Perfluorooctanoic acid inhibits androgen biosynthesis in rat immature Leydig cells.

Perfluorooctanoic acid (PFOA) is a commonly used short-chain synthetic perfluoroalkyl agent. Immature Leydig cells (ILCs) are localized in the testis and responsible for androgen biosynthesis and metabolism. Although PFOA shows toxicity in the reproductive system, it is not clear if it disrupts the function of ILCs. In the present study, primary ILCs were isolated from 35-day-old rats and exposed to a range of PFOA concentrations (0, 0.01, 0.1, or 1 µM). It was determined that 0.1 or 1 µM PFOA reduced total androgen biosynthesis in ILCs. Specifically, 22R-hydroxycholesterol (22R), and pregnenolone (P5) mediated androgen biosynthesis were reduced by 0.1 µM PFOA. PFOA also selectively downregulated mRNA and protein expressions of steroidogenic enzymes including LHCGR, CYP11A1, 3ß-HSD1, and NR5A1 at 0.01, 0.1, or 1 µM. Further analysis revealed that 0.1 µM PFOA inhibited CYP11A1 and 3ß-HSD1 enzyme activities. However, PFOA did not significantly affect androgen metabolism and turnover under any of the conditions tested. And PFOA gavaging to 35-day-old rats at 5 or 10 mg/kg for 7 or 14 days also reduced serum androgen levels secreted by ILCs. Moreover, PFOA gavaging also downregulated the mRNA and protein expression levels of LHCGR, CYP11A1, 3ß-HSD1, and NR5A1 in vivo. Taken together, these findings suggest that PFOA inhibits androgen biosynthesis in ILCs by selectively targeting key enzymes in the synthesis pathway.

In situ fabrication of covalent organic frameworks on solid-phase microextraction probes coupled with electrospray ionization mass spectrometry for enrichment and determination of androgens in biosamples.

Solid-phase microextraction (SPME) coupled with electrospray ionization mass spectrometry (ESI-MS) was developed for rapid and sensitive determination of endogenous androgens. The SPME probe is coated with covalent organic frameworks (COFs) synthesized by reacting 1,3,5-tri(4-aminophenyl)benzene (TPB) with 2,5-dioctyloxybenzaldehyde (C8PDA). This COFs-SPME probe offers several advantages, including enhanced extraction efficiency and stability. The analytical method exhibited wide linearity (0.1-100.0 µg L-1), low limits of detection (0.03-0.07 µg L-1), high enrichment factors (37-154), and satisfactory relative standard deviations (RSDs) for both within one probe (4.0-14.8%) and between different probes (3.4-12.7%). These remarkable performance characteristics highlight the reliability and precision of the COFs-SPME-ESI-MS method. The developed method was successfully applied to detect five kinds of endogenous androgens in female serum samples, indicating that the developed analytical method has great potential for application in preliminary clinical diagnosis.

[UPLC-Q-TOF-MS-based metabolomics reveals mechanism of Morinda officinalis iridoid glycosides in treating rheumatoid arthritis and bone loss].

This study aimed to investigate the therapeutic effects of Morinda officinalis iridoid glycosides(MOIG) on paw edema and bone loss of rheumatoid arthritis(RA) rats, and analyze its potential mechanism based on ultra-high performance liguid chromatography-guadrupole time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS) serum metabolomics. RA rats were established by injecting bovin type Ⅱ collagen. The collagen-induced arthritis(CIA) rats were administered drug by gavage for 8 weeks, the arthritic score were used to evaluate the severity of paw edem, serum bone metabolism biochemical parameters were measured by ELISA kits, Masson staining was used to observe the bone microstructure of the femur in CIA rats. UPLC-Q-TOF-MS was used to analyze the alteration of serum metabolite of CIA rats, principal component analysis(PCA) and partial least squares-discriminant analysis(PLS-DA) were used to screen the potential biomarkers, KEGG database analysis were used to construct related metabolic pathways. The results demonstrated that the arthritic score, serum levels of IL-6 and parameters related with bone metabolism including OCN, CTX-Ⅰ, DPD and TRAP were significantly increased, and the ratio of OPG and RANKL was significantly decreased, the microstructure of bone tissue and cartilage were destructed in CIA rats, while MOIG treatments could significantly reduce arthritis score, mitigate the paw edema, reverse the changes of serum biochemical indicators related with bone metabolism, and improve the microstructure of bone tissue and cartilage of CIA rats. The non-targeted metabolomics results showed that 24 altered metabolites were identified in serum of CIA rats; compared with normal group, 13 significantly altered metabolites related to RA were identified in serum of CIA rats, mainly involving alanine, aspartate and glutamate metabolism; compared with CIA model group, MOIG treatment reversed the alteration of 15 differential metabolites, mainly involving into alanine, aspartate and glutamate metabolism, D-glutamine and D-glutamate metabolism, taurine and hypotaurine metabolism, valine, leucine and isoleucine biosynthesis. Therefore, MOIG significantly alleviated paw edema, improved the destruction of microstructure of bone and cartilage in CIA rats maybe through involving into the regulation of amino acid metabolism.

