Biological role and expression of translationally controlled tumor protein (TCTP) in tumorigenesis and development and its potential for targeted tumor therapy.

Translationally controlled tumor protein (TCTP), also known as histamine-releasing factor (HRF) or fortilin, is a highly conserved protein found in various species. To date, multiple studies have demonstrated the crucial role of TCTP in a wide range of cellular pathophysiological processes, including cell proliferation and survival, cell cycle regulation, cell death, as well as cell migration and movement, all of which are major pathogenic mechanisms of tumorigenesis and development. This review aims to provide an in-depth analysis of the functional role of TCTP in tumor initiation and progression, with a particular focus on cell proliferation, cell death, and cell migration. It will highlight the expression and pathological implications of TCTP in various tumor types, summarizing the current prevailing therapeutic strategies that target TCTP.

Sampled-Data H∞ Dynamic Output-Feedback Control for NCSs With Successive Packet Losses and Stochastic Sampling.

The problem of sampled-data H∞ dynamic output-feedback control for networked control systems with successive packet losses (SPLs) and stochastic sampling is investigated in this article. The aim of using sampled-data control techniques is to alleviate network congestion. SPLs that occur in the sensor-to-controller (S-C) and controller-to-actuator (C-A) channels are modeled using a packet loss model. Additionally, it is assumed that stochastic sampling follows a Bernoulli distribution. A model is established to capture the stochastic characteristics of both the SPL model and stochastic sampling. This model is crucial as it allows us to determine the probability distribution of the sampling interval between successive update instants, which is essential for stability analysis. An exponential mean-square stability condition for the constructed equivalent discrete-time stochastic system, which also guarantees the prescribed H∞ performance, is established by incorporating probability theory. The desired controller is designed using a step-by-step synthesis approach, which may offer lower design conservatism compared to some existing methods. Finally, our designed approach using a networked F-404 engine system model is validated and its merits relative to existing results are discussed. The proposed method is finally validated by employing a networked model of the F-404 engine system. Furthermore, the advantages of our method are presented in comparison to previous results.

Stability and integrity of self-assembled bovine parvovirus virus­like particles (BPV­VLPs) of VP2 and combination of VP1VP2 assisted by baculovirus-insect cell expression: a potential logistical platform for vaccine deployment.

BACKGROUND: Bovine parvovirus (BPV) is an autonomous DNA virus with a smaller molecular size and subtle differences in its structural proteins, unlike other animal parvoviruses. More importantly, this virus has the potential to produce visible to silent economic catastrophes in the livestock business, despite receiving very little attention. Parvoviral virus-like particles (VLPs) as vaccines and as logistical platforms for vaccine deployment are well studied. However, no single experimental report on the role of VP1 in the assembly and stability of BPV-VLPs is available. Furthermore, the self-assembly, integrity and stability of the VLPs of recombinant BPV VP2 in comparison to VP1 VP2 Cap proteins using any expression method has not been studied previously. In this study, we experimentally evaluated the self-assembling ability with which BPV virus-like particles (VLPs) could be synthesized from a single structural protein (VP2) and by integrating both VP2 and VP1 amino acid sequences. METHODS: In silico and experimental cloning methods were carried out. His-tagged and without-His-tag VP2 and V1VP2-encoding amino acid sequences were cloned and inserted into pFastbacdual, and insect cell-generated recombinant protein was evaluated by SDS‒PAGE and western blot. Period of infectivity and expression level were determined by IFA. The integrity and stability of the BPV VLPs were evaluated by transmission electron microscopy. The secondary structure of the BPV VLPs from both VP2 and V1VP2 was analyzed by circular dichroism. RESULTS: Our findings show that VP2 alone was equally expressed and purified into detectable proteins, and the stability at different temperatures and pH values was not appreciably different between the two kinds of VLPs. Furthermore, BPV-VP2 VLPs were praised for their greater purity and integrity than BPV-VP1VP2 VLPs, as indicated by SDS‒PAGE. Therefore, our research demonstrates that the function of VP1 has no bearing on the stability or integrity of BPV-VLPs. CONCLUSIONS: In summary, incredible physiochemically stable BPV VP2-derived VLPs have been found to be promising candidates for the development of multivalent vaccines and immunodiagnostic kits against enteric viruses and to carry heterogeneous epitopes for various economically important livestock diseases.

