Machine Learning Algorithms for the Diagnosis of Class III Malocclusions in Children.

Artificial intelligence has been applied to medical diagnosis and decision-making but it has not been used for classification of Class III malocclusions in children. OBJECTIVE: This study aims to propose an innovative machine learning (ML)-based diagnostic model for automatically classifies dental, skeletal and functional Class III malocclusions. METHODS: The collected data related to 46 cephalometric feature measurements from 4-14-year-old children (n = 666). The data set was divided into a training set and a test set in a 7:3 ratio. Initially, we employed the Recursive Feature Elimination (RFE) algorithm to filter the 46 input parameters, selecting 14 significant features. Subsequently, we constructed 10 ML models and trained these models using the 14 significant features from the training set through ten-fold cross-validation, and evaluated the models' average accuracy in test set. Finally, we conducted an interpretability analysis of the optimal model using the ML model interpretability tool SHapley Additive exPlanations (SHAP). RESULTS: The top five models ranked by their area under the curve (AUC) values were: GPR (0.879), RBF SVM (0.876), QDA (0.876), Linear SVM (0.875) and L2 logistic (0.869). The DeLong test showed no statistical difference between GPR and the other models (p > 0.05). Therefore GPR was selected as the optimal model. The SHAP feature importance plot revealed that he top five features were SN-GoMe (the ratio of the length of the anterior skull base SN to that of the mandibular base GoMe), U1-NA (maxillary incisor angulation to NA plane), Overjet (the distance between two lines perpendicular to the functional occlusal plane from U1 and L), ANB (the difference between angles SNA and SNB), and AB-NPo (the angle between the AB and N-Pog line). CONCLUSIONS: Our findings suggest that ML models based on cephalometric data could effectively assist dentists to classify dental, functional and skeletal Class III malocclusions in children. In addition, features such as SN_GoMe, U1_NA and Overjet can as important indicators for predicting the severity of Class III malocclusions.

Targeting 5-Hydroxytryptamine Receptor 1A in the Portal Vein to Decrease Portal Hypertension.

BACKGROUNDS & AIMS: Portal hypertension (PH) is one of the most frequent complications of chronic liver disease. The peripheral 5-hydroxytryptamine (5-HT) level was increased in cirrhotic patients. We aimed to elucidate the function and mechanism of 5-HT receptor 1A (HTR1A) in the portal vein (PV) on PH. METHODS: PH models were induced by thioacetamide injection, bile duct ligation, or partial PV ligation. HTR1A expression was detected using real-time polymerase chain reaction, in situ hybridization, and immunofluorescence staining. In situ intraportal infusion was used to assess the effects of 5-HT, the HTR1A agonist 8-OH-DPAT, and the HTR1A antagonist WAY-100635 on portal pressure (PP). Htr1a-knockout (Htr1a-/-) rats and vascular smooth muscle cell (VSMC)-specific Htr1a-knockout (Htr1aΔVSMC) mice were used to confirm the regulatory role of HTR1A on PP. RESULTS: HTR1A expression was significantly increased in the hypertensive PV of PH model rats and cirrhotic patients. Additionally, 8-OH-DPAT increased, but WAY-100635 decreased, the PP in rats without affecting liver fibrosis and systemic hemodynamics. Furthermore, 5-HT or 8-OH-DPAT directly induced the contraction of isolated PVs. Genetic deletion of Htr1a in rats and VSMC-specific Htr1a knockout in mice prevented the development of PH. Moreover, 5-HT triggered adenosine 3',5'-cyclic monophosphate pathway-mediated PV smooth muscle cell contraction via HTR1A in the PV. We also confirmed alverine as an HTR1A antagonist and demonstrated its capacity to decrease PP in rats with thioacetamide-, bile duct ligation-, and partial PV ligation-induced PH. CONCLUSIONS: Our findings reveal that 5-HT promotes PH by inducing the contraction of the PV and identify HTR1A as a promising therapeutic target for attenuating PH. As an HTR1A antagonist, alverine is expected to become a candidate for clinical PH treatment.

Oxidative stress promotes liver fibrosis by modulating the microRNA-144 and SIN3A-p38 pathways in hepatic stellate cells.