Laser-induced graphene (LIG)-driven medical sensors for health monitoring and diseases diagnosis.

Laser-induced graphene (LIG) is a class of three-dimensional (3D) porous carbon nanomaterial. It can be prepared by direct laser writing on some polymer materials in the air. Because of its features of simplicity, fast production, and excellent physicochemical properties, it was widely used in medical sensing devices. This minireview gives an overview of the characteristics of LIG and LIG-driven sensors. Various methods for preparing graphene were compared and discussed. The applications of the LIG in biochemical sensors for ions, small molecules, microRNA, protein, and cell detection were highlighted. LIG-based physical physiological sensors and wearable electronics for medical applications were also included. Finally, our insights into current challenges and prospects for LIG-based medical sensing devices were presented.

High mobility and enhanced photoelectric performance of two-dimensional ternary compounds NaCuX (X = S, Se, and Te).

Two-dimensional (2D) materials have attracted great interest in the field of optoelectronics in recent years due to their atomically thin structure and various electronic properties. Based on the first-principles calculations combined with the non-equilibrium Green's function (NEGF) method, we predict a set of new 2D ternary materials, sodium copper chalcogenides (NaCuX, X = S, Se, and Te). These materials not only have direct band gaps ranging from 1.2 to 1.6 eV, but also possess relatively small carrier effective masses (0.1-0.2m0) at the band edges thus high carrier mobilities (103-104 cm2 V-1 s-1), which collectively imply that they are suitable for optical-electronic applications in the visible (even in the infrared) light region. Moreover, based on the high photo responsivity (Rph), e.g., up to 0.105 A W-1 for NaCuTe, we design a series of NaCuX monolayer based high performance optoelectronic junctions. These properties indicate that NaCuX monolayers are promising candidate materials for photodetectors and photovoltaic units.

Cell surface vimentin-positive circulating tumor cell-based relapse prediction in a long-term longitudinal study of postremission neuroblastoma patients.

Neuroblastoma (NB) is a deadly childhood disease that carries a 50% chance of relapse for anyone in remission and similar level of 5-year survival. We investigated the value of our proprietary approach-cell surface vimentin (CSV) positive circulating tumor cells (CTC) to monitor treatment response and predict relapse in NB patients under remission in a Phase II long-term preventative clinical trial. We longitudinally analyzed peripheral blood samples from 93 patients for 27 cycles (~25 months) and discovered that the presence of CSV+ CTCs in the first two sequential samples (baseline, cycle 4 [month 3-4]) was a significant indicator of earlier relapse. We observed strong correlation between relapse-free survival (RFS) and lack of CSV+ CTCs in first 4 cycles of therapy (95%). There was sensitivity reaching 100% in predicting RFS in patients who had neither CSV+ CTCs nor MycN amplification. Of note, the low number of CSV+ CTCs seems equivalent to low tumor load because the prevention therapy difluoromethylornithine yields faster reduction of relapse risk when none or only 1-2 CSV+ CTCs (every 6 mL) are present in the blood samples compared to >3 CSV+ CTCs. To the best of our knowledge, this is the first study that directly observes CTCs in under remission NB patients for relapse prediction and the first to gather sequential CSV+ CTC data in any study in a long-term longitudinal manner.

Rational design of [e]-fusion induced high-performance DHP/CPD based photoswitches.

