Mitochondrial calcium uniporter complex: Unveiling the interplay between its regulators and calcium homeostasis.

The mitochondrial calcium uniporter complex (MCUc), serving as the specific channel for calcium influx into the mitochondrial matrix, is integral to calcium homeostasis and cellular integrity. Given its importance, ongoing research spans various disease models to understand the properties of the MCUc in pathophysiological contexts, but reported a different conclusion. Therefore, this review delves into the profound connection between MCUc-mediated calcium transients and cellular signaling pathways, mitochondrial dynamics, metabolism, and cell death. Additionally, we shed light on the recent advancements concerning the structural intricacies and auxiliary components of the MCUc in both resting and activated states. Furthermore, emphasis is placed on novel extrinsic and intrinsic regulators of the MCUc and their therapeutic implications across a spectrum of diseases. Meanwhile, we employed molecular docking simulations and identified candidate traditional Chinese medicine components with potential binding sites to the MCUc, potentially offering insights for further research on MCUc modulation.

Prediction of myofascial pelvic pain syndrome based on random forest model.

Objective: The objective is to construct a random forest model for predicting the occurrence of Myofascial pelvic pain syndrome (MPPS) and compare its performance with a logistic regression model to demonstrate the superiority of the random forest model. Methods: We retrospectively analyze the clinical data of female patients who underwent pelvic floor screening due to chronic pelvic pain at the Pelvic Floor Rehabilitation Center of the Third Affiliated Hospital of Zhengzhou University from January 2021 to December 2023. A total of 543 female patients meeting the study's inclusion and exclusion criteria are randomly selected from this dataset and allocated to the MPPS group. Furthermore, 702 healthy female patients who underwent pelvic floor screening during routine physical examinations within the same timeframe are randomly selected and assigned to the non-MPPS group. Chi-square test and rank-sum test are used to select demographic variables, pelvic floor pressure assessment data variables, and modified Oxford muscle strength grading data for logistic univariate analysis. The selected variables are further subjected to multivariate logistic regression analysis, and a random forest model is also established. The predictive performance of the two models is evaluated by comparing their accuracy, sensitivity, specificity, precision, receiver operating characteristic (ROC) curve, and area under the curve (AUC) area. Results: Based on a dataset of 1245 cases, we implement the random forest algorithm for the first time in the screening of MPPS. In this investigation, the Logistic regression model forecasts the accuracy, sensitivity, specificity, and precision of MPPS at 69.96 %, 57.46 %, 79.63 %, and 68.57 % respectively, with an AUC of the ROC curve at 0.755. Conversely, the random forest prediction model exhibits accuracy, sensitivity, specificity, and precision rates of 87.11 %, 90.66 %, 90.91 %, and 83.51 % respectively, with an AUC of the ROC curve at 0.942. The random forest model showcases exceptional predictive performance during the initial screening of MPPS. Conclusion: The random forest model has exhibited exceptional predictive performance in the initial screening evaluation of MPPS disease. The development of this predictive framework holds significant importance in refining the precision of MPPS prediction within clinical environments and elevating treatment outcomes. This research carries profound global implications, given the potentially elevated misdiagnosis rates and delayed diagnosis proportions of MPPS on a worldwide scale, coupled with a potential scarcity of seasoned healthcare providers. Moving forward, continual refinement and validation of the model will be imperative to further augment the precision of MPPS risk assessment, thereby furnishing clinicians with more dependable decision-making support in clinical practice.

The factors of job crafting in emergency nurses: regression models versus qualitative comparative analysis.

BACKGROUND: Job crafting is defined as a series of proactive behaviors exhibited by employees in order to balance work resources and needs, which has a significant positive impact on the nurses. It is necessary to find the core factors that influence the job crafting, as emergency nurses deal with the most complex tasks, so as to improve their job satisfaction. OBJECTIVES: To investigate the core factors of job crafting among emergency nurses. METHODS: A cross-sectional design was used in the study. A total of 255 nurses were recruited from two hospitals in Zhengzhou and Shenzhen, China in December 2021. 255 nurses completed an online questionnaire. Hierarchical regression models and fsQCA models were used to explore the factors influencing job crafting among emergency nurses and helped us to identify core factors. RESULTS: The hierarchical regression model and the fsQCA model found that the occupational benefit, psychological empowerment, and research experience were the core factors affecting their job crafting. Job involvement was not significant in the regression model, but the QCA model indicated that it needs to be combined with other factors to impact on job crafting. The QCA model uncovered seven key conditional configurations that led to high and low job crafting among emergency nurses, explaining 80.0% of the results for high job crafting and 82.6% of the results for the low job crafting, respectively. CONCLUSIONS: The results of this study provide valuable insights into the job crafting experienced by emergency nurses. Junior emergency nurses should be granted a high level of psychological empowerment without assigning them overly complex tasks, such as research tasks, as these challenges can stop their job crafting. Intermediate and senior emergency nurses, on the other hand, can be assigned research tasks coupled with high psychological empowerment to enhance their job crafting.