Prelimbic cortex-nucleus accumbens core projection positively regulates itch and itch-related aversion.

Itch is one of the most common clinical symptoms in patients with diseases of the skin, liver, or kidney, and it strongly triggers aversive emotion and scratching behavior. Previous studies have confirmed the role of the prelimbic cortex (Prl) and the nucleus accumbens core (NAcC), which are reward and motivation regulatory centers, in the regulation of itch. However, it is currently unclear whether the Prl-NAcC projection, an important pathway connecting these two brain regions, is involved in the regulation of itch and its associated negative emotions. In this study, rat models of acute neck and cheek itch were established by subcutaneous injection of 5-HT, compound 48/80, or chloroquine. Immunofluorescence experiments determined that the number of c-Fos-immunopositive neurons in the Prl increased during acute itch. Chemogenetic inhibition of Prl glutamatergic neurons or Prl-NAcC glutamatergic projections can inhibit both histaminergic and nonhistaminergic itch-scratching behaviors and rectify the itch-related conditioned place aversion (CPA) behavior associated with nonhistaminergic itch. The Prl-NAcC projection may play an important role in the positive regulation of itch-scratching behavior by mediating the negative emotions related to itch.

High-dose Vitamin C injection ameliorates against sepsis-induced myocardial injury by anti-apoptosis, anti-inflammatory and pro-autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR signaling pathways in rats.

AIMS: This study aimed to evaluate the effects of VC on SIMI in rats. METHODS: In this study, the survival rate of high dose VC for SIMI was evaluated within 7 days. Rats were randomly assigned to three groups: Sham group, CLP group, and high dose VC (500 mg/kg i.v.) group. The animals in each group were treated with drugs for 1 day, 3 days or 5 days, respectively. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1ß, IL-6, IL-10 and TNF-α) in serum were measured using ELISA kits. Western blot was used to detect proteins related to apoptosis, inflammation, autophagy, MAPK, NF-κB and PI3K/Akt/mTOR signaling pathways. RESULTS: High dose VC improved the survival rate of SIMI within 7 days. Echocardiography, HE staining and myocardial enzymes showed that high-dose VC relieved SIMI in rats in a time-dependent manner. And compared with CLP group, high-dose VC decreased the expressions of pro-apoptotic proteins, while increased the expression of anti-apoptotic protein. And compared with CLP group, high dose VC decreased phosphorylation levels of Erk1/2, P38, JNK, NF-κB and IKK α/ß in SIMI rats. High dose VC increased the expression of the protein Beclin-1 and LC3-II/LC3-I ratio, whereas decreased the expression of P62 in SIMI rats. Finally, high dose VC attenuated phosphorylation of PI3K, AKT and mTOR compared with the CLP group. SIGNIFICANCE: Our results showed that high dose VC has a good protective effect on SIMI after continuous treatment, which may be mediated by inhibiting apoptosis and inflammatory, and promoting autophagy through regulating MAPK, NF-κB and PI3K/AKT/mTOR pathway.

Dual-functional ionic liquids additive enables dendrite-free Zn anode with ultra-long cycle life over one year.

Zn anodes suffer from the formation of uncontrolled dendrites aggravated by the uneven electric field and the insulating by-product accumulation in aqueous zinc-ion batteries (AZIBs). Here, an effective strategy implemented by 1-butyl-3-methylimidazolium hydrogen sulfate (BMIHSO4) additive is proposed to synergistically tune the crystallographic orientation of zinc deposition and suppress the formation of zinc hydroxide sulfate for enhancing the reversibility on Zn anode surface. As a competing cation, BMI+ is proved to preferably adsorb on Zn-electrode compared with H2O molecules, which shields the "tip effect" and inhibits the Zn-deposition agglomerations to inducing the horizontal growth along Zn (002) crystallographic texture. Simultaneously, the protonated BMIHSO4 additives could remove the detrimental OH- in real-time to fundamentally eliminate the accumulation of 6Zn(OH)2·ZnSO4·4H2O and Zn4SO4(OH)6·H2O on Zn anode surface. Consequently, Zn anode exhibits an ultra-long cycling stability of one year (8762 h) at 0.2 mA cm-2/0.2 mAh cm-2, 3600 h at 2 mA cm-2/2 mAh cm-2 with a high plating cumulative capacity of 3.6 Ah cm-2, and a high average Coulombic efficiency of 99.6 % throughout 1000 cycles. This work of regulating Zn deposition texture combined with eliminating notorious by-products could offer a desirable way for stabilizing the Zn-anode/electrolyte interface in AZIBs.