We report an effective strategy for improving the electronic transport and switching behaviors of dimethyldihydropyrene/cyclophanediene (DHP/CPD)-based molecular devices, an intriguing photoswitch that can be triggered by ultraviolet/visible (UV-vis) light irradiation. Aiming to obtain molecular devices with high on-off ratios, we assess a series of molecular designs formed by [e]-fusing different arenes on a conjugated macrocycle to modulate the photochemical and electronic properties. Here, the switching mechanism and transport properties of [e]-fused DHP/CPD-based nanojunctions are theoretically investigated by first-principles calculations. As a result, the large diversity in electrical conductance between the closed and open forms certifies the substantial switching behavior observed in these sandwich structures. The maximum on-off ratios in all designed photoswitches are greater than 102. Further analysis confirms the improvement of switching performance caused by [e]-fusion. Notably, in the benzo-fused molecular junctions, the maximum on-off ratio is up to 103, which is 55 times larger than that of the un-fused one. We also find that the position of the switch core can remarkably affect the performance of photoswichable nanodevices.

Metformin reverses the drug resistance of cisplatin in irradiated CNE-1 human nasopharyngeal carcinoma cells through PECAM-1 mediated MRPs down-regulation.

Objective: To explore a way to reverse the drug resistance for irradiated CNE-1 human nasopharyngeal carcinoma cells and try to develop a new high efficacy with low toxicity therapeutic approach. Methods: 300 Gy irradiated the CNE-1 human nasopharyngeal carcinoma cells, and then treated with single-agent cisplatin or metformin, or combination of both drugs. MTT assay and FCM were applied to detect cell viability and apoptosis. Western blot and RT-PCR were used to characterize the protein and mRNA expression after various drug administrations. Results: The results presented single-agent metformin was capable of arresting the tumor growth and inducing apoptosis in irradiated CNE-1 cells and also demonstrated a synergy effect with cisplatin. Furthermore, metformin down-regulates the PECAM-1 expression, which could regulate Multi-drug Resistance-associate Proteins (MRPs) expression leading to cisplatin resistance of irradiated CNE-1 cells. A pan-MRP inhibitor, probenecid, can resecure cisplatin resistance leading by radiation. Conclusions: Metformin, due to its independent effects on PECAM-1, had a unique anti-proliferative effect on irradiated CNE-1 cells. It would be a new therapeutic option to conquer cisplatin resistance for advanced NPC patients after radiotherapy.

Role of abnormal microRNA expression in Helicobacter pylori associated gastric cancer.

Epidemiological studies have shown that Helicobacter pylori (HP) infection is a risk factor for gastric cancer (GC). HP infection may induce the release of pro-inflammatory mediators, and abnormally increase the level of reactive oxygen species (ROS), nitric oxide (NO), and cytokines in mucosal epithelial cells of the stomach. However, the specific mechanism underlying the pathogenesis of HP-associated GC is still poorly understood. Recent studies have revealed that abnormal microRNA expression may affect the proliferation, differentiation, and apoptosis of mucosal epithelial cells of the stomach to further influence GC occurrence, development, and metastasis. Herein, we summarize the role of abnormal microRNAs in the regulation of HP-associated GC progression. Abnormal microRNA expression in HP-positive GC may be a biomarker for GC diagnosis, occurrence, and development as well as its targeted treatment and prognosis.

Exotic magnetism in As-doped α/ß-In2Se3 monolayers with tunable anisotropic carrier mobility.

The two-dimensional (2D) material family is expanding fast as novel metal chalcogenides are being continually fabricated and intriguingly, plenty of them are ideal candidates for future nanoscale electronic and magnetic devices. Based on first-principles calculations, we investigated the electronic and magnetic properties of α/ß-In2Se3 monolayers. We find singularities of density of states appear in the valence band and hole doping (such as a Se atom substituted by a lower valence atom) can induce various ferromagnetic phase transitions in the α/ß-In2Se3 monolayers. In particular, replacement by arsenic at the anion site can enhance ferromagnetism and drive α-In2Se3 to be a robust half-metal and ß-In2Se3 to be a bipolar magnetic semiconductor. Then, we proposed spin-polarized field-effect transistors based on α-In2Se3 and a bipolar field-effect spin-filter based on ß-In2Se3. Besides, we also discussed the influences of the molecules in air on the device performance such as carrier mobility. We found that the adsorption of either O2 or H2O on α/ß-In2Se3 induced changes in hole mobility in different directions. These findings reveal a new road to electronic and magnetic modulations in 2D materials.