Evaluation of G3BP1 in the prognosis of acute and acute-on-chronic liver failure after the treatment of artificial liver support system.

BACKGROUND: The increased expression of G3BP1 was positively correlated with the prognosis of liver failure. AIM: To investigate the effect of G3BP1 on the prognosis of acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) after the treatment of artificial liver support system (ALSS). METHODS: A total of 244 patients with ALF and ACLF were enrolled in this study. The levels of G3BP1 on admission and at discharge were detected. The validation set of 514 patients was collected to verify the predicted effect of G3BP1 and the viability of prognosis. RESULTS: This study was shown that lactate dehydrogenase (LDH), alpha-fetoprotein (AFP) and prothrombin time were closely related to the prognosis of patients. After the ALSS treatment, the patient' amount of decreased G3BP1 index in difference of G3BP1 between the value of discharge and admission (difG3BP1) < 0 group had a nearly 10-fold increased risk of progression compared with the amount of increased G3BP1 index. The subgroup analysis showed that the difG3BP1 < 0 group had a higher risk of progression, regardless of model for end-stage liver disease high-risk or low-risk group. At the same time, compared with the inflammatory marks [tumor necrosis factor-α, interleukin (IL)-1ß and IL-18], G3BP1 had higher discrimination and was more stable in the model analysis and validation set. When combined with AFP and LDH, concordance index was respectively 0.84 and 0.8 in training and validation cohorts. CONCLUSION: This study indicated that G3BP1 could predict the prognosis of ALF or ACLF patients treated with ALSS. The combination of G3BP1, AFP and LDH could accurately evaluate the disease condition and predict the clinical endpoint of patients.

GDI2 deletion alleviates neurodegeneration and memory loss in the 5xFAD mice model of Alzheimer's disease.

Accumulation of insoluble deposits of amyloid ß-peptide (Aß), derived from amyloid precursor protein (APP) processing, represents one of the major pathological hallmarks of Alzheimer's disease (AD). Perturbations in APP transport and hydrolysis could lead to increased Aß production. However, the precise mechanisms underlying APP transport remain elusive. The GDP dissociation inhibitor2 (GDI2), a crucial regulator of Rab GTPase activity and intracellular vesicle and membrane trafficking, was investigated for its impact on AD pathogenesis through neuron-specific knockout of GDI2 in 5xFAD mice. Notably, deficiency of GDI2 significantly ameliorated cognitive impairment, prevented neuronal loss in the subiculum and cortical layer V, reduced senile plaques as well as astrocyte activation in 5xFAD mice. Conversely, increased activated microglia and phagocytosis were observed in GDI2 ko mice. Further investigation revealed that GDI2 knockout led to more APP co-localized with the ER rather than the Golgi apparatus and endosomes in SH-SY5Y cells, resulting in decreased Aß production. Collectively, these findings suggest that GDI2 may regulate Aß production by modulating APP intracellular transport and localization dynamics. In summary, our study identifies GDI2 as a pivotal regulator governing APP transport and process implicated in AD pathology; thus highlighting its potential as an attractive pharmacological target for future drug development against AD.

AGK2 pre-treatment protects against thioacetamide-induced acute liver failure via regulating the MFN2-PERK axis and ferroptosis signaling pathway.

