Related Mechanisms Research Articles

Brain-derived neuerotrophic factor and related mechanisms that mediate and influence progesterone-induced neuroprotection.

Historically, progesterone has been studied significantly within the context of reproductive biology. However, there is now an abundance of evidence for its role in regions of the central nervous system (CNS) associated with such non-reproductive functions that include cognition and affect. Here, we describe mechanisms of progesterone action that support its brain-protective effects, and focus particularly on the role of neurotrophins (such as brain-derived neurotrophic factor, BDNF), the receptors that are critical for their regulation, and the role of certain microRNA in influencing the brain-protective effects of progesterone. In addition, we describe evidence to support the particular importance of glia in mediating the neuroprotective effects of progesterone. Through this review of these mechanisms and our own prior published work, we offer insight into why the effects of a progestin on brain protection may be dependent on the type of progestin (e.g., progesterone versus the synthetic, medroxyprogesterone acetate) used, and age, and as such, we offer insight into the future clinical implication of progesterone treatment for such disorders that include Alzheimer's disease, stroke, and traumatic brain injury.

Vagococcus fluvialis isolation from the urine of a bladder cancer patient: a case report

Vagococcus fluvialis infection is rare in humans, and there is limited research on the clinical manifestations and antimicrobial susceptibility testing of Vagococcus fluvialis infection. Here, We isolated Vagococcus fluvialis from the urine samples of bladder cancer patients at Hunan Provincial People’s Hospital, and it is the first reported case of Vagococcus fluvialis isolated from the urine. The fully automated microbial identification system and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) identified the bacterium as Vagococcus fluvialis with a confidence level of 99.9%. The VITEK-2Compact fully automated microbial susceptibility analysis system indicated that it was most sensitive to tigecycline, vancomycin, quinupristin/dalfopristin, linezolid, and showed moderate sensitivity to erythromycin, levofloxacin, ciprofloxacin, ampicillin/sulbactam, and tetracycline. Additionally, it exhibited synergy when combined with high-level gentamicin and vancomycin, showing sensitivity. However, it displayed poor activity against penicillin and furanth. According to our knowledge, this is the first study to isolate and identify Vagococcus fluvialis from the urine of bladder cancer patients and the systematically reviewed other reported Vagococcus infections on human, which provide an experimental basis for guiding the rational use of drugs in the clinical treatment and diagnose of Vagococcus fluvialis infection and related pathogenic mechanism research. Meanwhile, we have systematically reviewed other reported.

Roles of SP/KLF transcription factors in odontoblast differentiation: From development to diseases.

A zinc-finger transcription factor family comprising specificity proteins (SPs) and Krüppel-like factor proteins (KLFs) plays an important role in dentin development and regeneration. However, a systematic regulatory network involving SPs/KLFs in odontoblast differentiation has not yet been described. This review examined the expression patterns of SP/KLF gene family members and their current known functions and mechanisms in odontoblast differentiation, and discussed prospective research directions for further exploration of mechanisms involving the SP/KLF gene family in dentin development. Relevant literature on SP/KLF gene family members and dentin development was acquired from PubMed and Web of Science. We discuss the expression patterns, functions, and related mechanisms of eight members of the SP/KLF gene family in dentin development and genetic disorders with dental problems. We also summarize current knowledge about their complementary or synergistic actions. Finally, we propose future research directions for investigating the mechanisms of dentin development. The SP/KLF gene family plays a vital role in tooth development. Studying the complex complementary or synergistic interactions between SPs/KLFs is helpful for understanding the process of odontoblast differentiation. Applications of single-cell and spatial multi-omics may provide a more complete investigation of the mechanism involved in dentin development.

