Targeting Mitochondria-Located circRNA SCAR Alleviates NASH via Reducing mROS Output.

Mitochondria, which play central roles in immunometabolic diseases, have their own genome. However, the functions of mitochondria-located noncoding RNAs are largely unknown due to the absence of a specific delivery system. By circular RNA (circRNA) expression profile analysis of liver fibroblasts from patients with nonalcoholic steatohepatitis (NASH), we observe that mitochondrial circRNAs account for a considerable fraction of downregulated circRNAs in NASH fibroblasts. By constructing mitochondria-targeting nanoparticles, we observe that Steatohepatitis-associated circRNA ATP5B Regulator (SCAR), which is located in mitochondria, inhibits mitochondrial ROS (mROS) output and fibroblast activation. circRNA SCAR, mediated by PGC-1α, binds to ATP5B and shuts down mPTP by blocking CypD-mPTP interaction. Lipid overload inhibits PGC-1α by endoplasmic reticulum (ER) stress-induced CHOP. In vivo, targeting circRNA SCAR alleviates high fat diet-induced cirrhosis and insulin resistance. Clinically, circRNA SCAR is associated with steatosis-to-NASH progression. Collectively, we identify a mitochondrial circRNA that drives metaflammation and serves as a therapeutic target for NASH.

Defects engineering on CrOOH by Ni doping for boosting electrochemical oxygen evolution reaction.

The design and construction of active centres are key to exploring advanced electrocatalysts for oxygen evolution reaction (OER). In this work, we demonstrate thein situconstruction of point defects on CrOOH by Ni doping (Ni-CrOOH/NF). Compared with pure CrOOH/NF, Ni-CrOOH/NF showed enhanced OER activity. The effect of the amount of Ni introduced on the OER performance was investigated. Ni0.2-CrOOH/NF, the best introduction of Ni, uses a low overpotential of 253 mV to achieve a current density of 10 mA cm-2with a high turnover frequency of 0.27 s-1in 1.0 M NaOH. In addition, the electrocatalytic performance of Ni0.2-CrOOH/NF showed little deterioration after 1000-cycle cyclic voltammetry scanning. In the potentiostatic test, activity was stable for at least 20 h.

Discovery of novel bis-evodiamine derivatives with potent antitumor activity.

Inspired by antitumor natural product evodiamine, a series of novel bis-evodiamine derivatives were designed and synthesized, which showed potent antitumor activity. In particular, compound 13b effectively inhibited the proliferation and migration of HCT116 cells. Further mechanism studies revealed that compound 13b acted by inducing HCT116 cell apoptosis and arresting the cell cycle at the G2/M phase. Thus, compound 13b represents a promising lead compound for the discovery of novel antitumor agents.

Design, Synthesis, and Structure-Activity relationships of Evodiamine-Based topoisomerase (Top)/Histone deacetylase (HDAC) dual inhibitors.

On the basis of synergistic effect between topoisomerase (Top) and histone deacetylase (HDAC) inhibitors, a series of novel evodiamine-based Top/HDAC dual inhibitors were designed and synthesized. Systematic structure-activity relationship (SAR) studies led to the discovery of compounds 29b and 45b, which simultaneously inhibited Top and HDAC and exhibited potent antitumor activities against the HCT116 cell line. Compounds 29b and 45b efficiently induced apoptosis with G2 cell cycle arrest and significantly inhibited cellular HDACs in HCT116 cells with good in vitro metabolic stabilities. Collectively, this work provides valuable SAR information and lead compounds for evodiamine-based Top/HDAC dual inhibitors.

Electrochemiluminescence immunosensor based on the quenching effect of CuO@GO on m-CNNS for cTnI detection.