Background & Aims: Reactive oxygen species (ROS) act as modulators triggering cellular dysfunctions and organ damage including liver fibrosis in which hepatic stellate cell (HSC) activation plays a key role. Previous studies suggest that microRNA-144 (miR-144) acts as a pro-oxidant molecule; however, whether and how miR-144 affects HSC activation and liver fibrosis remain unknown. Methods: Carbon tetrachloride (CCl4) and bile duct ligation (BDL)-induced experimental liver fibrosis models were used. Hepatic miR-144 expression was analyzed by miRNA in situ hybridization with RNAscope probe. The in vivo effects of silencing or overexpressing miR-144 were examined with an adeno-associated virus 6 (AAV6) carrying miR-144 inhibitor or mimics in fibrotic mouse experimental models. Results: In this study, we demonstrated that ROS treatment significantly upregulated miR-144 in HSCs, which further promoted HSC activation in vitro. Interestingly, miR-144 was preferentially elevated in HSCs of experimental liver fibrosis in mice and in human liver fibrotic tissues. Furthermore, in vivo loss or gain-of-function experiments via AAV6 carrying miR-144 antagomir or agomir revealed that blockade of miR-144 in HSCs mitigated, while overexpression of miR-144 in HSCs accelerated the development of experimental liver fibrosis. Mechanistically, SIN3 transcription regulator family member A (SIN3A), a transcriptional repressor, was identified to be the target of miR-144 in HSCs. MiR-144 downregulated Sin3A, and in line with this result, specific knockdown of Sin3a in HSCs remarkedly activated p38 MAPK signaling pathway to promote HSC activation, eventually exacerbating liver fibrosis. Conclusions: Oxidative stress-driven miR-144 fuels HSC activation and liver fibrogenesis by limiting the SIN3A-p38 axis. Thus, a specific inhibition of miR-144 in HSCs could be a novel therapeutic strategy for the treatment of liver fibrosis.

Chemical constituents of Penicillium ferraniaense GE-7 and their cytotoxicities.

Phytochemical investigation on the plant endophytic fungus Penicillium ferraniaense GE-7 led to the isolation of 18 compounds including one new α-pyrone derivative, peniferranige A (1). The structure including the absolute configuration of compound 1 was elucidated by NMR, HRMS, and ECD data. Demethoxyfumitremorgin C (16) and meleagrin (17) possessed moderate activities against the human lung cancer cell line H1975 with IC50 values of 28.52 ± 1.07 and 13.94 ± 1.92 µM, respectively.

miR-541 is associated with the prognosis of liver cirrhosis and directly targets JAG2 to inhibit the activation of hepatic stellate cells.

BACKGROUND: The activation of hepatic stellate cells (HSCs) has been emphasized as a leading event of the pathogenesis of liver cirrhosis, while the exact mechanism of its activation is largely unknown. Furthermore, the novel non-invasive predictors of prognosis in cirrhotic patients warrant more exploration. miR-541 has been identified as a tumor suppressor in hepatocellular carcinoma and a regulator of fibrotic disease, such as lung fibrosis and renal fibrosis. However, its role in liver cirrhosis has not been reported. METHODS: Real-time PCR was used to detect miR-541 expression in the liver tissues and sera of liver cirrhosis patients and in the human LX-2. Gain- and loss-of-function assays were performed to evaluate the effects of miR-541 on the activation of LX-2. Bioinformatics analysis and a luciferase reporter assay were conducted to investigate the target gene of miR-541. RESULTS: miR-541 was downregulated in the tissues and sera of patients with liver cirrhosis, which was exacerbated by deteriorating disease severity. Importantly, the lower expression of miR-541 was associated with more episodes of complications including ascites and hepatic encephalopathy, a shorter overall lifespan, and decompensation-free survival. Moreover, multivariate Cox's regression analysis verified lower serum miR-541 as an independent risk factor for liver-related death in cirrhotic patients (HR = 0.394; 95% CI: 0.164-0.947; P = 0.037). miR-541 was also decreased in LX-2 cells activated by TGF-ß and the overexpression of miR-541 inhibited the proliferation, activation and hydroxyproline secretion of LX-2 cells. JAG2 is an important ligand of Notch signaling and was identified as a direct target gene of miR-541. The expression of JAG2 was upregulated in the liver tissues of cirrhotic patients and was inversely correlated with miR-541 levels. A rescue assay further confirmed that JAG2 was involved in the function of miR-541 when regulating LX-2 activation and Notch signaling. CONCLUSIONS: Dysregulation of miR-541/JAG2 axis might be a as a new mechanism of liver fibrosis, and miR-541 could serve as a novel non-invasive biomarker and therapeutic targets for liver cirrhosis.