BACKGROUND: Acute liver failure (ALF) is an unpredictable and life-threatening critical illness. The pathological characteristic of ALF is massive necrosis of hepatocytes and lots of inflammatory cells infiltration which may lead to multiple organ failure. METHODS: Animals were divided into 3 groups, normal, thioacetamide (TAA, ALF model) and TAA + AGK2. Cultured L02 cells were divided into 5 groups, normal, TAA, TAA + mitofusin 2 (MFN2)-siRNA, TAA + AGK2, and TAA + AGK2 + MFN2-siRNA groups. The liver histology was evaluated with hematoxylin and eosin staining, inositol-requiring enzyme 1 (IRE1), activating transcription factor 6ß (ATF6ß), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) and phosphorylated-PERK (p-PERK). C/EBP homologous protein (CHOP), reactive oxygen species (ROS), MFN2 and glutathione peroxidase 4 (GPX4) were measured with Western blotting, and cell viability and liver chemistry were also measured. Mitochondria-associated endoplasmic reticulum membranes (MAMs) were measured by immunofluorescence. RESULTS: The liver tissue in the ALF group had massive inflammatory cell infiltration and hepatocytes necrosis, which were reduced by AGK2 pre-treatment. In comparison to the normal group, apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ in the TAA-induced ALF model group were significantly increased, which were decreased by AGK2 pre-treatment. The levels of MFN2 and GPX4 were decreased in TAA-induced mice compared with the normal group, which were enhanced by AGK2 pre-treatment. Compared with the TAA-induced L02 cell, apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ were further increased and levels of MFN2 and GPX4 were decreased in the MFN2-siRNA group. AGK2 pre-treatment decreased the apoptosis rate and levels of IRE1, ATF6ß, p-PERK, CHOP, ROS and Fe2+ and enhanced the protein expression of MFN2 and GPX4 in MFN2-siRNA treated L02 cell. Immunofluorescence observation showed that level of MAMs was promoted in the AGK2 pre-treatment group when compared with the TAA-induced group in both mice and L02 cells. CONCLUSIONS: The data suggested that AGK2 pre-treatment had hepatoprotective role in TAA-induced ALF via upregulating the expression of MFN2 and then inhibiting PERK and ferroptosis pathway in ALF.

[Research advances in the role of Rab GTPases in Alzheimer's disease].

Extracellular deposition of ß-amyloid (Aß) and intracellular hyperphosphorylated tau are the predominant pathological changes in Alzheimer's disease (AD). Increasing evidence demonstrates a critical role of a variety of small GTPases, namely Ras-related proteins (Rabs), in the pathogenesis of AD. As crucial regulators of intracellular membrane trafficking, alteration in Rab protein expression and function represents one of the primary factors contributing to the abnormal membrane trafficking in AD. Additionally, the Rab GTPases are also involved in the development of Aß, tau and other pathological changes associated with AD. In this article, we conduct a comprehensive review on the primary functions of multiple Rab proteins and their involvement in the pathogenesis of AD.

Bioinspired soft robots for deep-sea exploration.

The deep ocean, Earth's untouched expanse, presents immense challenges for exploration due to its extreme pressure, temperature, and darkness. Unlike traditional marine robots that require specialized metallic vessels for protection, deep-sea species thrive without such cumbersome pressure-resistant designs. Their pressure-adaptive forms, unique propulsion methods, and advanced senses have inspired innovation in designing lightweight, compact soft machines. This perspective addresses challenges, recent strides, and design strategies for bioinspired deep-sea soft robots. Drawing from abyssal life, it explores the actuation, sensing, power, and pressure resilience of multifunctional deep-sea soft robots, offering game-changing solutions for profound exploration and operation in harsh conditions.

Comparison of efficacy between laparoscopic pectopexy and laparoscopic high uterosacral ligament suspension in the treatment of apical prolapse-short term results.