A sandwich-type electrochemiluminescence (ECL) immunosensor based on the resonance energy transfer (RET) was proposed for ultrasensitive detection of cardiac troponin I (cTnI). The RET behavior could be generated between graphite carbon nitride nanosheets (m-CNNS) as donor and copper oxide@graphene oxide (CuO@GO) as acceptor, achieving the quenching effect of CuO@GO on m-CNNS for cTnI detection. The m-CNNS synthesized by mechanical grinding of the graphite carbon nitride (CN) not only has better dispersion and higher specific surface area, but also has high luminous efficiency and stable chemical properties. Therefore, m-CNNS was used as the matrix material and luminophore. As the acceptor, CuO@GO prepared by in-situ chemical synthesis of CuO NPs onto GO sheets also has a high specific surface area, which could be used as a label of secondary antibody (Ab2). Under optimal conditions, cTnI could be determined within the linear range of 0.1 pg mL-1 to 100 ng mL-1 and had a low detection limit (0.028 pg mL-1, S/N = 3). Meanwhile, the prepared ECL immunosensor possessed great stability, specificity and reproducibility, providing a new method for detecting cTnI and other biomarkers.

Mitochondrial noncoding RNAs: new wine in an old bottle.

Mitochondrial noncoding RNAs (mt-ncRNAs) include noncoding RNAs inside the mitochondria that are transcribed from the mitochondrial genome or nuclear genome, and noncoding RNAs transcribed from the mitochondrial genome that are transported to the cytosol or nucleus. Recent findings have revealed that mt-ncRNAs play important roles in not only mitochondrial functions, but also other cellular activities. This review proposes a classification of mt-ncRNAs and outlines the emerging understanding of mitochondrial circular RNAs (mt-circRNAs), mitochondrial microRNAs (mitomiRs), and mitochondrial long noncoding RNAs (mt-lncRNAs), with an emphasis on their identification and functions.

Two new species of Hypodontolaiminae (Nematoda, Chromadorida, Chromadoridae) from the Yellow Sea with a phylogenetic analysis in the subfamily.

Two new species of Hypodontolaiminae, Dichromadoramediasp. nov. and Neochromadoraparabilineatasp. nov., were isolated and described from the Yellow Sea, China. Dichromadoramediasp. nov. is characterized by four long cephalic setae, the amphidial fovea transverse oval in the male and slit-shaped in the female, the pharynx with a single posterior bulb, spicules curved and distally bifurcated, gubernaculum jointed, four (1+3) precloacal supplements papilliform, and the tail conical elongated with a short spinneret. Neochromadoraparabilineatasp. nov. is characterized by the buccal cavity with one large hollow dorsal tooth and two small subventral teeth, the pharynx with an obvious posterior bulb, spicules L-shaped and widened medially, gubernaculum boat-shaped, seven cup-shaped and equidistant precloacal supplements, and a long and gradually tapering tail. The phylogenetic analysis of maximum likelihood and Bayesian inference based on rDNA sequences confirmed the taxonomic positions of Neochromadoraparabilineatasp. nov. and Dichromadoramediasp. nov. within Hypodontolaiminae. Tree topology in Hypodontolaiminae shows the genera Neochromadora, Dichromadora, Ptycholaimellus, and Spilophorella as polyphyletic groups, and the genus Chromadorita as a paraphyletic group.

3D printed barium titanate/calcium silicate composite biological scaffold combined with structural and material properties.

In the case of a large bone defect, the human endogenous electrical field is no longer sufficient. Therefore, it is necessary to support structural electrical bone scaffolds. Barium titanate (BT) has received much attention in bone tissue engineering applications due to its biocompatibility and ability to maintain charged surfaces. However, its processability is poor and it does not have the biological activity to promote mineralization, which limits its use in bone repair. In this paper, a composite bone scaffold with excellent piezoelectric properties was prepared by combining 20 wt% calcium silicate. The influence of the light curing process on the properties of the piezoelectric biological scaffold was investigated by comparing it with the traditional piezoelectric ceramic molding method (dry pressing). Despite the structural features of 3D printing (layered structure, pore features), the piezoelectric and mechanical properties of the scaffold are weakened. However, 3D-printed scaffolds can combine structural and piezoelectric properties, which makes the 3D-printed scaffold more effective in terms of degradation and antibacterial performance. In terms of cell activity, piezoelectric properties attract proteins and nutrients into the scaffold, promoting cell growth and differentiation. Besides, it is undeniable that the pore structure of the scaffolds plays an important role in the biological properties. Finally, the 3D printed scaffolds have excellent antimicrobial properties due to the redox reaction under piezoelectric effect as well as structural characterization.