High CTCF expression mediated by FGD5-AS1/miR-19a-3p axis is associated with immunosuppression and pancreatic cancer progression.

The most common reason for cancer-related death globally is predicted to be pancreatic cancer (PC), one of the deadliest cancers. The CCCTC-binding factor (CTCF) regulates the three-dimensional structure of chromatin, was reported to be highly regulated in various malignancies. However, the underlying biological functions and possible pathways via which CTCF promotes PC progression remain unclear. Herein, we examined the CTCF function in PC and discovered that CTCF expression in PC tissues was significantly raised compared to neighboring healthy tissues. Additionally, Kaplan-Meier survival analysis demonstrated a strong connection between elevated CTCF expression and poor patient prognosis. A study of the ROC curve (receiver operating characteristic) revealed an AUC value for CTCF of 0.968. Subsequent correlation analysis exhibited a strong relationship between immunosuppression and CTCF expression in PC. CTCF knockdown significantly inhibited the malignant biological process of PC in vitro and in vivo, suggesting that CTCF may be a potential PC treatment target. We also identified the FGD5 antisense RNA 1 (FGD5-AS1)/miR-19a-3p axis as a possible upstream mechanism for CTCF overexpression. In conclusion, our data suggest that ceRNA-mediated CTCF overexpression contributes to the suppression of anti-tumor immune responses in PC and could be a predictive biomarker and potential PC treatment target.

Three-dimensional analysis of the morphological changes of the craniofacial jaw and condyle in patients with idiopathic condylar resorption.

In this study we aim to describe the three-dimensional analysis of condylar deformation of the temporomandibular joint (TMJ) and morphological changes of the craniofacial jaw in patients with idiopathic condylar resorption (ICR). We also compare those with a control group that is healthy and matched for age and gender. Cone-beam computed tomography (CBCT) and cephalometric radiograph (X-ray) were conducted and analysis of craniofacial measurement, condylar width, length, height, and condylar axial angle changes were done three-dimensionally using ProPlan CMF™ 3.0 software (Materialise). The craniofacial jaw measurements of the ICR patients were significantly different than the control group and the significant changes in the mandible can be seen in ICR patients according to the results of this study. The results of smaller condylar width and height in the ICR group reflect the smaller size of the condyle compared with an unaffected condyle. Also, both right and left sagittal condylar angles (p = 0.001 and p = 0.003), respectively, and axial condylar angles (p = 0.01 and p = 0.02), respectively, displayed significant differences between the two groups. In conclusion, the vertical development of the condyle decreased along with reduced measurements in the width and height of the condyle in ICR patients, and differences in the morphology of the craniofacial jaw and condylar angles were observed between study groups.

BHLHE40, a potential immune therapy target, regulated by FGD5-AS1/miR-15a-5p in pancreatic cancer.

Pancreatic cancer, as one of the neoplasms with the highest degree of malignancy, has become a main disease of concerns in recent years. BHLHE40, a critical transcription factor for remodeling of the tumor immune microenvironment, has been described to be substantially increased in a variety of tumor-associated immune cells. Nevertheless, the pro-cancer biological functions and underlying molecular mechanisms of BHLHE40 for pancreatic cancer and its unique microenvironment are unclear. Hereby, we investigated the pro-oncogenic role of BHLHE40 in the pancreatic cancer microenvironment by bioinformatics analysis and cell biology experiments and determined that the expression of BHLHE40 was obviously elevated in pancreatic cancer tissues than in adjacent normal tissues. In parallel, Kaplan-Meier survival analysis unveiled that lower expression of BHLHE40 was strongly associated with better prognosis of patients. Receiver operating characteristic (ROC) curve analysis confirmed the accuracy of the BHLHE40-related prediction model. Subsequent, spearman correlation analysis observed that higher expression of BHLHE40 might be involved in immunosuppression of pancreatic cancer. Silencing of BHLHE40 could inhibit proliferation, invasion, and apoptosis of pancreatic cancer in vitro and in vivo, implying that BHLHE40 is expected to be a potential therapeutic target for pancreatic cancer. In addition, we explored and validated the FGD5-AS1/miR-15a-5p axis as a potential upstream regulatory mode for high expression of BHLHE40 in pancreatic cancer. In summary, our data showed that ceRNA involved in the regulation of BHLHE40 contributes to the promotion of immunosuppressive response in pancreatic and is expected to be a diagnostic marker and potential immunotherapeutic target for pancreatic cancer.