IGF-1R Inhibition Suppresses Cell Proliferation and Increases Radiosensitivity in Nasopharyngeal Carcinoma Cells.

Although ionizing radiation (IR) has provided considerable improvements in nasopharyngeal carcinoma (NPC) treatment, radioresistance is still a major threat for some subsets of patients. The insulin-like growth factor-1 receptor (IGF-1R) signaling pathway is tightly regulated and plays critical roles in mediating cell proliferation, growth, and survival. Thus, IGF-1R may be a potential therapeutic target for patients with different malignancies. However, its mechanism in NPC is not fully investigated. Linsitinib is an oral small molecule and is a tyrosine kinase inhibitor (TKI) of IGF-1R, which has been known for antitumor effects used widely. Here, we evaluated the proliferation and radiosensitivity of NPC cell lines (CNE-2 and SUNE-1) after linsitinib treatment. We found that linsitinib suppresses IGF-1-induced cell proliferation through inhibiting Akt and ERK phosphorylation. Moreover, linsitinib further boosted IR-induced DNA damage, G2-M cell cycle delay, and apoptosis in NPC cells. Finally, linsitinib reversed radioresistant NPC cells by decreasing the phosphorylation of IGF-1R. Our data indicated that the combination of linsitinib and IR and targeting IGF-1R by linsitinib could be a promising therapeutic strategy for NPC.

IGF-IR signaling in epithelial to mesenchymal transition and targeting IGF-IR therapy: overview and new insights.

The insulin-like growth factor-I (IGF-I) signaling induces epithelial to mesenchymal transition (EMT) program and contributes to metastasis and drug resistance in several subtypes of tumors. In preclinical studies, targeting of the insulin-like growth factor-I receptor (IGF-IR) showed promising anti-tumor effects. Unfortunately, high expectations for anti-IGF-IR therapy encountered challenge and disappointment in numerous clinical trials. This review summarizes the regulation of EMT by IGF-I/IGF-IR signaling pathway and drug resistance mechanisms of targeting IGF-IR therapy. Most importantly, we address several factors in the regulation of IGF-I/IGF-IR-associated EMT progression that may be potential predictive biomarkers in targeted therapy.

Hyperfibrinogenemia predicts poor prognosis in patients with advanced biliary tract cancer.

Hyperfibrinogenemia reportedly predicts poor prognosis in several cancers but has not been reviewed for biliary tract cancer (BTC). The aim of the present study was to evaluate associations between baseline plasma fibrinogen concentrations, clinicopathological characteristics, and survival parameters in patients with BTC. Data for 127 patients with BTC diagnosed at the Zhongshan Affiliated Hospital of Dalian University (Liaoning, China) from January 2011 to December 2014 were retrospectively evaluated. Associations between baseline fibrinogen concentrations, selected clinicopathological characteristics, and the prognostic value were examined using SPSS software. Data for 37 patients (29.1 % of study cohort) who had undergone curative intent surgery and 90 (70.9 %) with advanced biliary tract cancer (ABTC) were analyzed. The mean plasma fibrinogen concentration 4.0 ± 0.9 g/L for the entire cohort. The percentages with hyperfibrinogenemia (>4 g/L) were 45.7, 37.8, and 48.9 % overall and in the surgical and ABTC groups, respectively. Hyperfibrinogenemia was associated with performance status (PS) and neutrophil/lymphocyte ratio in the entire cohort but not with other relevant clinicopathological factors. Log-rank test indicated that baseline hyperfibrinogenemia was associated with decreased progression-free survival (PFS) and overall survival (OS) for patients with unresectable ABTC (P > 0.05). Multivariate analysis showed that poor PS and baseline hyperfibrinogenemia were independently associated with worse survival (HR: 1.39, 95 % CI: 1.02-1.90, P = 0.04; HR: 1.75.95 %, 95 % CI: 1.01-3.01, P = 0.04, respectively). Baseline hyperfibrinogenemia is an independent predictor of poor prognosis in patients with ABTC. Baseline plasma fibrinogen concentrations may be a readily available and inexpensive prognostic biomarker in patients with ABTC; this needs further validation in large prospective clinical trials.