PROTAC derivatization of natural products for target identification and drug discovery: Design of evodiamine-based PROTACs as novel REXO4 degraders.

INTRODUCTION: Natural products (NPs) play a crucial role in the development of therapeutic drugs. However, it is still highly challenging to identify the targets of NPs. Besides, NPs usually exert their pharmacological activities via acting on multiple targets or pathways, which also poses great difficulties for the target identification of NPs. OBJECTIVES: Inspired by our continuous efforts in designing drug-like protein degraders, this study introduced a successful example for the target identification and drug discovery of natural products evodiamine by employing PROTAC technology. METHODS: Taking advantages of proteolysis targeting chimera (PROTAC), herein an integrated strategy combining PROTAC derivatization, quantitative proteomic analysis and binding affinity validation was developed for target identification and drug discovery of antitumor NP evodiamine. RESULTS: In this study, both highly potent PROTACs and negative controls were designed for quantitative proteomic analysis. Furthermore, REXO4 was confirmed as a direct target of 3-fluoro-10-hydroxylevodiamine, which induced cell death through ROS. In addition, the PROTAC 13c effectively degraded REXO4 both in vitro and in vivo, leading to potent antitumor activities and reduced toxic side effects. CONCLUSION: In summary, we developed an integrated strategy for the target identification and drug discovery of NPs, which was successfully applied to the PROTAC derivatization and target characterization of evodiamine. This proof-of-concept study highlighted the superiority of PROTAC technology in target identification of NPs and accelerated the process of NPs-based drug discovery, exhibiting broad application in NP-based drug development.

Biocompatibility and antibacterial activity of MgO/Ca3(PO4)2 composite ceramic scaffold based on vat photopolymerization technology.

Recent advancements in medical technology and increased interdisciplinary research have facilitated the development of the field of medical engineering. Specifically, in bone repair, researchers and potential users have placed greater demands on orthopedic implants regarding their biocompatibility, degradation rates, antibacterial properties, and other aspects. In response, our team developed composite ceramic samples using degradable materials calcium phosphate and magnesium oxide through the vat photopolymerization (VP) technique. The calcium phosphate content in each sample was, respectively, 80 %, 60 %, 40 %, and 20 %. To explore the relationship between the biocompatibility, antibacterial activity, and MgO content of the samples, we cultured them with osteoblasts (MC3T3-E1), Escherichia coli (a gram-negative bacterium), and Staphylococcus aureus (a gram-positive bacterium). Our results demonstrate that as the MgO content of the sample increases, its biocompatibility improves but its antibacterial activity decreases. Regarding the composite material samples, the 20 % calcium phosphate content group exhibited the best biocompatibility. However, after 0.5 h of co-cultivation, the antibacterial rates of all groups except the 20 % calcium phosphate content group co-cultured with S. aureus exceed 80 %. Furthermore, after 3 h, the antibacterial rates against E. coli exceed 95 % in all groups. This is because higher levels of MgO correspond to lower pH values and Mg2+ concentrations in the cell and bacterial culture solutions, which ultimately promote cell and bacterial proliferation. This elevates the biocompatibility of the samples, albeit at the expense of their antimicrobial efficacy. Thus, modulating the MgO content in the composite ceramic samples provides a strategy to develop gradient composite scaffolds for better control of their biocompatibility and antibacterial performance during different stages of bone regeneration.

Zn-doped chitosan/alginate multilayer coatings on porous hydroxyapatite scaffold with osteogenic and antibacterial properties.