Automated Sagittal Skeletal Classification of Children Based on Deep Learning.

Malocclusions are a type of cranio-maxillofacial growth and developmental deformity that occur with high incidence in children. Therefore, a simple and rapid diagnosis of malocclusions would be of great benefit to our future generation. However, the application of deep learning algorithms to the automatic detection of malocclusions in children has not been reported. Therefore, the aim of this study was to develop a deep learning-based method for automatic classification of the sagittal skeletal pattern in children and to validate its performance. This would be the first step in establishing a decision support system for early orthodontic treatment. In this study, four different state-of-the-art (SOTA) models were trained and compared by using 1613 lateral cephalograms, and the best performance model, Densenet-121, was selected was further subsequent validation. Lateral cephalograms and profile photographs were used as the input for the Densenet-121 model, respectively. The models were optimized using transfer learning and data augmentation techniques, and label distribution learning was introduced during model training to address the inevitable label ambiguity between adjacent classes. Five-fold cross-validation was conducted for a comprehensive evaluation of our method. The sensitivity, specificity, and accuracy of the CNN model based on lateral cephalometric radiographs were 83.99, 92.44, and 90.33%, respectively. The accuracy of the model with profile photographs was 83.39%. The accuracy of both CNN models was improved to 91.28 and 83.98%, respectively, while the overfitting decreased after addition of label distribution learning. Previous studies have been based on adult lateral cephalograms. Therefore, our study is novel in using deep learning network architecture with lateral cephalograms and profile photographs obtained from children in order to obtain a high-precision automatic classification of the sagittal skeletal pattern in children.

Enzyme coordination conferring stable monodispersity of diverse metal-organic frameworks for photothermal/starvation therapy.

The agglomeration of metal-organic frameworks (MOFs) has long been a problem, and achieving stable monodispersity in water remains a great challenge. This paper reports a universal strategy that functionalizes MOFs by using an endogenous bioenzyme namely glucose oxidase (GOx), to achieve stable water monodispersity, and integrates it as a highly efficient nanoplatform for cancer synergistic therapy. Phenolic hydroxyl groups in GOx chain confers robust coordination interactions with MOFs, which not only endows stable monodispersion in water, but also provides many reactive sites for further modification. Silver nanoparticles are uniformly deposited onto MOFs@GOx to achieve high conversion efficiency from near-infrared light to heat, resulting in an effective starvation and photothermal synergistic therapy model. In vitro and in vivo experiments confirm excellent therapeutic effect at very low doses without using any chemotherapeutics. In addition, the nanoplatform generates large amounts of reactive oxygen species, induces heavy cell apoptosis, and demonstrates the first experimental example to effectively inhibit cancer migration. Our universal strategy enables stable monodispersity of various MOFs via GOx functionalization and establishes a non-invasive platform for efficient cancer synergistic therapy.

Single-cell RNA-seq revealing the immune features of donor liver during liver transplantation.

Immune cells, including T and B cells, are key factors in the success of liver transplantation. And the repertoire of T cells and B cells plays an essential function in mechanism of the immune response associated with organ transplantation. An exploration of their expression and distribution in donor organs could contribute to a better understanding of the altered immune microenvironment in grafts. In this study, using single-cell 5' RNA sequence and single-cell T cell receptor (TCR)/B cell receptor (BCR) repertoire sequence, we profiled immune cells and TCR/BCR repertoire in three pairs of donor livers pre- and post-transplantation. By annotating different immune cell types, we investigated the functional properties of monocytes/Kupffer cells, T cells and B cells in grafts. Bioinformatic characterization of differentially expressed genes (DEGs) between the transcriptomes of these cell subclusters were performed to explore the role of immune cells in inflammatory response or rejection. In addition, we also observed shifts in TCR/BCR repertoire after transplantation. In conclusion, we profiled the immune cell transcriptomics and TCR/BCR immune repertoire of liver grafts during transplantation, which may offer novel strategies for monitoring recipient immune function and treatment of rejection after liver transplantation.