Macroscale preparation of CoS2 nanoparticles for ultra-high fast-charging performance in sodium-ion batteries.

Improving the fast-charging capabilities and energy storage capacity of electric vehicles presents a feasible strategy for mitigating the prevalent concern of range anxiety in the market. Nanostructure electrode materials play a crucial role in this process. However, the current method of preparation is arduous and yields restricted quantities. In view of this, we have devised an innovative approach that provides convenience and efficacy, facilitating the large-scale synthesis of CoS2 nanoparticles, which exhibited exceptional performance. When the current density was 1000 mA g-1, the discharging capacity reached 760 mAh g-1 after 400 cycles. Remarkably, even at an increased current density of 5000 mA g-1, the discharging capacity of CoS2 remained at 685.5 mAh g-1. The ultra-high performance could be attributed to the specific surface area, which minimized the diffusion distance of sodium-ions during the charging and discharging processes and mitigated the extent of structural damage. Our straightforward preparation techniques facilitate the mass production and present a novel approach for the development of cost-effective and high-performing anode materials for sodium-ion batteries.

Acetylated tau exacerbates apoptosis by disturbing mitochondrial dynamics in HEK293 cells.

An increase in tau acetylation at K274 and K281 and abnormal mitochondrial dynamics have been observed in the brains of Alzheimer's disease (AD) patients. Here, we constructed three types of tau plasmids, TauKQ (acetylated tau mutant, by mutating its K274/K281 into glutamine to mimic disease-associated lysine acetylation), TauKR (non-acetylated tau mutant, by mutating its K274/K281 into arginine), and TauWT (wild-type human full-length tau). By transfecting these tau plasmids in HEK293 cells, we found that TauWT and TauKR induced mitochondrial fusion by increasing the level of mitochondrial fusion proteins. Conversely, TauKQ induced mitochondrial fission by reducing mitochondrial fusion proteins, exacerbating mitochondrial dysfunction and apoptosis. BGP-15 ameliorated TauKQ-induced mitochondrial dysfunction and apoptosis by improving mitochondrial dynamics. Our findings suggest that acetylation of K274/281 represents an important post-translational modification site regulating mitochondrial dynamics, and that BGP-15 holds potential as a therapeutic agent for mitochondria-associated diseases such as AD.

Short-term clinical efficacy observation of lesion removal, bone graft fusion, and external brace treatment for late-stage wrist tuberculosis / 中国骨伤

OBJECTIVE@#To observe the clinical efficacy of lesion removal, bone grafting, fusion, and external fixation in the treatment of late-stage wrist tuberculosis.@*METHODS@#From October 2015 to May 2019, 25 patients with late-stage wrist tuberculosis were treated using lesion removal, bone grafting, fusion, and external fixation. Among these patients, there were 14 males and 11 females, aged from 40 to 74 years old, with an average age of (60.72±8.45) years old. The duration of the disease ranged from 5 to 24 months, with an average of (11.52±7.61) months. There were 11 cases of left wrist tuberculosis and 14 cases of right wrist tuberculosis, with 5 cases accompanied by sinus formation. Postoperative regular anti-tuberculosis treatment was continued. Visual analogue score (VAS), inflammatory indicators, Gartland-Werley wrist function score, and upper limb function score were observed before and after treatment.@*RESULTS@#All 25 patients were followed up for ranging from 12 to 36 months with an average of (19.7±6.3) months. At the latest follow-up, all wounds were healed satisfactorily, and there was no recurrence of tuberculosis or infection. VAS at one week before operation and three months after operation were (5.16±1.14) score and (1.68±0.80) score respectively. One week before operation and three months after operation, erythrocyte sedimentation rate (ESR) was (44.20±20.56) mm·h-1 and (14.44±1.14) mm·h-1, and C-reactive protein (CRP) was (12.37±7.95) mg·L-1 and (4.3±3.37) mg·L-1. The differences in all three data sets were statistically significant (P<0.01). According to Gartland-Werley wrist function scoring, the scores at one week before operation and one year after operation were (21.32±3.44) and (14.96±1.37) respectively, showed a statistically significant difference (P<0.01). According to the upper limb function score (disabilities of the arm, shoulder, and hand, DASH), the score was (70.52±7.95) at one week before operation and(28.84±2.30) at one year after operation. The difference was statistically significant (P<0.01). At the latest follow-up, no patient had a recurrence of tuberculosis.@*CONCLUSION@#The short-term clinical efficacy of treating wrist tuberculosis with lesion removal, bone grafting, fusion, and external fixation is satisfactory.