Porous hydroxyapatite (HA) scaffolds prepared by three-dimensional (3D) printing have wide application prospects owing to personalized structural design and excellent biocompatibility. However, the lack of antimicrobial properties limits its widespread use. In this study, a porous ceramic scaffold was fabricated by digital light processing (DLP) method. The multilayer chitosan/alginate composite coatings prepared by layer-by-layer method were applied to scaffolds and Zn2+ was doped into coatings in the form of ion crosslinking. The chemical composition and morphology of coatings were characterized by scanning electron microscope (SEM) and X-ray photoelectron spectroscopy (XPS). Energy dispersive spectroscopy (EDS) analysis demonstrated that Zn2+ was uniformly distributed in the coating. Besides, the compressive strength of coated scaffolds (11.52 ± 0.3 MPa) was slightly improved compared with that of bare scaffolds (10.42 ± 0.56 MPa). The result of soaking experiment indicated that coated scaffolds exhibited delayed degradation. In vitro experiments demonstrated that within the limits of concentration, a higher Zn content in the coating has a stronger capacity to promote cell adhesion, proliferation and differentiation. Although excessive release of Zn2+ led to cytotoxicity, it presented a stronger antibacterial effect against Escherichia coli (99.4%) and Staphylococcus aureus (93%).

Niche stiffness sustains cancer stemness via TAZ and NANOG phase separation.

Emerging evidence shows that the biomechanical environment is required to support cancer stem cells (CSCs), which play a crucial role in drug resistance. However, how mechanotransduction signals regulate CSCs and its clinical significance has remained unclear. Using clinical-practice ultrasound elastography for patients' lesions and atomic force microscopy for surgical samples, we reveal that increased matrix stiffness is associated with poor responses to neoadjuvant chemotherapy, worse prognosis, and CSC enrichment in patients with breast cancer. Mechanically, TAZ activated by biomechanics enhances CSC properties via phase separation with NANOG. TAZ-NANOG phase separation, which is dependent on acidic residues in the N-terminal activation domain of NANOG, promotes the transcription of SOX2 and OCT4. Therapeutically, targeting NANOG or TAZ reduces CSCs and enhances the chemosensitivity in vivo. Collectively, this study demonstrated that the phase separation of a pluripotency transcription factor links mechanical cues in the niche to the fate of CSCs.

Tumor Cell-Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid ß-Oxidation.

Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long-term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell-intrinsic CD96 enhances the chemotherapeutic response in a patient-derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid ß-oxidation via the CD155-CD96-Src-Stat3-Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell-intrinsic CD96 and an attractive target in improving the chemotherapeutic response.

Design of a Haversian system-like gradient porous scaffold based on triply periodic minimal surfaces for promoting bone regeneration.

INTRODUCTION: The bone ingrowth depth in the porous scaffolds is greatly affected by the structural design, notably the pore size, pore geometry, and the pore distribution. To enhance the bone regeneration capability of scaffolds, the bionic design can be regarded as a potential solution. OBJECTIVES: We proposed a Haversian system-like gradient structure based on the triply periodic minimal surface architectures with pore size varying from the edge to the center. And its effects in promoting bone regeneration were evaluated in the study. METHODS: The gradient scaffold was designed using the triply periodic minimal surface architectures. The mechanical properties were analyzed by the finite element simulation and confirmed using the universal machine. The fluid characteristics were calculated by the computational fluid dynamics analysis. The bone regeneration process was simulated using a in silico computational model containing the main biological, physical, and chemical variation during the bone growth process. Finally, the in vitro and in vivo studies were carried out to verify the actual osteogenic effect. RESULTS: Compared to the uniform scaffold, the biomimetic gradient scaffold demonstrated better performance in stress conduction and reduced stress shielding effects. The fluid features were appropriate for cell migration and flow diffusion, and the permeability was in the same order of magnitude with the natural bone. The bone ingrowth simulation exhibited improved angiogenesis and bone regeneration. Higher expression of the osteogenesis-related genes, higher alkaline phosphatase activity, and increased mineralization could be observed on the gradient scaffold in the in vitro study. The 12-week in vivo study proved that the gradient scaffold had deeper bone inserting depth and a more stable bone-scaffold interface. CONCLUSION: The Haversian system-like gradient structure can effectively promote the bone regeneration. This structural design can be used as a new solution for the clinical application of prosthesis design.