To compare the clinical efficacy of laparoscopic pectopexy and laparoscopic high uterosacral ligament suspension in women suffering from apical prolapse. The clinical data of 170 patients with apical prolapse (POP-Q score ≥ II) treated in the Third Affiliated Hospital of Zhengzhou University from January 2018 to July 2020 were retrospectively analyzed to assess the clinical efficacy of three surgical methods [laparoscopic pectopexy with uterine preservation, laparoscopic pectopexy with hysterectomy, laparoscopic high uterosacral ligament suspension (LHUSLS) with hysterectomy]. Patients were divided into three groups depending on Surgical methods: laparoscopic uterine pectopexy group (n = 23), laparoscopic pectopexy with hysterectomy group (n = 78) and LHUSLS with hysterectomy group (n = 69). The POP-Q points before and after operation were analyzed. The operation-related indices, perioperative periods and post-operative complications were compared. 1. The operation time of laparoscopic uterine pectopexy group was the shortest (p < 0.05). There was no significant difference in the incidence of apical prolapse and new stress urinary incontinence among the three groups during the follow-up period (p > 0.05). 2. The POP-Q points (Aa, Ba, C) in the three groups were better than those before operation (p < 0.05). Laparoscopic pectopexy with hysterectomy group had better Ap, Bp and C points and a longer TVL than LHUSLS with hysterectomy group (p < 0.05). 3. The postoperative PFDI-20, PFIQ-7 and PISQ-12 scores of the three groups were significantly improved than those before operation (p < 0.05). The PISQ-12 scores in laparoscopic uterine pectopexy group were significantly higher than that in the other two groups one year after operation (p < 0.05). The study concludes that laparoscopic pectopexy and LHUSLS can significantly improve the quality of life and sexual function for patients with apical prolapse. One year after operation, laparoscopic pectopexy has a more satisfactory anatomical reduction than LHUSLS with hysterectomy. The laparoscopic uterine pectopexy group had lower postoperative complications and better sexual function than that with hysterectomy group. Laparoscopic pectopexy should be used for the treatment of apical prolapse (POP-Q score ≥ II) patients who aim to better clinical efficacy and sexual function improvement.

Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity.

OBJECTIVE: Acute liver failure (ALF) is characterized by severe liver dysfunction, rapid progression and high mortality and is difficult to treat. Studies have found that sulforaphane (SFN), a nuclear factor E2-related factor 2 (NRF2) agonist, has anti-inflammatory, antioxidant and anticancer effects, and has certain protective effects on neurodegenerative diseases, cancer and liver fibrosis. This paper aimed to explore the protective effect of SFN in ALF and it possible mechanisms of action. METHODS: Lipopolysaccharide and D-galactosamine were used to induce liver injury in vitro and in vivo. NRF2 agonist SFN and histone deacetylase 6 (HDAC6) inhibitor ACY1215 were used to observe the protective effect and possible mechanisms of SFN in ALF, respectively. Cell viability, lactate dehydrogenase (LDH), Fe2+, glutathione (GSH) and malondialdehyde (MDA) were detected. The expression of HDAC6, NRF2, glutathione peroxidase 4 (GPX4), acyl-CoA synthetase long-chain family member 4 (ACSL4) and solute carrier family 7 member 11 (SLC7A11) were detected by Western blotting and immunofluorescence. RESULTS: Our results show that NRF2 was activated by SFN. LDH, Fe2+, MDA and ACSL4 were downregulated, while GSH, GPX4 and SLC7A11 were upregulated by SFN in vitro and in vivo, indicating the inhibitory effect of SFN on ferroptosis. Additionally, HDAC6 expression was decreased in the SFN group, indicating that SFN could downregulate the expression of HDAC6 in ALF. After using the HDAC6 inhibitor, ACY1215, SFN further reduced HDAC6 expression and inhibited ferroptosis, indicating that SFN may inhibit ferroptosis by regulating HDAC6 activity. CONCLUSION: SFN has a protective effect on ALF, and the mechanism may include reduction of ferroptosis through the regulation of HDAC6. Please cite this article as: Zhang YQ, Shi CX, Zhang DM, Zhang LY, Wang LW, Gong ZJ. Sulforaphane, an NRF2 agonist, alleviates ferroptosis in acute liver failure by regulating HDAC6 activity. J Integr Med. 2023; 21(5): 464-473.

Effect of P53 nuclear localization mediated by G3BP1 on ferroptosis in acute liver failure.

This study investigated whether G3BP1 could regulate ferroptosis in hepatocytes during ALF by affecting the entry of P53 into the nucleus. Promoting G3BP1 expression could inhibit P53 entry by binding to the nuclear localization sequence of P53. The inhibition of SLC7A11 transcription was weakened after blocking of P53 binding to the promoter region of the SLC7A11 gene. The SLC7A11-GSH-GPX4 antiferroptotic pathway was subsequently activated, and the level of ferroptosis in ALF hepatocytes was inhibited.

PANoptosis: A Cell Death Characterized by Pyroptosis, Apoptosis, and Necroptosis.