Novel insights into the regulatory role of N6-methyladenosine methylation modified autophagy in sepsis.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is characterized by high morbidity and mortality and one of the major diseases that seriously hang over global human health. Autophagy is a crucial regulator in the complicated pathophysiological processes of sepsis. The activation of autophagy is known to be of great significance for protecting sepsis induced organ dysfunction. Recent research has demonstrated that N6-methyladenosine (m6A) methylation is a well-known post-transcriptional RNA modification that controls epigenetic and gene expression as well as a number of biological processes in sepsis. In addition, m6A affects the stability, export, splicing and translation of transcripts involved in the autophagic process. Although it has been suggested that m6A methylation regulates the biological metabolic processes of autophagy and is more frequently seen in the progression of sepsis pathogenesis, the underlying molecular mechanisms of m6A-modified autophagy in sepsis have not been thoroughly elucidated. The present article fills this gap by providing an epigenetic review of the processes of m6A-modified autophagy in sepsis and its potential role in the development of novel therapeutics.

Ultra-high Q alumina optical microresonators in the UV and blue bands.

UV and visible photonics enable applications ranging from spectroscopic sensing to communication and quantum information processing. Photonics structures in these wavelength regimes, however, tend to experience higher loss than their IR counterpart. Particularly in the near-UV band, on-chip optical microresonators have not yet achieved a quality factor beyond 1 million. Here, we report ultra-low-loss photonic waveguides and resonators patterned from alumina thin films prepared by a highly scalable atomic layer deposition process. We demonstrate ultra high Q factor of 1.5×106 at 390 nm, a record value at UV bands, and 1.9×106 at 488.5 nm.

CDK13 promotes lipid deposition and prostate cancer progression by stimulating NSUN5-mediated m5C modification of ACC1 mRNA.

Cyclin-dependent kinases (CDKs) regulate cell cycle progression and the transcription of a number of genes, including lipid metabolism-related genes, and aberrant lipid metabolism is involved in prostate carcinogenesis. Previous studies have shown that CDK13 expression is upregulated and fatty acid synthesis is increased in prostate cancer (PCa). However, the molecular mechanisms linking CDK13 upregulation and aberrant lipid metabolism in PCa cells remain largely unknown. Here, we showed that upregulation of CDK13 in PCa cells increases the fatty acyl chains and lipid classes, leading to lipid deposition in the cells, which is positively correlated with the expression of acetyl-CoA carboxylase (ACC1), the first rate-limiting enzyme in fatty acid synthesis. Gain- and loss-of-function studies showed that ACC1 mediates CDK13-induced lipid accumulation and PCa progression by enhancing lipid synthesis. Mechanistically, CDK13 interacts with RNA-methyltransferase NSUN5 to promote its phosphorylation at Ser327. In turn, phosphorylated NSUN5 catalyzes the m5C modification of ACC1 mRNA, and then the m5C-modified ACC1 mRNA binds to ALYREF to enhance its stability and nuclear export, thereby contributing to an increase in ACC1 expression and lipid deposition in PCa cells. Overall, our results disclose a novel function of CDK13 in regulating the ACC1 expression and identify a previously unrecognized CDK13/NSUN5/ACC1 pathway that mediates fatty acid synthesis and lipid accumulation in PCa cells, and targeting this newly identified pathway may be a novel therapeutic option for the treatment of PCa.