Non-Invasive Prediction Models for Esophageal Varices and Red Signs in Patients With Hepatitis B Virus-Related Liver Cirrhosis.

Background: Red signs are closely related to esophageal variceal bleeding, and, despite improvements in therapy, the mortality rate remains high. We aimed to identify non-invasive predictors of esophageal varices and red signs in patients with hepatitis B virus-related liver cirrhosis. Methods: This retrospective study included 356 patients with hepatitis B virus-related liver cirrhosis after applying inclusion and exclusion criteria among 661 patients. All patients underwent endoscopy, ultrasonography, laboratory examinations, and computed tomography/magnetic resonance imaging. Univariate and multivariate logistic regression analysis were performed, and prediction models for esophageal varices and red signs were constructed. Results: Multivariate analysis revealed that spleen diameter, splenic vein diameter, and lymphocyte ratio were independent risk factors for esophageal varices and red signs. On this basis, we proposed two models: i) a spleen diameter-splenic vein diameter-lymphocyte ratio-esophageal varices prediction model (SSL-EV model); and ii) a spleen diameter-splenic vein diameter-lymphocyte ratio-red sign prediction model (SSL-RS model). The areas under the receiver operating characteristic curve for the two prediction models were 0.843 and 0.783, respectively. With a cutoff value of 1.55, the first prediction model had 81.3% sensitivity and 76.1% specificity for esophageal varices prediction. With a cutoff value of -0.20, the second prediction model had 72.1% sensitivity and 70.7% specificity for the prediction of red signs. Conclusions: We proposed a new statistical model, the spleen diameter-splenic vein diameter-lymphocyte ratio-red sign prediction model (SSL-RS model), to predict the presence of red signs non-invasively. Combined with the spleen diameter-splenic vein diameter-lymphocyte ratio-esophageal varices prediction model (SSL-EV model), these non-invasive prediction models will be helpful in guiding clinical decision-making and preventing the occurrence of esophageal variceal bleeding.

Fibroblast growth factor 21: A "rheostat" for metabolic regulation?

Fibroblast growth factor 21 is an evolutionarily conserved factor that plays multiple important roles in metabolic homeostasis. During the past two decades, extensive investigations have improved our understanding of its delicate metabolic roles and identified its pharmacological potential to mitigate metabolic disorders. However, most clinical trials have failed to obtain the desired results, which raises issues regarding its clinical value. Fibroblast growth factor 21 is dynamically regulated by nutrients derived from food intake and hepatic/adipose release, which in turn act on the central nervous system, liver, and adipose tissues to influence food preference, hepatic glucose, and adipose fatty acid output. Based on this information, we propose that fibroblast growth factor 21 should not be considered merely an anti-hyperglycemia or anti-obesity factor, but rather a means of balancing of nutrient fluctuations to maintain an appropriate energy supply. Hence, the specific functions of fibroblast growth factor 21 in glycometabolism and lipometabolism depend on specific metabolic states, indicating that its pharmacological effects require further consideration.

Self-compassion mediates the perfectionism and depression link on Chinese undergraduates.