Spraying L-phenylalanine during fruit development alleviates chilling injury in harvested muskmelons by regulating membrane lipid metabolism

L-phenylalanine (L-Phe) is an aromatic essential amino acid. Although postharvest L-Phe treatment can alleviate chilling injury (CI) of fruit by scavenging excessive reactive oxygen species (ROS), there are no reports on whether L-Phe spraying during fruit development affects the CI of harvested muskmelon by regulating membrane lipid metabolism. In this study, plants and fruit of muskmelon (cv. Manao) were sequentially sprayed with 8 mM L-Phe four times at the young fruit stage, early expansion stage, late expansion stage and mature stage. The effect of L-Phe spraying during fruit development on CI of harvested muskmelon fruit was studied and to the related mechanism of membrane lipid metabolism was investigated. The results showed that L-Phe sprays activated phospholipase A2 (PLA2) and increased the content of unsaturated fatty acids such as linoleic acid, linolenic acid and oleic acid, and improved the double bond index of unsaturated fatty acids (DBI) in harvested muskmelons during cold storage. L-Phe sprays inhibited the phospholipase C (PLC) and phospholipase D (PLD), increased the content of phosphatidylinositol (PI) and phosphatidylcholine (PC), but decreased the content of phosphatidic acid (PA) in harvested muskmelons during cold storage. In addition, L-Phe sprays inhibited lipoxygenase (LOX), reduced malondialdehyde (MDA) levels and cell membrane permeability, and effectively reduced the CI index of harvested muskmelons during cold storage. Taken together, L-Phe sprays during fruit development alleviated CI in harvested muskmelons by regulating membrane lipid metabolism.

3-O-Methyl-D-Glucose Blunts Cold Ischemia Damage in Kidney via Inhibiting Ferroptosis

BackgroundThe glucose derivative 3-O-methyl-D-glucose (OMG) is used as a cryoprotectant in freezing cells. However, its protective role and the related mechanism in static cold storage (CS) of organs are unknown. The present study aimed to investigate the effect of OMG on cod ischemia damage in cold preservation of donor kidney. MethodsPretreatment of OMG on kidney was performed in an isolated renal cold storage model in rats. LDH activity in renal efflux was used to evaluate the cellular damage. Indicators including iron levels, mitochondrial damage, MDA level, and cellular apoptosis were measured. Kidney quality was assessed via a kidney transplantation (KTx) model in rats. The grafted animals were followed up for 7 days. Ischemia reperfusion (I/R) injury and inflammatory response were assessed by biochemical and histological analyses. ResultsOMG pretreatment alleviated prolonged CS-induced renal damage as evidenced by reduced LDH activities and tubular apoptosis. Kidney with pCS has significantly increased iron, MDA, and TUNEL+ cells, implying the increased ferroptosis, which has been partly inhibited by OMG. OMG pretreatment has improved the renal function (p <0.05) and prolonged the 7-day survival of the grafting recipients after KTx, as compared to the control group. OMG has significantly decreased inflammation and tubular damage after KTx, as evidenced by CD3-positive cells and TUNEL-positive cells. ConclusionOur study demonstrated that OMG protected kidney against the prolonged cold ischemia-caused injuries through inhibiting ferroptosis. Our results suggested that OMG might have potential clinical application in cold preservation of donor kidney.

MicroRNA-302a enhances 5-fluorouracil sensitivity in HepG2 cells by increasing AKT/ULK1-dependent autophagy-mediated apoptosis