PANoptosis is a new cell death proposed by Malireddi et al in 2019, which is characterized by pyroptosis, apoptosis and necroptosis, but cannot be explained by any of them alone. The interaction between pyroptosis, apoptosis and necroptosis is involved in PANoptosis. In this review, from the perspective of PANoptosis, we focus on the relationship between pyroptosis, apoptosis and necroptosis, the key molecules in the process of PANoptosis and the formation of PANoptosome, as well as the role of PANoptosis in diseases. We aim to understand the mechanism of PANoptosis and provide a basis for targeted intervention of PANoptosis-related molecules to treat human diseases.

Stress granules inhibit endoplasmic reticulum stress-mediated apoptosis during hypoxia-induced injury in acute liver failure.

BACKGROUND: Stress granules (SGs) could be formed under different stimulation to inhibit cell injury. AIM: To investigate whether SGs could protect hepatocytes from hypoxia-induced damage during acute liver failure (ALF) by reducing endoplasmic reticulum stress (ERS) mediated apoptosis. METHODS: The agonist of SGs, arsenite (Ars) was used to intervene hypoxia-induced hepatocyte injury cellular model and ALF mice models. Further, the siRNA of activating transcription factor 4 (ATF4) and SGs inhibitor anisomycin was then used to intervene in cell models. RESULTS: With the increase of hypoxia time from 4 h to 12 h, the levels of HIF-1α, ERS and apoptosis gradually increased, and the expression of SGs marker G3BP1 and TIA-1 was increased and then decreased. Compared with the hypoxia cell model group and ALF mice model, the levels of HIF-1α, apoptosis and ERS were increased in the Ars intervention group. After siRNA-ATF4 intervention, the level of SGs in cells increased, and the levels of HIF-1α, ERS and apoptosis decreased. Compared with the siRNA-ATF4 group, the levels of G3BP1 in the siRNA-ATF4+anisomycin group were decreased, and the levels of HIF-1α, ERS and apoptosis were increased. Moreover, compared with the ALF group, the degree of liver injury and liver function, the levels of HIF-1α, ERS and apoptosis in the Ars intervention group were decreased, the level of SGs was increased. CONCLUSION: SGs could protect hepatocytes from hypoxia-induced damage during ALF by reducing ERS-mediated apoptosis.

NOD2-mediated HDAC6/NF-κb signalling pathway regulates ferroptosis induced by extracellular histone H3 in acute liver failure.

Acute liver failure (ALF) is life-threatening and often associated with high mortality rates. The aim of the present study was to investigate whether extracellular histone H3 could induce ferroptosis in hepatic macrophages in ALF and explore its potential mechanism. RAW264.7 macrophages and C57BL/6 mice were used in this study. LPS, D-galactosamine (D-Gal), histone H3, histone H3 antibody, NOD2 agonist Muramyl Dipeptide (MDP) and HDAC6-siRNA were administered in this study. The key molecules of ferroptosis, NOD2, HDAC6 and the NF-κb pathway, were detected. In vitro, histone H3 was released into the extracellular environment from cell nucleus after LPS exposure. In addition, histone H3 could induce ferroptosis in RAW264.7 macrophages with increased level of Fe2+ and ROS and decreased levels of GPX4 and GSH. MDP further aggravated ferroptosis in RAW264.7 macrophages stimulated by histone H3, which was accompanied by elevated NOD2, HDAC6, p-P65 and IκBα. HDAC6-siRNA ameliorated ferroptosis in RAW264.7 macrophages induced by histone H3, which was accompanied by decreased levels of HDAC6, p-P65 and IκBα. However, HDAC6-siRNA did not alter NOD2 levels in RAW264.7 macrophages administered histone H3. In vivo, the levels of NOD2, HDAC6 the NF-κb pathway and ferroptosis were increased in ALF mice, which were downregulated by histone H3 antibody and upregulated by histone H3. Extracellular histone H3 could induce ferroptosis in hepatic macrophages in ALF by regulating theNOD2-mediated HDAC6/NF-κb signalling pathway.

SIRT3 inhibitor 3-TYP exacerbates thioacetamide-induced hepatic injury in mice.