Experimental Investigation on Laser-Induced Electrochemical Silver Plating Technology.

The silver coating is widely used in electronic device manufacturing due to its excellent conductivity and soldering properties. Conventional preparation of local silver coating often uses the preplated silver, mask high-speed silver plating, and deplated silver processes. In this paper, the laser-induced electrodeposition technique is used to perform maskless laser-induced localized electrodeposition on a copper substrate preplated with a layer of silver. After the deplated silver process, ultrathin silver coatings with high dimensional accuracy, good corrosion resistance, and good bonding were obtained. The spatial distribution of the transient temperature field under laser irradiation is studied, the variation pattern of cathode substrate current under laser irradiation is tested, and finally, the spatial distribution of the pressure field under laser irradiation is simulated by Comsol. The effect of different laser scanning methods on the coating morphology was investigated, and the experimental study of the different single pulse energy-induced localized silver coatings was systematically carried out. The results show that the localized coating obtained by cross-line scanning with a laser single pulse energy of 93 µJ is flat with a film thickness of 0.23 µm, high dimensional accuracy, and good bonding force and corrosion resistance properties. This method provides a new approach for the preparation of a localized silver coating.

The mechanism of dehydroandrographolide inhibiting metastasis in gastric cancer based on network pharmacology and bioinformatics.

Gastric cancer (GC) is the most aggressive malignant tumor of the digestive tract. However, there is still a lack of effective treatment methods in clinical practice. Studies have shown that dehydroandrographolide (DA) has been shown to have anti-cancer activity in a variety of cancers, but it has not been reported in GC. Firstly, we obtained data on DA target genes, GC-related genes, and differentially expressed genes (DEGs) from the PharmMapper, GeneCards, and GEO databases, respectively. Then, the STRING database was used to construct the protein-protein interaction network of intersection genes, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses of intersection genes were performed. Finally, 8 hub target genes were identified by analyzing their expression and prognostic survival, and molecular docking between the hub genes and DA was performed. In this study, 293 DA drug target genes, 11,366 GC-related genes, and 3184 DEGs were identified. Gene Ontology and KEGG analysis showed that the intersection genes of DA targets and GC-related genes were mainly related to cancer pathways involving apoptosis and cell adhesion. The intersection genes of DEGs, DA targets, and GC-related genes were also mainly related to cancer pathways involving chemical carcinogenesis, and drug metabolism. The molecular docking results showed that the 8 hub target genes had an apparent affinity for DA, which could be used as potential targets for DA treatment of GC. The results of this study show that the molecular mechanism by which DA inhibits GC metastasis involves multiple target genes. It may play an essential role in inhibiting the invasion and metastasis of GC by regulating the expression and polymorphism of hub target genes, such as MMP9, MMP12, CTSB, ESRRG, GSTA1, ADHIC, CA2, and AKR1C2.

Adhesion-regulating molecule 1 (ADRM1) can be a potential biomarker and target for bladder cancer.

Adhesion-regulating molecule 1 (ADRM1) has been implicated in tumor development, yet its specific role in bladder cancer (BC) remains undefined. This study aimed to elucidate the function of ADRM1 in BC through a combination of bioinformatics analysis and immunohistochemical analysis (IHC). Utilizing R version 3.6.3 and relevant packages, we analyzed online database data. Validation was conducted through IHC data, approved by the Institutional Ethics Committee (Approval No. K20220830). In both paired and unpaired comparisons, ADRM1 expression was significantly elevated in BC tissues compared to adjacent tissues, as evidenced by the results of TCGA dataset and IHC data. Patients with high ADRM1 expression had statistically worse overall survival than those with low ADRM1 expression in TCGA dataset, GSE32548 dataset, GSE32894 dataset, and IHC data. Functional analysis unveiled enrichment in immune-related pathways, and a robust positive correlation emerged between ADRM1 expression and pivotal immune checkpoints, including CD274, PDCD1, and PDCD1LG2. In tumor microenvironment, samples with the high ADRM1 expression contained statistical higher proportion of CD8 + T cells and Macrophage infiltration. Meanwhile, these high ADRM1-expressing samples displayed elevated tumor mutation burden scores and stemness indices, implying potential benefits from immunotherapy. Patients with low ADRM1 expression were sensitive to cisplatin, docetaxel, vinblastine, mitomycin C, and methotrexate. According to the findings from bioinformatics and IHC analyses, ADRM1 demonstrates prognostic significance for BC patients and holds predictive potential for both immunotherapy and chemotherapy responses. This underscores its role as a biomarker and therapeutic target in BC.

