more conducive to vertical jump growth, while pneumatic resistance appears to be more conducive to maximal strength gains; however, the maximal strength gains from pneumatic resistance may not be well applied to athletic performance. In addition, the body adapts more quickly to pneumatic resistance than to free weight resistance.

Superior Anticancer Potential of Nano-Paclitaxel Combined Bevacizumab Treatment in Ovarian Cancer.

BACKGROUND: Ovarian cancer is the second most common cancer to cause large death among gynecological tumors. Paclitaxel is important to the standard treatment for epithelial ovarian cancer. Due to its low solubility and permeability, nano-paclitaxel came into public view. OBJECTIVE: To evaluate the effect of nano-paclitaxel in ovarian cancer. METHODS: Considering the importance of bevacizumab in clinical treatment, we set four groups for research: control, paclitaxel, paclitaxel + bevacizumab, and nano-paclitaxel + bevacizumab. CCK-8, apoptosis, and cell cycle assays were used to detect the cell survival condition. qRT-PCR and western blot were used to detect the gene mRNA and protein expression level. Tumor xenograft in nude mice was used to detect the effect in vivo. RESULTS: The nano-paclitaxel combined with bevacizumab had the best curative effect. Moreover, the downstream indicators, such as caspases, BAX, FAS, OGFr, PD-L1 and VEGF, changed in four groups, which suggested that the therapy worked by affecting the cell apoptosis, cell cycle, angiogenesis, and immune reaction. CONCLUSION: In conclusion, the study helped us better commandof nano-paclitaxel for ovarian cancer treatment and thus could play a role in OC therapy.

Extracellular Vesicle Content Changes Induced by Melatonin Promote Functional Recovery of Pancreatic Beta Cells in Acute Pancreatitis.

Aim: Acute pancreatitis is an inflammatory disorder of the pancreas, which causes abnormal activation of immune cells. The macrophages were accumulated in pancreas and infiltrated into islets during the AP process to induce abnormal glucose metabolism. However, the role of macrophages in abnormal glucose metabolism remains understood. Extracellular vesicles act in the regulation of intercellular function, but whether EVs secreted by macrophages contribute to ß cell failure and apoptosis in AP is unclear. Based on this, the aim of this study was to reveal the role of macrophages-EVs in AP and develop a treatment for symptoms of hyperglycemia in AP. Methods: The AP model was established and treated by various doses of melatonin to analyze the therapeutic effect. The accumulation and polarization of macrophages in the AP pancreas were observed, and the ß cells were incubated with pancreatic derived EVs to analyze the role in ß cell failure and apoptosis. Results: The results showed that macrophages were recruited and polarized to M1 phenotype macrophages in the pancreas of AP mice, which obtained inflammatory EVs that contained specific miRNAs to induce ß cell failure and apoptosis. Then, the EVs derived from M1 macrophages triggered ß cell failure and apoptosis. Melatonin prevented polarization of macrophages to the M1 phenotype in vivo, which reduced the secretion of inflammatory EVs, changed the abundance of miRNAs in EVs, and therefore decreased inflammatory EV-mediated ß cell failure and apoptosis. Conclusion: Our results demonstrate that similar to 20S proteasome inhibitor MG132, analyses indicated that melatonin prevented degradation of IκBα through the ubiquitylation pathway to restrict p50 subunits to the cytoplasm of macrophages, inhibited activation of the NF-κB pathway to downregulate the transcription of specific miRNAs, and reduced miRNA transport into EVs.

Immune cell-derived extracellular vesicular microRNAs induce pancreatic beta cell apoptosis.