The purpose of the study was to explore the effects of SIRT3 inhibitor 3-TYP on acute liver failure (ALF) in mice and its underlying mechanism. The mice were treated with thioacetamide (TAA, 300 mg/kg) for inducing ALF model. 3-TYP (50 mg/kg) was administered 2 h prior to TAA. The liver histological changes were measured by HE staining. Blood samples were collected for analysis of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). MDA and GSH were used to evaluate the oxidative stress of liver. The expression levels of inflammatory cytokines (TNF-α and IL-1ß) were measured by ELISA and Western blotting. The cell type expression of IL-1ß in liver tissue was detected by immunofluorescent staining. The expression of SIRT3, MnSOD, ALDH2, MAPK, NF-κB, Nrf2/HO-1, p-elF2α/CHOP, and cleaved caspase 3 was determined by Western blotting. TUNEL staining was performed to detect the apoptosis cells of liver tissues. 3-TYP exacerbated the liver injury of ALF mice. 3-TYP increased the inflammatory responses and activation of MAPK and NF-κB pathways. In addition, 3-TYP administration enhanced the damage of oxidative stress, endoplasmic reticulum stress, and promoted hepatocyte apoptosis in ALF mice. 3-TYP exacerbates thioacetamide-induced hepatic injury in mice. Activation of SIRT3 could be a promising target for the treatment of ALF.

Effect of Nrf2 on Phenotype Changes of Macrophages in the Anterior Vaginal Wall of Women With Pelvic Organ Prolapse.

OBJECTIVE: The aim of this study was to observe the effect of nuclear factor-erythroid 2-related factor 2 (Nrf2) on the phenotype changes of macrophages in the anterior vaginal wall of patients with pelvic organ prolapse (POP). METHODS: The tissues of the anterior vaginal wall of the control group (n = 30) and POP groups (n = 60) were collected during operation. The expressions of Nrf2, iNOS (representative factor of M1 macrophages), and CD206 (representative factor of M2 macrophages) were determined by immunohistochemical staining and Western blot. Morphological changes and collagen distribution of the anterior vaginal wall were observed by hematoxylin-eosin staining and Masson trichrome staining. RESULTS: Compared with the control group, the expression levels of Nrf2 and CD206 protein in the anterior vaginal wall tissues of the POP groups were significantly decreased ( P < 0.05), and were negatively proportional to the degree of prolapse ( P < 0.05). The expression of iNOS was significantly increased and was directly proportional to the degree of prolapse ( P < 0.05). Hematoxylin-eosin staining and Masson trichrome staining showed that the collagen fibers are more sparsely arranged and disordered in the POP group than the control. CONCLUSIONS: In patients with POP, the expression of antioxidant factor Nrf2 is reduced in the vaginal anterior wall tissues and the antioxidant capacity is weakened, leading to the blocked polarization of macrophages and the accumulation of a large number of M1 macrophages in the tissue, affecting the occurrence and development of POP.

Fusobacterium nucleatum promotes the development of acute liver failure by inhibiting the NAD+ salvage metabolic pathway.

BACKGROUND: Acute liver failure (ALF) patients are often accompanied by severe energy metabolism abnormalities and intestinal microecological imbalance. The intestinal mucosal barrier is severely damaged. Intestinal endotoxin can induce intestinal endotoxemia through the "Gut-Liver axis". More and more evidence shows that members of the gut microbiota, especially Fusobacterium nucleatum (F. nucleatum), are related to inflammatory bowel disease, but whether F. nucleatum is involved in the development of ALF and whether it affects the liver energy metabolism is unclear. METHODS: This study first detected the abundance of F. nucleatum and its effect on ALF disease, and explored whether F. nucleatum aggravated liver inflammation in vitro and in vivo. RESULTS: Our data showed that liver tissues of ALF patients contained different abundances of F. nucleatum, which were related to the degree of liver inflammation. In addition, we found that F. nucleatum infection affected the energy metabolism of the liver during the development of ALF, inhibited the synthesis pathway of nicotinamide adenine dinucleotide (NAD+)'s salvage metabolism, and promoted inflammatory damage in the liver. In terms of mechanism, F. nucleatum inhibited NAD+ and the NAD+-dependent SIRT1/AMPK signaling pathway, and promoted liver damage of ALF. CONCLUSIONS: Fusobacterium nucleatum coordinates a molecular network including NAD+ and SIRT1 to control the progress of ALF. Detection and targeting of F. nucleatum and its related pathways may provide valuable insights for the treatment of ALF.