Abstract Objectives MicroRNA-302a (miR-302a) has been implicated in the oncogenic processes, but its role in hepatocellular carcinoma (HCC) chemoresistance and related mechanisms are still unclear. Therefore, the aim of this study was to investigate the role of miR-302a in HCC chemoresistance and elucidate its underlying mechanism. Methods In this study, we detected the level of miR-302a in HCC tissues (including chemoresistant and chemosensitive tissues), non-tumor tissues, liver cancer cell lines, and 5-fluorouracil (5-FU)-resistant cells (HepG2/R). Additionally, we conducted cell viability, apoptosis, and autophagy analyses as well as assessed the levels of cleaved caspase-3, cleaved caspase-9, microtubule-associated protein 1 light chain 3 beta II (LC3B-II), Akt, and UNC-51 like kinase 1 (ULK1) in HepG2 cells transfected with miR-302a mimic or inhibitor prior to 5-FU treatment. Lastly, we predicted the target of miR-302a and verified the relationship between miR-302a and Akt by luciferase reporter and functional repair assays. Results Our results revealed that miR-302a was down-regulated in HCC tissues (p&lt;0.01), especially in chemoresistant tissues (p&lt;0.01). Consistently, the miR-302a level exhibited a lower expression in HepG2/R cells compared to their parental cells (p&lt;0.01). Furthermore, the 5-FU-induced apoptosis and autophagy of HepG2 cells were promoted by miR-302a over-expression and diminished by miR-302a inhibition (p&lt;0.01). Target analysis revealed that miR-302a could directly target Akt. Moreover, miR-302a inhibited Akt expression and subsequently elevated ULK1 expression (p&lt;0.01). Inhibition of ULK1 could abrogate the sensitization of overexpressed miR-302a to 5-FU in HepG2 cells (p&lt;0.01). Conclusions Altogether, our results demonstrate that the down-regulation of miR-302a promotes 5-FU resistance in HCC by attenuating the Akt/ULK1 axis-dependent autophagy and apoptosis.

Exploring tensions of Industry 4.0 adoption in lean production systems from a dialectical perspective

PurposeThis paper uses dialectical inquiry to explore tensions that arise when adopting Industry 4.0 technologies in a lean production system and their reconciliation mechanisms.Design/methodology/approachWe conducted an in-depth qualitative case study over a 3-year period on an Italian division of an international electrotechnical organisation that produces electrical switches. This organisation successfully adopted Industry 4.0 technologies in a lean production system. The study is based on primary data such as observations and semi-structured interviews, along with secondary data.FindingsWe identify four empirically validated dialectic tensions arising across different Industry 4.0 adoption stages due to managers’ and workers’ contrasting interpretations of technologies. Consequently, we define the related reconciliation mechanisms that allow the effective adoption of various Industry 4.0 technologies to support a lean production system.Originality/valueThis is the first empirical investigation of tensions in the adoption of Industry 4.0 technologies in a lean production system. Furthermore, the paper presents four theoretical propositions and a conceptual model describing which tensions arise during the adoption of Industry 4.0 technologies in a lean production system and the reconciliation mechanisms that prevent lean production system deterioration.

Unraveling Interface-Driven and Loss Mechanism-Centric Phenomena in 3D/2D Halide Perovskites: Prospects for Optoelectronic Applications.

In recent years, organic-inorganic metal halide perovskite solar cells (PSCs) have attracted considerable interest due to their remarkable and rapidly advancing efficiencies. Over the past decade, PSC efficiencies have significantly approached those of state-of-the-art silicon-based photovoltaics, making them a promising material. Currently, the scientific community widely recognizes the performance of 3D-PSCs and 2D-PSCs individually. However, when both are combined to form a heterostructure, the lattice and charge dynamics at the interface undergo a multitude of mechanisms that affect their performance. The interface between heterostructures facilitates the degradation of PSCs. The degradation pathways can be attributed to lattice distortions, inhomogeneous energy landscapes, interlayer ion migration, nonradiative recombination, and charge accumulation. This Review is dedicated to examining the phenomena that arise at the interface of 3D/2D halide perovskites and their related photophysical properties and loss mechanism processes. We mainly focus on the impact of lattice mismatch, energy level alignment, anomalous carrier dynamics, and loss mechanisms. We propose a "cause-impact-identify-rectify" approach to gain a comprehensive understanding of the ultrafast processes occurring within the material. Finally, we highlight the importance of advanced spectroscopic and imaging techniques in unraveling these intricate mechanisms. This discussion delves into the future possibilities of fabricating 3D/2D heterostructure-based optoelectronic devices, pushing the boundaries of performance across diverse fields. It envisions the creation of devices with unparalleled capabilities, exceeding the limitations of current technologies.