Ubiquitin ligase Cbl-b represses IGF-I-induced epithelial mesenchymal transition via ZEB2 and microRNA-200c regulation in gastric cancer cells.

BACKGROUND: Insulin-like growth factor I (IGF-I) can induce epithelial mesenchymal transition (EMT) in many epithelial tumors; however, the molecular mechanism by which this occurs is not clearly understood. Additionally, little is known about the involvement of IGF-I in gastric cancer. METHODS: Two gastric cancer cell lines were treated with IGF-I to induce EMT and levels of transcription factor ZEB2 and microRNA-200c (miR-200c) were measured. Cells were treated with Akt/ERK inhibitors to investigate the role of these pathways in IGF-I-mediated EMT. Transfection of shRNA plasmids was used to silence the ubiquitin ligase Cbl-b to assess its involvement in this process. The relationship between IGF-IR and Cbl-b expression, and the effect of IGF-IR and Cbl-b on metastasis were analyzed in primary gastric adenocarcinoma patients. RESULTS: IGF-I-induced gastric cancer cell EMT was accompanied by ZEB2 up-regulation. Furthermore, both Akt/ERK inhibitors and knockdown of Akt/ERK gene reversed IGF-I-induced ZEB2 up-regulation and EMT through up-regulation of miR-200c, suggesting the involvement of an Akt/ERK-miR-200c-ZEB2 axis in IGF-I-induced EMT. The ubiquitin ligase Cbl-b also ubiquitinated and degraded IGF-IR and inhibited the Akt/ERK-miR-200c-ZEB2 axis, leading to the repression of IGF-I-induced EMT. There was a significant negative correlation between the expression of IGF-IR and Cbl-b in gastric cancer patient tissues (r = -0.265, p < 0.05). More of patients with IGF-IR-positive expression and Cbl-b-negative expression were with lymph node metastasis (p < 0.001). CONCLUSIONS: Together, these findings demonstrate that the ubiquitin ligase Cbl-b represses IGF-I-induced EMT, likely through targeting IGF-IR for degradation and further inhibiting the Akt/ERK-miR-200c-ZEB2 axis in gastric cancer cells.

Crown Ether Copolymerized Polyimide Film: Enhanced Mechanical, Thermal Properties and Low Dielectric Constant under High Frequency.

Polymer materials with a low dielectric constant and low dielectric loss have the potential to be applied to high-frequency signal transmissions, such as mobile phone antennas and millimeter wave radars. Two types of diamines, 4,4'-diamino-p-tetraphenyl (DPT) and crown ether diamine (CED), were prepared for ternary copolymerization with BPDA in this study. Cross-links with molecular chains were formed, increasing molecular chain distance by utilizing rings of CED. The MPI films exhibit a good thermal performance with the increase in CED addition, with Tg > 380 °C and CTE from -4 × 10-6 K-1 to 5 × 10-6 K-1. The Young's modulus can reach 8.6 GPa, and the tensile strength is above 200 MPa when 5% and 7% CED are introduced. These MPI films exhibit good mechanical performances. The dielectric constant of PI-10% film can go as low as 3.17. Meanwhile, the relationship between dielectric properties and molecular structure has been demonstrated by Molecular Simulation (MS). PI molecules are separated by low dielectric groups, resulting in a decrease in the dielectric constant.

Fluorine-functionalized covalent organic framework coated solid-phase microextraction probe coupled with electrospray ionization mass spectrometry for monitoring triclosan, triclocarban, and chlorophenols in mice.