ASPP2 suppresses tumour growth and stemness characteristics in HCC by inhibiting Warburg effect via WNT/ß-catenin/HK2 axis.

Abnormal energy metabolism is one of the characteristics of tumours. In the last few years, more and more attention is being paid to the role and regulation of tumour aerobic glycolysis. Cancer cells display enhanced aerobic glycolysis, also known as the Warburg effect, whereby tumour cells absorb glucose to produce a large amount of lactic acid and energy under aerobic conditions to favour tumour proliferation and metastasis. In this study, we report that the haploinsufficient tumour suppressor ASPP2, can inhibit HCC growth and stemness characteristics by regulating the Warburg effect through the WNT/ß-catenin pathway. we performed glucose uptake, lactate production, pyruvate production, ECAR and OCR assays to verify ASPP2 can inhibit glycolysis in HCC cells. The expression of ASPP2 and HK2 was significantly inversely correlated in 80 HCC tissues. Our study reveals downregulation of ASPP2 can promote the aerobic glycolysis metabolism pathway, increasing HCC proliferation, glycolysis metabolism, stemness and drug resistance. This ASPP2-induced inhibition of glycolysis metabolism depends on the WNT/ß-catenin pathway. ASPP2-regulated Warburg effect is associated with tumour progression and provides prognostic value. and suggest that may be promising as a new therapeutic strategy in HCC.

Dimethyl fumarate protects against hepatic ischemia-reperfusion injury by alleviating ferroptosis via the NRF2/SLC7A11/HO-1 axis.

Dimethyl fumarate (DMF), a therapeutic agent for relapsing-remitting multiple sclerosis, has cytoprotective and antioxidant effects. Ferroptosis, a pathological cell death process, is recently shown to play a vital part in ischemia-reperfusion injury (IRI). This study aimed to unveil the suppressive role of DMF on ferroptosis in liver IRI. The anti-ferroptosis effect of DMF on hepatic IRI was investigated using a liver IRI mouse model and a hypoxia-reoxygenation injury (HRI) model in alpha mouse liver (AML12) cells. Serum transaminase concentrations reflected liver function. Hematoxylin and eosin staining was used to assess liver damage. Cell viability was evaluated utilizing the CCK-8 assay. Malondialdehyde (MDA), the reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, and BODIPY 581/591C11 were measured to estimate the injury caused by lipid peroxidation. Western blotting and real-time polymerase chain reaction (RT-PCR) were performed to explore the underlying molecular mechanisms. We demonstrated the anti-ferroptosis effects of DMF both in vivo and in vitro. DMF treatment ameliorated hepatic IRI. KEGG enrichment analysis and transmission electron microscopy revealed a close relationship between ferroptosis and liver IRI. Furthermore, DMF protected against HRI by inhibiting ferroptosis via activating the nuclear factor E2-related factor 2 (NRF2) pathway. Interestingly, NRF2 knockdown notably decreased the expression of SLC7A11 and HO-1 and blocked the anti-ferroptosis effects of DMF. DMF inhibits ferroptosis by activating the NRF2/SLC7A11/HO-1 axis and exerts a protective effect against hepatic IRI.

Transverse differences between cleft lip and palate and non-cleft palate with skeletal Class III malocclusion using buccolingual inclination: a cone-beam computed tomography retrospective study.