Antitumoral Potential of the Histone Demethylase Inhibitor GSK-J4 in Retinoblastoma.

The purpose of this study was to investigate the antitumor effects of GSK-J4 on retinoblastoma, as well as its related biological functions and molecular mechanisms. The antitumor effect of GSK-J4 on retinoblastoma was evaluated by in vitro and in vivo assays. CCK-8, EdU incorporation, and soft agar colony formation assays were performed to examine the effect of GSK-J4 on cell proliferation. Flow cytometry was used to evaluate the effect of GSK-J4 on the cell cycle and apoptosis. RNA-seq and Western blotting were conducted to explore the molecular mechanisms of GSK-J4. An orthotopic xenograft model was established to determine the effect of GSK-J4 on tumor growth. GSK-J4 significantly inhibited retinoblastoma cell proliferation both in vitro and in vivo, arrested the cell cycle at G2/M phase, and induced apoptosis. Mechanistically, GSK-J4 may suppress retinoblastoma cell growth by regulating the PI3K/AKT/NF-κB signaling pathway. The antitumor effects of GSK-J4 were noticeable in retinoblastoma and were at least partially mediated by PI3K/AKT/NF-κB pathway suppression. Our study provides a novel strategy for the treatment of retinoblastoma.

Unraveling psychological dilemma among miners in the context of low-carbon transformation: an ISM-MICMAC approach

Purpose With the rapid low-carbon transformation in China, the industrial approach and labor structure of mining enterprises are undergoing constant changes, leading to an increasing psychological dilemma faced by coal miners. This study aims to reveal the relationship and mechanism of factors influencing the psychological dilemma of miners, and to provide optimal intervention strategies for the safety and sustainable development of employees and enterprises. Design/methodology/approach To effectively address the complex issue of the psychological dilemma faced by miners, this study identifies and constructs five-dimensional elements, comprising 20 indicators, that influence psychological dilemmas. The relational mechanism of action of factors influencing psychological dilemma was then elucidated using an integration of interpretive structural modeling and cross-impact matrix multiplication. Findings Industry dilemma perception is a “direct” factor with dependent attributes. The perceptions of management response and relationship dilemmas are “root” factors with driving attributes. Change adaptation dilemma perception is a “susceptibility” factor with linkage attributes. Work dilemma perception is a “blunt” factor with both dependent and autonomous attributes. Originality/value The aforementioned findings offer a critical theoretical and practical foundation for developing systematic and cascading intervention strategies to address the psychological dilemma mining enterprises face, which contributes to advancing a high-quality coal industry and efficient energy development.

Aerobic exercise modulates the striatal Erk/MAPK signaling pathway and improves LID in a mouse model of Parkinson's disease

ObjectiveTo investigate the role of the striatal extracellular signal-regulated kinase (Erk1/2) and its phosphorylation (p-Erk1/2) in aerobic training to alleviate the development of the L-DOPA induced dyskinesia (LID) in PD mice. MethodsForty-eight male C57BL/6 N mice were randomly divided into the 6-OHDA surgery group (6-OHDA, n=42) and the sham surgery group (Sham, n=6). A two-point injection of 6-OHDA into the right striatum was used to establish a lateralized injury PD model. PD mice were randomly divided into a PD control group (PD, n=13) and a PD exercise group (PDE, n=16), this is followed by 4 weeks of L-DOPA treatment, and PDE mice received concurrent running table training (18 m/min, 40 min/day, 5 times/week). AIM scores were performed weekly, and mice were assessed for motor function after 4 weeks using the rotarod, open field, and gait tests. Immunohistochemistry was used to test nigrostriatal TH expression, Western blot was used to determine Erk1/2 and p-Erk1/2 protein expression, and immunofluorescence double-labeling technique was used to detect Erk1/2 and p-Erk1/2 co-expression with prodynorphin (PDYN). Results(1) All AIM scores of PD and PDE mice increased significantly (P < 0.05) with the prolongation of L-DOPA treatment. Compared with PD, all AIM scores were significantly lower in PDE mice (P < 0.05). (2) After 4 weeks, the motor function of PD mice was significantly reduced compared with Sham (P < 0.05 or P < 0.01); compared with PD, the motor function of PDE mice was significantly increased (P < 0.05). (3) Compared with Sham, the expression of Erk1/2 protein, the number of positive cells of Erk1/2 and p-Erk1/2 and the number of positive cells co-expressed with PDYN were significantly increased in PD mice (P < 0.05); compared with PD, Erk1/2 protein expression was significantly decreased in PDE mice (P < 0.05), and the number of Erk1/2 and p-Erk1/2 positive cells was significantly reduced (P < 0.05). Conclusion4 weeks of aerobic exercise can effectively alleviate the development of L-DOPA-induced dyskinesia and improve motor function in PD mice. The related mechanism may be related to the inhibition of striatal Erk/MAPK signaling pathway overactivation by aerobic exercise, but this change did not occur selectively in D1-MSNs.