Background: Type 1 diabetes mellitus (T1DM) is an autoimmune disease caused by an autoimmune response against pancreatic islet ß cells. Increasing evidence indicates that specific microRNAs (miRNAs) from immune cells extracellular vesicles are involved in islet ß cells apoptosis. Methods: In this study, the microarray datasets GSE27997 and GSE137637 were downloaded from the Gene Expression Omnibus (GEO) database. miRNAs that promote islet ß cells apoptosis in T1DM were searched in PubMed. We used the FunRich tool to determine the miRNA expression in extracellular vesicles derived from immune cells associated with islet ß cell apoptosis, of which we selected candidate miRNAs based on fold change expression. Potential upstream transcription factors and downstream target genes of candidate miRNAs were predicted using TransmiR V2.0 and starBase database, respectively. Results: Candidate miRNAs expressed in extracellular vesicles derived from T cells, pro-inflammatory macrophages, B cells, and dendritic cells were analyzed to identify the miRNAs involved in ß cells apoptosis. Based on these candidate miRNAs, 25 downstream candidate genes, which positively regulate ß cell functions, were predicted and screened; 17 transcription factors that positively regulate the candidate miRNAs were also identified. Conclusions: Our study demonstrated that immune cell-derived extracellular vesicular miRNAs could promote islet ß cell dysfunction and apoptosis. Based on these findings, we have constructed a transcription factor-miRNA-gene regulatory network, which provides a theoretical basis for clinical management of T1DM. This study provides novel insights into the mechanism underlying immune cell-derived extracellular vesicle-mediated islet ß cell apoptosis.

Uterine macrophages as treatment targets for therapy of premature rupture of membranes by modified ADSC-EVs through a circRNA/miRNA/NF-κB pathway.

BACKGROUND: Circular RNA (circRNA) is a type of stable non-coding RNA that modifies macrophage inflammation by sponging micro RNAs (miRNAs), binding to RNA-binding proteins, and undergoing translation into peptides. Activated M1 phenotype macrophages secrete matrix metalloproteinases to participate in softening of the cervix uteri to promote vaginal delivery. METHODS: In this study, the premature rupture of membranes (PROM) mouse model was used to analyze the role of macrophages in this process. Profiling of circRNAs was performed using a competing endogenous RNA microarray, and their functions were elucidated in vitro. Meanwhile, adipose tissue-derived stem cell-secreted extracellular vesicles (EVs) were applied as a vehicle to transport small interfering RNAs (siRNAs) targeting the circRNAs to demonstrate their biological function in vivo. RESULTS: The miRNA miR-1931 is dependent on the nuclear factor kappa-B (NF-κB) pathway but negatively regulates its activation by targeting the NF-κB signaling transducer TRAF6 to prevent polarization of M1 macrophages and inhibit matrix metalloproteinase (MMP) secretion. The host gene of circRNA B4GALNT1, also an NF-κB pathway-dependent gene, circularizes to form circRNA_0002047, which sponges miR-1931 to maintain NF-κB pathway activation and MMP secretion in vitro. In the PROM model, EVs loaded with siRNAs targeting circRNAs demonstrated that the circRNAs reduced miR-1931 expression to maintain NF-κB pathway activation and MMP secretion for accelerating PROM in vivo. CONCLUSIONS: Our data provide insights into understanding PROM pathogenesis and improving PROM treatment.

Flywheel eccentric overload exercises versus barbell half squats for basketball players: Which is better for induction of post-activation performance enhancement?

OBJECTIVE: This study compared the post-activation performance enhancement (PAPE) effects of a flywheel eccentric overload (FEOL) exercise and barbell half squats (BHS) on countermovement jump (CMJ) and 30 m sprint performance. METHODS: Twelve male collegiate competitive basketball players were enrolled in this study and they implemented two training protocols: barbell half squat (BHS) and flywheel eccentric overload (FEOL) training. The BHS protocol included three intensities of load: low (40% 1RM), medium (60% 1RM), and high (80% 1RM), with each intensity consisting of 5 sets of 3 repetitions. The FEOL protocol included three inertia intensities: low (0. 015 kg∙m2), medium (0.035 kg∙m2), and high (0.075 kg∙m2), with each intensity consisting of 3 sets of 6 repetitions. The measurement time points were before training (baseline) and at 3, 6, 9, and 12 minutes after training. A two-stage (stage-I and stage-II) randomized crossover design was used to determine the acute effects of both protocols on CMJ and sprint performance. RESULTS: At each training intensity, the jump height, jump peak power output (PPO), jump impulse and 30m sprint speed at 3, 6, 9, and 12 minutes after BHS and FEOL training did not change significantly compared to the baseline. A 2-way ANOVA analysis indicated significant main effects of rest intervals on jump height, jump PPO, and jump impulse, as well as 30m sprint speed. The interaction of the Time × protocol showed a significant effect on jump height between BHS and FEOL groups at high intensity in stage-I (F = 3.809, p = 0.016, df = 4) and stage-II (F = 3.044, p = 0.037, df = 4). And in high training intensity, the jump height at 3 (7.78 ± 9.90% increase, ES = 0.561), 6 (8.96 ± 12.15% increase, ES = 0.579), and 9 min (8.78 ± 11.23% increase, ES = 0.608) were enhanced in I-FEOL group compared with I-BHS group (F = 3.044, p = 0.037, df = 4). In stage-II, the impulse and sprint speed of the FEOL group were significantly higher than those of the BHS group at 6, 9, and 12 min under low (FEOL = 0.015kg∙m2, BHS = 40%1RM), medium(FEOL = 0.035kg∙m2, BHS = 60%1RM), and high (FEOL = 0.075kg∙m2, BHS = 80%1RM) intensities. Furthermore, the sprint speed of the two training protocols did not change at different time points. The interaction of Time × training intensity showed lower sprint speeds in the II-BHS group at a high intensity (BHS = 80%1RM) compared to low (BHS = 40%1RM) and medium (BHS = 60%1RM) training intensities, especially at 9 min and 12 min rest intervals. CONCLUSION: Although barbell half squat training and flywheel eccentric overload training did not provide a significant PAPE effect on explosive power (CMJ and sprint) in male basketball players, FEOL training showed a better potential effect on enhanced CMJ jump performance at the high training intensity.