BACKGROUND: The purpose of this study was to evaluate the differences between buccolingual inclination (BI) of maxillary posterior teeth in patients with cleft lip and palate (CLP) and non-cleft palate with skeletal Class III malocclusion. We propose a method of maxillary expansion which is more suitable for patients with CLP. METHODS: For this retrospective study, 40 patients with CLP and 21 patients with skeletal Class III malocclusion were selected. The CLP group was divided into the unilateral cleft lip and palate (UCLP) and bilateral cleft lip and palate (BCLP) groups. The BI of the maxillary first premolar (BI4), maxillary second premolar (BI5) and first molar (BI6) were measured using cone-beam computed tomography, and the differences between them were compared and analyzed by Student's t-test. RESULTS: There were significant differences between cleft side BI4 and non-cleft side BI4 in the UCLP group, BI5 in the BCLP group, BI4 and BI5 in all CLP groups and the skeletal Class III malocclusion group. BI6 was similar across all three groups. CONCLUSIONS: The premolars of patients with CLP do not exhibit the same regularity as those with Class III malocclusion; this may be related to surgical scarring of the cleft palate. Greater attention should be paid to the correction of BI in the maxillary expansion of patients with CLP.

Polydatin ameliorates hepatic ischemia-reperfusion injury by modulating macrophage polarization.

BACKGROUND: Polydatin, a glucoside of resveratrol, has been shown to have protective effects against various diseases. However, little is known about its effect on hepatic ischemia-reperfusion (I/R) injury. This study aimed to elucidate whether polydatin protects liver against I/R-induced injury and to explore the underlying mechanism. METHODS: After gavage feeding polydatin once daily for a week, mice underwent a partial hepatic I/R procedure. Serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST), hematoxylin-eosin (H&E) and TdT-mediated dUTP nick-end labeling (TUNEL) staining were used to evaluate liver injury. The severity related to the inflammatory response and reactive oxygen species (ROS) production was also investigated. Furthermore, immunofluorescence and Western blotting were used to detect macrophage polarization and the NF-κB signaling pathway in macrophages. RESULTS: Compared with the I/R group, polydatin pretreatment significantly attenuated I/R-induced liver damage and apoptosis. The oxidative stress marker (dihydroethidium fluorescence, malondialdehyde, superoxide dismutase and glutathione peroxidase) and I/R related inflammatory cytokines (interleukin-1ß, interleukin-10 and tumor necrosis factor-α) were significantly suppressed after polydatin treatment. In addition, the result of immunofluorescence indicated that polydatin reduced the polarization of macrophages toward M1 macrophages both in vivo and in vitro. Western blotting showed that polydatin inhibited the pro-inflammatory function of RAW264.7 via down-regulating the NF-κB signaling pathway. CONCLUSIONS: Polydatin protects the liver from I/R injury by remodeling macrophage polarization via NF-κB signaling.

Cyclometalated iridium(III) dithioformic acid complexes as mitochondria-targeted imaging and anticancer agents.

Four neutral cyclometalated iridium(III) (IrIII) dithioformic acid complexes ([(ppy)2Ir(S^S)], Ir1-Ir4) were designed and synthesized. Toxicity assay revealed that these complexes showed favorable anticancer activity, especially for human non-small cell lung cancer cells (A549). Ir1 exhibited the best anticancer activity (11.0 ± 0.4 µM) was about twice that of cisplatin, meanwhile, which could availably restrain A549 cells migration. Complexes could target mitochondria, induce a decrease in mitochondrial membrane potential (MMP), result in an increase of intracellular reactive oxygen species (ROS) and disruption of the cell cycle, and ultimately generate apoptosis. Western blotting experiment indicated that complexes could inhibit the expression of B cell CLL/lymphoma-2 protein (Bcl-2), induce the expression of BCL2-associated X protein (Bax) and lead to a massive release of Cytochrome C (Cyt-c), which amplified apoptosis signals by activating downstream pathway to promote apoptosis. All these confirmed the existence of mitochondrial anticancer channels for these complexes. Above all, cyclometalated iridium(III) dithioformic acid complexes possess the prospect of becoming a multifunctional cancer therapeutic platform, including mitochondria-targeted imaging, anti-migration, and anticancer agents.

Hepatic Ischemia-reperfusion Injury in Mice was Alleviated by Rac1 Inhibition - More Than Just ROS-inhibition.