Oxidative Dissolution Mechanisms of Pyrite {100} and {210} Faces: An Atomic Study

ABSTRACT The oxidative dissolution of pyrite discharging into tailing pond as gangue minerals attracts intensive interesting as this forms the main source of acid mine drainage. However, the related dissolution mechanisms on the individual crystal faces of pyrite particles remain unclear. In this study, the oxidative dissolution mechanisms of pyrite {100} and {210} faces under acidic and neutral conditions were investigated. The results indicated that the dissolution rate of pyrite correlates positively to the reactivity of pyrite face. The reactivity of {210} was higher than that of {100}, mainly due to the geometric arrangements of the atoms. In addition, the oxidative dissolution on pyrite faces follows the chemical reaction model. Further density functional theoretical (DFT) calculation indicated that {210} face showed obvious Fe-S breakage and S-S formation while {100} face only showed slight atoms movement during relaxation process. Moreover, a higher conductivity and electron transfer ability of {210} faces than that of {100} face was found base on scanning electrochemical microscopy. This study therefore provides new insights into oxidative dissolution of pyrite crystal faces at an atomic level.

Multiscale evaluation of hydrogen-assisted mechanical degradation in grade 2 titanium

The mechanism of hydrogen embrittlement in grade 2 titanium was studied by a combined micro and nanoscale approach. Insights into the hydrogen related deformation and degradation mechanisms were acquired via a unique characterisation procedure, correlating the topological observations on the fracture surface after tensile testing to the dislocation arrangement underneath. Focused ion beam lift-out was employed to extract a subsurface slice perpendicular to the fracture surface. High resolution characterisation provided information about the dislocation configuration and active hydrogen-assisted degradation mechanism. A high hydrogen content forms a brittle titanium hydride phase, failing via hydride cleavage. At a moderate hydrogen quantity, hydrogen in solid solution is responsible for a ductility decrease via the hydrogen-enhanced localised plasticity mechanism.

Insight into the Alkali Resistance Mechanism of FeMoTiOx Catalysts for NH3 Selective Catalytic Reduction of NO: Self-Defense Effects of MoOx for Alkali Capture.