Sirtuin1 attenuates acute liver failure by reducing reactive oxygen species via hypoxia inducible factor 1α.

BACKGROUND: The occurrence and development of acute liver failure (ALF) is closely related to a series of inflammatory reactions, such as the production of reactive oxygen species (ROS). Hypoxia inducible factor 1α (HIF-1α) is a key factor that regulates oxygen homeostasis and redox, and the stability of HIF-1α is related to the ROS level regulated by Sirtuin (Sirt) family. The activation of Sirt1 will lead to a powerful antioxidant defense system and therapeutic effects in liver disease. However, little is known about the relationship between HIF-1α and Sirt1 in the process of ALF and the molecular mechanism. AIM: To investigate whether HIF-1α may be a target of Sirt1 deacetylation and what the effects on ALF are. METHODS: Mice were administrated lipopolysaccharide (LPS)/D-gal and exposed to hypoxic conditions as animal model, and resveratrol was used as an activator of Sirt1. The cellular model was established with L02 cells stimulated by LPS. N-acetyl-L-cysteine was used to remove ROS, and the expression of Sirt1 was inhibited by nicotinamide. Western blotting was used to detect Sirt1 and HIF-1α activity and related protein expression. The possible signaling pathways involved were analyzed by immunofluorescent staining, co-immunoprecipitation, dihydroethidium staining, and Western blotting. RESULTS: Compared with mice stimulated with LPS alone, the expression of Sirt1 decreased, the level of HIF-1α acetylation increased in hypoxic mice, and the levels of carbonic anhydrase 9 and Bcl-2-adenovirus E1B interacting protein 3 increased significantly, which was regulated by HIF-1α, indicating an increase of HIF-1α activity. Under hypoxia, the down-regulation of Sirt1 activated and acetylated HIF-1α in L02 cells. The inhibition of Sirt1 significantly aggravated this effect and the massive production of ROS. The regulation of ROS was partly through peroxisome proliferator-activated receptor alpha or AMP-activated protein kinase. Resveratrol, a Sirt1 activator, effectively relieved ALF aggravated by hypoxia, the production of ROS, and cell apoptosis. It also induced the deacetylation of HIF-1α and inhibited the activity of HIF-1α. CONCLUSION: Sirt1 may have a protective effect on ALF by inducing HIF-1α deacetylation to reduce ROS.

Effects of miR-363 on the Biological Activities of Eutopic Endometrial Stromal Cells in Endometriosis.

EMs is a kind of benign disease with certain malignant behaviors. The adhesion, invasive growth, and angiogenesis of ectopic endometrial cells are the pathological basis of EMs occurrence, but its etiology and pathogenesis have not been completely illustrated yet. In our research, we aim to investigate the role of miR-363 in the pathogenesis of endometriosis. Real-time quantitative PCR was used to detect the expression of miR-363 before and after ESC/NSC transfection. CCK-8, flow cytometry, and transwell assay were used to detect the effect of the miR-363 expression on cell proliferation, apoptosis, and invasion. The effects of the miR-363 expression on the contents of Fas/APO-1 and ICAM-1 in cell culture supernatant were detected by ELISA. qRT-PCR and WB assay were used to detect the effects of the miR-363 expression on the mRNA and protein expression levels of ICAM-1, MMP-7, and VEGF in ESC. The increased expression of miR-363 could inhibit the proliferation and invasion of ESC, promote apoptosis, and inhibit the secretion of FAS/APO-1 and ICAM-1. The knockdown expression of miR-363 promoted proliferation and invasion of NSC, inhibited apoptosis, and promoted secretion of FAS/APO-1 and ICAM-1. VCAM-1, VEGF, and MMP-7 were detected in ESCs before transfection. The protein expression level was higher than that of NSCs. Compared with pretransfection, the protein levels of VCAM-1, VEGF, and MMP-7 in the M-363 group were significantly downregulated. The downregulated expression of miR-363 was associated with a stronger cell proliferation ability, a lower cell apoptosis rate, and a stronger ESC. Migration is associated with invasiveness, proliferation, angiogenesis, and immune escape. The low expression of miR-363 promotes endogenesis through posttranscriptional regulation of target genes VCAM-1, MMP-7, and VEGF. The differential expression of miR-363 between ESC and NSC may be an important factor in the many biological differences between ESC and NSC.