Triclosan (TCS), triclocarban (TCC), and chlorophenols (CPs) are broad-spectrum antibacterials widely used in dermatological and oral hygiene products, which could induce severe liver and intestine injuries. Hence, it is essential to establish a rapid and sensitive method to monitor TCS, TCC, and CPs in various organisms. In this work, fluorine-functionalized covalent organic framework (COF-F) was prepared by using 4,4',4''-(1,3,5-triazine-2,4,6-triyl)tri-aniline and 2,3,5,6-tetrafluoroterephthalaldehyde as two building units and employed as a solid phase microextraction (SPME) probe for the extraction of TCS, TCC and CPs. The COF-F possessed excellent hydrophobicity, a large specific surface area (1354.3 m2 g-1) and high uniform porosity (3.2 nm), which facilitated high selectivity and adsorption properties towards TCS, TCC, and CPs. Therefore, the as-prepared COF-F-SPME in combination with electrospray ionization mass spectrometry has been developed to provide fast and ultrasensitive detection of TCS, TCC, and CPs in biological samples. The established method demonstrated satisfactory linear ranges (0.01-100.00 µg L-1) and low limits of detection (0.003-0.040 µg L-1) for TCS, TCC and CPs. The developed method could be successfully applied to detect TCS, TCC and CPs in the liver and kidney tissues of mice, demonstrating the potential for the detection of chlorinated aromatic pollutants in the biological samples.

Imidacloprid-induced lung injury in mice: Activation of the PI3K/AKT/NF-κB signaling pathway via TLR4 receptor engagement.

Significant impairment of pulmonary function has been demonstrated through long-term exposure to neonicotinoid insecticides, such as imidacloprid (IMI). However, the underlying mechanisms of lung injury induced by IMI remain unclear. In this study, a mouse model of IMI-induced pulmonary injury was established, and the toxicity and lung damage were assessed through mouse body weight, organ index, hematological parameters, and histopathological analysis of lung tissues. Furthermore, metabolomics and transcriptomics techniques were employed to explore the mechanistic aspects. Results from the toxicity assessments indicated that mouse body weight was significantly reduced by IMI, organ index was disturbed, and hematological parameters were disrupted, resulting in pulmonary injury. The mechanistic experimental results indicate that the differences in metabolites and gene expression in mouse lungs could be altered by IMI. Validation of the results through combined analysis of metabolomics and transcriptomics revealed that the mechanism by which IMI induces lung injury in mice might be associated with the activation of the TLR4 receptor, thereby activating the PI3K/AKT/NF-κB signaling pathway to induce inflammation in mouse lungs. This study provided valuable insights into the mechanisms underlying IMI-induced pulmonary damage, potentially contributing to the development of safer pest control strategies. The knowledge gained served as a robust scientific foundation for the prevention and treatment of IMI-related pulmonary injuries.

Adhesion and Transparency Enhancement between Flexible Polyimide-PDMS Copolymerized Film and Copper Foil for LED Transparent Screen.

With the increasing demand for innovative electronic products, LED transparent screens are gradually entering the public eye. Polyimide (PI) materials combine high temperature resistance and high transparency, which can be used to prepare flexible copper-clad laminate substrates. The physical and chemical properties of PI materials differ from copper, such as their thermal expansion coefficients (CTEs), surface energy, etc. These differences affect the formation and stability of the interface between copper and PI films, resulting in a short life for LED transparent screens. To enhance PI-copper interfacial adhesion, aminopropyl-terminated polydimethylsiloxane (PDMS) can be used to increase the adhesive ability. Two diamine monomers with a trifluoromethyl structure and a sulfone group structure were selected in this research. Bisphenol type A diether dianhydride is a dianhydride monomer. All three of the above monomers have non-coplanar structures and flexible structural units. The adhesion and optical properties can be improved between the interface of the synthesized PI films and copper foil. PI films containing PDMS 0, 1, 3, and 5 wt% were analyzed using UV spectroscopy. The transmittance of the PI-1/3%, PI-1/5%, PI-2/3%, and PI-2/5% films were all more than 80% at 450 nm. Meanwhile, the Td 5% and Td 10% heat loss and Tg temperatures decreased gradually with the increase in PDMS. The peel adhesion of PI-copper foil was measured using a 180° peel assay. The effect of PDMS addition on peel adhesion was analyzed. PIs-3% films had the greatest peeling intensities of 0.98 N/mm and 0.85 N/mm.

Morinda officinalis iridoid glycosides alleviate methotrexate-induced liver injury in CIA rats by increasing liver autophagy and improving lipid metabolism homeostasis.