The deactivation of selective catalytic reduction (SCR) catalysts caused by alkali metal poisoning remains an insurmountable challenge. In this study, we examined the impact of Na poisoning on the performance of Fe and Mo co-doped TiO2 (FeaMobTiOx) catalysts in the SCR reaction and revealed the related alkali resistance mechanism. On the obtained Fe1Mo2.6TiOx catalyst, the synergistic catalytic effect of uniformly dispersed FeOx and MoOx species leads to remarkable catalytic activity, with over 90% NO conversion achieved in a wide temperature range of 210-410 °C. During the Na poisoning process, Na ions predominantly adsorb on the MoOx species, which exhibit stronger alkali resistance, effectively safeguarding the FeOx species. This preferential adsorption minimizes the negative effect of Na poisoning on Fe1Mo2.6TiOx. Moreover, Na poisoning has little influence on the Eley-Rideal reaction pathway involving adsorbed NHx reacting with gaseous NOx. After Na poisoning, the Lewis acid sites were deteriorated, while the abundant Brønsted acid sites ensured sufficient NHx adsorption. As a benefit from the self-defense effects of active MoOx species for alkali capture, FeaMobTiOx exhibits exceptional alkali resistance in the SCR reaction. This research provides valuable insights for the design of highly efficient and alkali-resistant SCR catalysts.

The role of relational mechanisms in the executive coaching process on client outcomes in distance coaching relationships

PurposeWe examine the relationships between clients’ level of coaching readiness and trust in their executive coach and increases to both personal learning improved work performance. Distance relationships, the setting for this study, epitomize the norms of the New World of Work (NWoW), but also provide particular challenges for building trust and recognizing similarities between client and coach.Design/methodology/approachThis study investigates distance coaching relationships in matched-pairs, longitudinal investigation of formal executive coaching.FindingsResults support the proposed moderated mediation path. Findings reveal that both coaches’ perceptions of client readiness for coaching and client trust in coach each predict both client personal skill development and performance improvement.Research limitations/implicationsWhile important toward gaining a better understanding of the relational functioning of distance coaching relationships, inclusion of only distance relationships may truncate the generalizability of our findings.Practical implicationsThe study’s findings have practical implications for organizations that invest in executive coaching with regard to the importance of evaluating the candidates' readiness for coaching before the assignment, trust-building throughout distance coaching relationships and perceptions of similarity on client coaching outcomes.Originality/valueDistance relationships, the setting for this study, provide particular challenges for building trust and recognizing similarities between client and coach and the current investigation points to the relevance of these relational mechanisms to client outcomes. In so doing, this study explores how perceptions of deep-level similarity between a coach and client may serve as moderators of these relationships.

PFKFB3 facilitates cell proliferation and migration in anaplastic thyroid carcinoma via the WNT/β-catenin signaling pathway.

Despite the involvement of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase3 (PFKFB3) in the proliferation and metastasis of diverse tumor types, its biological functions and related molecular mechanisms in anaplastic thyroid carcinoma (ATC) remain largely unclear. Datasets from the Gene Expression Omnibus, the Cancer Genome Atlas and immunohistochemistry (IHC) analyses were employed to measure the expression level of PFKFB3 in ATC. A series of assays were performed to analyze the role of PFKFB3 and its inhibitor KAN0438757 in ATC cell proliferation and migration. Furthermore, Western blotting (WB), IHC and luciferase reporter assay were conducted to investigate the potential mechanisms underlying the involvement of PFKFB3 and KAN0438757 in ATC. Additionally, we established a subcutaneous xenograft tumor model in nude mice to evaluate the in vivo tumor growth. PFKFB3 exhibited a significant increase in its expression level in ATC tissues. The overexpression of PFKFB3 resulted in the stimulation of ATC cell proliferation and migration. Furthermore, this overexpression was associated with the elevated expression levels of p-AKT (ser473), p-GSK3α/β (ser21/9), nuclear β-catenin, fibronectin1 (FN1), matrix metallopeptidase 9 (MMP-9) and cyclin D1. It also promoted the nuclear translocation of β-catenin and the transcription of downstream molecules. Conversely, contrasting results were observed with the downregulation or KAN0438757-mediated inhibition of PFKFB3 in ATC cells. The selective AKT inhibitor MK2206 was noted to reverse the increased expression of p-AKT (ser473) and p-GSK3α/β (ser21/9) induced by PFKFB3 overexpression. The level of lactate was increased in PFKFB3-overexpressing ATC cells, while the presence of KAN0438757 inhibited lactate production. Moreover, the simultaneous use of PFKFB3 downregulation and KAN0438757 was found to suppress subcutaneous tumor growth in vivo. PFKFB3 can enhance ATC cell proliferation and migration via the WNT/β-catenin signaling pathway and plays a crucial role in the regulation of aerobic glycolysis in ATC cells.