BACKGROUND AND AIMS: Reducing reactive oxygen species (ROS) production has proven an effective way for alleviating oxidative stress during ischemia-reperfusion injury (IRI). Moreover, inhibition of Rac1 could reduce ROS production and prevent oxidative stress injury. Previous studies have suggested a positive interactivation feedback loop between Rac1 and hypoxia-inducible factor (HIF)-1α, the latter being up-regulated early during ischemia. The positive inter-activation between Rac1 and HIF-1α would aggravate ROS production, thereby promoting IRI. This study was designed to verify the effects of Rac1 inhibition on hepatic IRI both at animal and cellular levels and to explore the interaction between Rac1 and HIF-1α during hepatic IRI. METHODS: C57B/6 mice and AML-12 cells were used for the construction of hepatic IRI animal and cell models. Rac1 inhibition was achieved by NSC23766 (a specific Rac1 inhibitor). Lentiviral vectors were used for Rac1 knockdown. At designated time points, serum and liver tissues were collected from the mice and treated cells were collected for further analysis. RESULTS: NSC23766 treatment significantly alleviated the hepatic IRI in mice, manifesting as lower vacuolation score and less apoptosis cells, lower ROS and serum/liver alanine aminotransferase/aspartate aminotransferase levels, and fewer activated inflammatory cells. IRI of AML-12 was also alleviated by 50 µM NSC23766 or Rac1-knockdown, manifesting as reduced cell apoptosis, less extensive interruption of mitochondrial membrane potential, down-regulation of apoptosis, and effects on DNA damage-related proteins. Interestingly, Rac1 knockdown also down-regulated the expression level of HIF-1α. CONCLUSIONS: Our study supports a protective effect of Rac1 inhibition on hepatic IRI. Aside from the classic topics of reducing ROS production and oxidative stress, our study showed an interaction between Rac1 and HIF-1α signaling during hepatic IRI.

Biomimetic synthesis of a novel O2-regeneration nanosystem for enhanced starvation/chemo-therapy.

Glucose oxidase-mediated starvation therapy that effectively cuts off energy supply holds great promise in cancer treatment. However, high glutathione (GSH) contents and anoxic conditions severely reduce therapy efficiency and cannot fully kill cancer cells. Herein, to resolve the above problem, this study constructed a biomimetic nanosystem based on nanreproo-MnO2with porous craspedia globose-like structure and high specific surface area, and it was further modified with dopamine and folic acid to guarantee good biocompatibility and selectivity toward cancer cells. This nanosystem responsively degraded and reacted with GSH and acid to regenerate O2, which significantly increased intracellular O2levels, accelerated glucose consumption, and improved starvation therapy efficiency. Moreover, anticancer drug of camptothecin was further loaded, and notably enhanced cancer growth inhibition was obtained at very low drug concentrations. Most importantly, this novel therapy could unprecedentedly inhibit cancer cell migration to a very low ratio of 19%, and detailed cell apoptosis analyses revealed late stage apoptosis contributed most to the good therapeutic effect. This work reported a new train of thought to improve starvation therapy in biomedicine, and provided a new strategy to design targeted nanocarrier to delivery mixed drugs to overcome the restriction of starvation therapy and develop new therapy patterns.

Aged-related Function Disorder of Liver is Reversed after Exposing to Young Milieu via Conversion of Hepatocyte Ploidy.

Previous study showed that senescent hepatocytes from aged liver could be rejuvenated after repopulated in the young recipient liver. The proliferative capacity of hepatocytes was restored with the senescence reversal. However, it is unknown whether metabolic and homeostatic function of aged liver, as well as age-dependent liver steatosis could be rejuvenated or alleviated. Here, we found that senescent hepatocytes from aged liver were rejuvenated after exposing to young blood. An autonomous proliferation of senescent hepatocytes which resulting in ploidy reversal might be the underlying mechanism of senescent reversal. After performing 2/3 partial hepatectomy (2/3PHx) in young blood exposed old liver, delayed DNA synthesis of senescent hepatocytes was rescued and the number of BrdU positive hepatocytes was restored from 4.39±2.30% to 17.85±3.21%, similarly to that in the young mice at 36 hours post 2/3PHx. Moreover, Cyclin A2 and Cyclin E1 overexpression of hepatocytes in aged liver facilitating the G1/S phase transition was contributed to enhance liver regeneration. Furthermore, lipid droplet spread widely in the elderly human liver and old mouse liver, but this aged-associated liver steatosis was alleviated as senescence reversal. Collectively, our study provides new thoughts for effectively preventing age-related liver diseases.