ETHNOPHARMACOLOGICAL RELEVANCE: Morinda officinalis How. is a commonly used traditional Chinese herb with the pharmacological properties of tonifying liver and kidney, and enhancing bone and muscle. Iridoid glycosides are the predominant components of this plant, including monotropein, asperuloside, deacetylasperuloside and deacetylasperulosidic acid with their contents reaching more than 2%. Methotrexate (MTX) is the drug of choice for the treatment of rheumatoid arthritis (RA), but liver injury induced by MTX limits its wider use for RA. Morindaofficinalis iridoid glycoside (MOIG) is reported as having anti-RA and hepatoprotective effects, but the exact efficacy on MTX-induced liver injury and the underlying molecular mechanism remain unclear. AIM: To elucidate the mitigating effect of MOIG against liver injury in RA rats treated with MTX, and explore the possible mechanism. MATERIALS AND METHODS: The effect and mechanism of MOIG were investigated in Wistar rats with collagen-induced arthritis (CIA) which were then treated with MTX, and MTX-induced hepatocyte injury in vitro. Network pharmacological and transcriptomic analyses were conducted to predict the possible mechanisms of MOIG in mitigating MTX-induced liver injury, and lipidomic analysis was performed to further verify the regulatory effects of MOIG on lipid metabolism. BRL-3A hepatocytes were used to evaluate the regulatory effects of MOIG against MTX-associated liver injury. RESULTS: MOIG treatment enhanced the anti-RA effect of MTX, and mitigated oxidative damage, inflammation and apoptosis of liver tissues in CIA rats treated with MTX. Network pharmacological and transcriptomic analyses demonstrated that MOIG attenuated liver injury by regulating autophagy and lipid metabolism. The result of lipidomic analysis showed that MOIG reversed the disturbance of lipid metabolism of the liver tissue in CIA rats after MTX treatment. In addition, MOIG also inhibited the apoptosis, reduced the levels of lactate dehydrogenase (LDH), aspartate aminotransferase (ALT) and alanine aminotransferase (AST), regulated oxidative stress, and increased the formation of autophagosome and translocation of LC3 in the nucleus and expression of autophagy regulatory genes Beclin-1, ATG5, LC3Ⅱ, ATG7 and ATG12 in hepatocytes subjected to MTX damage. CONCLUSION: Our findings demonstrated that MOIG could ameliorate MTX-induced liver injury in the treatment of RA through increasing hepatocyte autophagy and improving lipid metabolism homeostasis.

Knockdown of Smox protects the integrity of the blood-brain barrier through antioxidant effect and Nrf2 pathway activation in stroke.

Once an ischemic stroke occurs, reactive oxygen species (ROS) and oxidative stress degrade the tight connections between cerebral endothelial cells resulting in their damage. The expression of antioxidant genes may be enhanced, and ROS formation may be reduced following Nrf2 activation, which is associated with protection against ischemic stroke. Overexpression of spermine oxidase (Smox) in the neocortex led to increased H2O2 production. However, how Smox impacts the regulation of the blood-brain barrier (BBB) through antioxidants has not been examined yet. We conducted experiments both in the cell level and in the transient middle cerebral artery occlusion (tMCAO) model to evaluate the effect of Smox siRNA lentivirus (si-Smox) knockdown on BBB protection against ischemic stroke. Mice treated with si-Smox showed remarkably decreased BBB breakdown and reduced endothelial inflammation following stroke. The treatment with si-Smox significantly elevated the Bcl-2 to Bax ratio and decreased the production of cleaved caspase-3 in the tMCAO model. Further investigation revealed that the neuroprotective effect was the result of the antioxidant properties of si-Smox, which reduced oxidative stress and enhanced CD31+ cells in the peri-infarct cortical areas. Of significance, si-Smox activated Nrf2 in both bEnd.3 cells and tMCAO animals, and blocking Nrf2 with brusatol diminished the protective effects of si-Smox. The study findings suggest that si-Smox exerts neuroprotective effects and promotes angiogenesis by activating the Nrf2 pathway, thus decreasing oxidative stress and apoptosis caused by tMCAO. As a result, si-Smox may hold potential as a therapeutic candidate for preserving BBB integrity while treating ischemic stroke.