Circ-Luc7l Absence Attenuates Diabetic Nephropathy Progression by Reducing Mesangial Cell Excessive Proliferation, Inflammation, and Extracellular Matrix Accumulation via Mediating the miR-205-5p/Tgfbr1 Pathway.

Diabetic nephropathy (DN) threatens the survival quality of patients, with complex pathogenesis. Circular RNA (circRNA) dysregulation occurs in DN development. This work aimed to investigate the role of circ-Luc7l in DN cell models and related molecular mechanisms. The expression of circ-Luc7l, microRNA (miR)-205-5p, and transforming growth factor-beta receptor 1 (Tgfbr1) was examined by real-time quantitative PCR (RT-qPCR). Cell viability and proliferation were detected by Cell Counting Kit-8 (CCK-8) assay and EdU assay. The expression of extracellular matrix (ECM)-related markers and Tgrbr1 protein was measured by Western blot. The binding between miR-205-5p and circ-Luc7l or Tgfbr1 was validated by dual-luciferase reporter assay, RNA immunoprecipitation (RIP) assay, or RNA pull-down assay. Experimental animal models were established to elucidate the function of circ-Luc7l in vivo. Circ-Luc7l expression was notably enhanced in high glucose (HG)-treated mesangial cells. Knockdown of circ-Luc7l attenuated HG-induced cell proliferation, inflammation, and ECM accumulation in vitro and relieved inflammation and ECM accumulation of kidneys of diabetic mice in vivo. Circ-Luc7l targeted miR-205-5p, and miR-205-5p inhibition rescued the depletion effects of circ-Luc7l knockdown on cell proliferation, inflammation, and ECM accumulation. MiR-205-5p bound to Tgfbr1 whose expression was negatively regulated by circ-Luc7l. Tgfbr1 overexpression also rescued the depletion effects of circ-Luc7l knockdown on cell proliferation, inflammation, and ECM accumulation. In HG conditions, increased circ-Luc7l upregulated Tgfbr1 expression via targeting miR-205-5p to induce DN progression.

Chronic restraint stress induces abnormal behaviors in pain sensitivity and cognitive function in mice: the role of Keap1/Nrf2 pathway

Stress is a series of physical and psychological responses to external and internal environmental stimuli. Growing studies have demonstrated the detrimental impacts of acute restraint stress (ARS) and chronic restraint stress (CRS) on animal behavior. However, the related pathogenesis and therapeutic mechanisms remain unclear. Hence, the present study aimed to examine whether unfolded protein response (UPR) and Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2 related factor 2 (Nrf2) pathway are associated with ARS- and CRS- induced abnormal behaviors of pain sensitivity and cognitive function. We here used four behavioral tests to evaluate pain sensitivity and cognitive function in ARS and CRS mice. CRS markedly decreased Paw Withdrawal Mechanical Threshold (PWMT) and Tail-flick Latency (TFL) scores, whereas ARS altered TFL but had no effect on PWMT scores. Additionally, CRS, but not ARS, significantly changed behaviors in nest building behavior and MWMT. Intriguingly, the expression of Keap1 and Nrf2 protein were decreased in the spinal cord and hippocampus in CRS mice, but not in ARS mice. Moreover, neither the ARS nor the CRS groups significantly differed from the control group in terms of endoplasmic reticulum stress (ERS). Taken together, this study demonstrated that CRS could induce abnormal pain sensitivity and cognitive function probably via Keap1/Nrf2 pathway in spinal cord and hippocampus. It is therefore likely that effective intervention of Keap1/Nrf2 pathway may contribute to preventing and treating hyperalgesia and cognitive dysfunction in CRS.