BACKGROUND: The prevalence of depression among Chinese college students tends to be higher in recent years, which has caused a series of negative effects in their lives. One of the factors is perfectionism, and few researches have been conducted to examine the role of self-compassion in perfectionism and depression link. The purpose of the study was to explore the relationships between perfectionism, self-compassion, and depression in the context of Chinese undergraduates. METHODS: The anonymous self-reported questionnaires including three scales on perfectionism, selfcompassion, and depression were utilized in the study. A total of 540 undergraduates were recruited from three universities in Nanjing and Xi'an by using convenient cluster sampling and were required to complete the questionnaires. Pearson correlation analysis was used to examine the correlation between variables. Multiple linear regression analysis was used to examine the predictive effects of perfectionism and selfcompassion on depression. Hierarchical multiple regression analysis was used to evaluate the mediating effect of self-compassion. RESULTS: Regression analyses demonstrated that the maladaptive perfectionism was positively associated with depression, while adaptive perfectionism and self-compassion were negatively associated with depression. The mediation tests showed that the self-compassion partially mediated the relationship between the two types of perfectionism and depression. CONCLUSIONS: This study revealed the mediating effect of self-compassion in the relation between perfectionism and depression in Chinese undergraduates. Self-compassion is likely to be an effective psychological intervention method to relieve the depressive symptoms in college students, and further study is needed to verify this possibility.

Analysis of Mechanical Properties and Permeability of Trabecular-Like Porous Scaffold by Additive Manufacturing.

Human bone cells live in a complex environment, and the biomimetic design of porous structures attached to implants is in high demand. Porous structures based on Voronoi tessellation with biomimetic potential are gradually used in bone repair scaffolds. In this study, the mechanical properties and permeability of trabecular-like porous scaffolds with different porosity levels and average apertures were analyzed. The mechanical properties of bone-implant scaffolds were evaluated using finite element analysis and a mechanical compression experiment, and the permeability was studied by computational fluid dynamics. Finally, the attachment of cells was observed by confocal fluorescence microscope. The results show that the performance of porous structures can be controlled by the initial design of the microstructure and tissue morphology. A good structural design can accurately match the performance of the natural bone. The study of mechanical properties and permeability of the porous structure can help address several problems, including stress shielding and bone ingrowth in existing biomimetic bone structures, and will also promotes cell adhesion, migration, and eventual new bone attachment.

Robotic in situ 3D bio-printing technology for repairing large segmental bone defects.

Introduction: The traditional clinical treatment of long segmental bone defects usually requires multiple operations and depends on donor availability. The 3D bio-printing technology constitutes a great potential therapeutic tool for such an injury. However, in situ 3D bio-printing remains a major challenge. Objectives: In this study, we report the repair of long segmental bone defects by in situ 3D bio-printing using a robotic manipulator 3D printer in a swine model. Methods: We systematically optimized bio-ink gelation under physiological conditions to achieve desirable mechanical properties suitable for bone regeneration, and a D-H kinematic model was used to improve printing accuracy to 0.5 mm. Results: These technical improvements allowed the repair of long segmental defects generated on the right tibia of pigs using 3D bio-printing within 12 min. The 3D bio-printing group showed improved treatment effects after 3 months. Conclusion: These findings indicated that robotic in situ 3D bio-printing is promising for direct clinical application.

3D-printed composite, calcium silicate ceramic doped with CaSO4·2H2O: Degradation performance and biocompatibility.

Calcium silicate is a common implant material with excellent mechanical strength and good biological activity. In recent years, the addition of strengthening materials to calcium silicate has been proven to promote bone tissue regeneration, but its degradation properties require further improvements. In this paper, calcium silicate was used as the matrix, and 10 wt% hydroxyapatite and 10 wt% strontium phosphate were added to im prove the biological activity of the scaffold. The effect of adding different amounts of calcium sulfate dihydrate (CaSO4·2H2O) on the degradation of the scaffold was explored. A porous ceramic scaffold was prepared by digital light processing (DLP) technology, and its performance was evaluated. Cell experiments showed that the addition of calcium sulfate improved cell proliferation and differentiation. Simulated body fluid (SBF) immersion tests showed that small amounts of apatite deposits appeared on the fourth day, larger deposits appeared on the 14th day, and degradation occurred on the surface after 28 days of immersion. Mechanical tests showed that the addition of 5 wt% CaSO4·2H2O improved the compressibility of the composite. After soaking in SBF for 14 days, it retained its compressive strength (11.8 MPa), which meets the requirements of cancellous bone, demonstrating its potential application value for bone repair.