Association of electroencephalogram epileptiform discharges during cardiac surgery with postoperative delirium: An observational study.

Background: Delirium is a frequent and serious complication following cardiac surgery involving cardiopulmonary bypass (CPB). Electroencephalography reflects the electrical activity of the cerebral cortex. The impact of electroencephalographic epileptiform discharges during cardiac surgery on postoperative delirium remains unclear. This study was designed to investigate the relationship between intraoperative epileptiform discharges and postoperative delirium in patients undergoing cardiac surgery. Methods: A total of 76 patients who underwent cardiac surgery under CPB were included. The baseline cognitive status was measured before surgery. Electroencephalograms were monitored continuously from entry into the operating room to the end of surgery. The presence of delirium was assessed through the Confusion Assessment Method or the Confusion Assessment Method for the Intensive Care Unit on the first 3 days after surgery. Univariate and multivariate logistic regression analyses were performed to evaluate the association between epileptiform discharges and delirium. Results: Delirium occurred in 31% of patients and epileptiform discharges were present in 26% of patients in the study. Patients with delirium had a higher incidence of epileptiform discharges (52.63% vs. 13.95%, P < 0.001) and longer durations of anesthesia and CPB (P = 0.023 and P = 0.015, respectively). In addition, patients with delirium had a longer length of hospital stay and a higher incidence of postoperative complications. Multivariate logistic regression analysis showed that age and epileptiform discharges were significantly associated with the incidence of postoperative delirium [odds ratio, 4.75 (1.26-17.92), P = 0.022; 5.00 (1.34-18.74), P = 0.017, respectively]. Conclusions: Postoperative delirium is significantly related to the occurrence of epileptiform discharges during cardiac surgery.

Hepatocyte-Specific Knock-Out of Nfib Aggravates Hepatocellular Tumorigenesis via Enhancing Urea Cycle.

Nuclear Factor I B (NFIB) has been reported to promote tumor growth, metastasis, and liver regeneration, but its mechanism in liver cancer is not fully elucidated. The present study aims to reveal the role of NFIB in hepatocellular carcinogenesis. In our study, we constructed hepatocyte-specific NFIB gene knockout mice with CRISPR/Cas9 technology (Nfib-/-; Alb-cre), and induced liver cancer mouse model by intraperitoneal injection of DEN/CCl4. First, we found that Nfib-/- mice developed more tumor nodules and had heavier livers than wild-type mice. H&E staining indicated that the liver histological severity of Nfib-/- group was more serious than that of WT group. Then we found that the differentially expressed genes in the tumor tissue between Nfib-/- mice and wild type mice were enriched in urea cycle. Furthermore, ASS1 and CPS1, the core enzymes of the urea cycle, were significantly upregulated in Nfib-/- tumors. Subsequently, we validated that the expression of ASS1 and CPS1 increased after knockdown of NFIB by lentivirus in normal hepatocytes and also promoted cell proliferation in vitro. In addition, ChIP assay confirmed that NFIB can bind with promoter region of both ASS1 and CPS1 gene. Our study reveals for the first time that hepatocyte-specific knock-out of Nfib aggravates hepatocellular tumor development by enhancing the urea cycle.