Ligand-Functionalized MIL-68-type Indium(III) Metal-Organic Frameworks with Prominent Intrinsic Proton Conductivity.

Indium-based metal-organic frameworks (In-MOFs) have now become an attractive class of porous solids in materials science and electrochemistry due to their diverse structures and promising applications. In the field of proton conduction, to find more crystalline MOFs with splendid proton-conductive properties, herein, five three-dimensional isostructural In-MOFs, MIL-68-In or MIL-68-In-X (X = NH2, OH, Br, or NO2) using terephthalic acid (H2BDC) or functionalized terephthalic acids (H2BDC-X) as multifunctional linkages were efficiently fabricated. First, the outstanding structural stability of the five MOFs, including thermal and water stability, was verified by thermal analysis and powder X-ray diffraction. Subsequently, the H2O-mediated proton conductivities (σ) were fully assessed and compared. Notably, their σ evinced a significant positive correlation between the temperature or relative humidity (RH) and varied with the functional groups on the organic ligands. Impressively, their highest σ values are up to 10-3-10-4 S/cm (100 °C/98% RH) and change in this order: MIL-68-In-OH (1.72 × 10-3 S/cm) > MIL-68-In-NH2 (1.70 × 10-3 S/cm) > MIL-68-In-NO2 (4.47 × 10-4 S/cm) > MIL-68-In-Br (4.11 × 10-4 S/cm) > MIL-68-In (2.37 × 10-4 S/cm). Finally, the computed activation energy values under 98 or 68% RHs are assessed, and the related proton conduction mechanisms are speculated. Moreover, after electrochemical testing, these MOFs illustrate remarkable structural rigidity, laying a meritorious material foundation for future applications.

Salvianolic acid extract prevents Tripterygium wilfordii polyglycosides-induced acute liver injury by modulating bile acid metabolism

Ethnopharmacological relevanceTripterygium wilfordii polyglycosides (TWP) tablet is the most widely used traditional Chinese medicine preparation for the treatment of rheumatoid arthritis (RA), but the hepatotoxicity often limits its widespread application. In traditional use, Salvia miltiorrhiza has cardioprotective and hepatoprotective effects. Salvianolic acid extract (SA) is a hydrophilic component of Salvia miltiorrhiza and has significant antioxidant and hepatoprotective effects. Aim of the studyTo investigate the protective effects of SA on the TWP-induced acute liver injury in rats and to explore the related mechanisms by integration of metabolomics and transcriptomics. Materials and methodsSA and TWP extracts were identified by UPLC-Q/TOF-MS. SA (200 mg/kg) was administered for consecutive 7 days. On day 7, TWP (360 mg/kg) was administered by gavage to induce the acute liver injury in rats. Serum biochemical assay and H&E staining were used to evaluate liver damage. Liver metabolomics and transcriptomics were used to explore the potential mechanisms, and further molecular biological experiments such as qPCR and IHC were utilized to validate the relevant signaling pathways. ResultsSA can prevent liver injury symptoms caused by TWP, such as elevated liver index, elevated ALT and AST, and pathological changes in liver tissue. Liver metabolomics studies showed that TWP can significantly alter the content of individual bile acid in the liver and SA had the most significant impact on the biosynthetic pathway of bile acids. The transcriptomics results of the liver indicated that the genes changed in the SA + TWP group were mainly involved in sterol metabolism, lipid regulation and bile acid homeostasis pathways. The gene expression of Nr1h4, which encodes farnesoid X receptor (FXR), an important regulator of bile acid homeostasis, was significantly changed. Further studies confirmed that SA can prevent the downregulation of FXR and its downstream signaling induced by TWP, thereby regulating bile acid metabolism, ultimately preventing acute liver injury caused by TWP. ConclusionOur results demonstrated that SA could protect the liver from TWP-induced hepatic injury by modulation of the bile acid metabolic pathway. SA may provide a new strategy for the protection against TWP-induced acute liver injury.