A Four-Port MIMO Cylindrical DRA with High Isolation in Ultra-Compact Size for WLAN Applications.

A novel ultra-compact four-port multiple-input-multiple-output (MIMO) cylindrical dielectric resonator antenna (DRA) with improved isolation is proposed for WLAN applications in this paper. The antenna is originally radiated with the assistance of two different excitation mechanisms to generate decoupled orthogonal modes. To further diminish the coupling field and improve the isolation, a suitable U-shaped slot is created on the common ground plane. Two additional rectangular slits are also etched to adjust the impedance matching of other ports. To better reveal the operating mechanism of the decoupling scheme, the common mode (CM) and differential mode (DM) impedance analysis methods between DRA ports are presented. The etched U-shaped slot can tune the impedance of CM and DM to be consistent to realize the decoupling. The antenna is simulated, fabricated, and tested to verify the decoupling mechanism. The results demonstrate that the isolation between ports 1 and 2 is enhanced from 5 dB to 23 dB, and other ports exhibit low coupling of better than 12 dB. Moreover, the antenna with the full size of 30 × 30 × 8.1 mm3 can be used either as a four-port DRA with a bandwidth of 300 MHz or as a two-port DRA with a bandwidth of 700 MHz, at a center frequency of 5.6 GHz.

Hyperphosphorylation of BCL-2 family proteins underlies functional resistance to venetoclax in lymphoid malignancies.

The B cell leukemia/lymphoma 2 (BCL-2) inhibitor venetoclax is effective in chronic lymphocytic leukemia (CLL); however, resistance may develop over time. Other lymphoid malignancies such as diffuse large B cell lymphoma (DLBCL) are frequently intrinsically resistant to venetoclax. Although genomic resistance mechanisms such as BCL2 mutations have been described, this probably only explains a subset of resistant cases. Using 2 complementary functional precision medicine techniques - BH3 profiling and high-throughput kinase activity mapping - we found that hyperphosphorylation of BCL-2 family proteins, including antiapoptotic myeloid leukemia 1 (MCL-1) and BCL-2 and proapoptotic BCL-2 agonist of cell death (BAD) and BCL-2 associated X, apoptosis regulator (BAX), underlies functional mechanisms of both intrinsic and acquired resistance to venetoclax in CLL and DLBCL. Additionally, we provide evidence that antiapoptotic BCL-2 family protein phosphorylation altered the apoptotic protein interactome, thereby changing the profile of functional dependence on these prosurvival proteins. Targeting BCL-2 family protein phosphorylation with phosphatase-activating drugs rewired these dependencies, thus restoring sensitivity to venetoclax in a panel of venetoclax-resistant lymphoid cell lines, a resistant mouse model, and in paired patient samples before venetoclax treatment and at the time of progression.

18ß-glycyrrhetinic acid promotes gastric cancer cell autophagy and inhibits proliferation by regulating miR-328-3p/signal transducer and activator of transcription 3.

BACKGROUND: Gastric cancer (GC) is one of the most common cancer types worldwide, and its prevention and treatment methods have garnered much attention. As the active ingredient of licorice, 18ß-glycyrrhetinic acid (18ß-GRA) has a variety of pharmacological effects. The aim of this study was to explore the effective target of 18ß-GRA in the treatment of GC, in order to provide effective ideas for the clinical prevention and treatment of GC. AIM: To investigate the mechanism of 18ß-GRA in inhibiting cell proliferation and promoting autophagy flux in GC cells. METHODS: Whole transcriptomic analyses were used to analyze and screen differentially expressed microRNAs (miRNAs) in GC cells after 18ß-GRA intervention. Lentivirus-transfected GC cells and the Cell Counting Kit-8 were used to detect cell proliferation ability, cell colony formation ability was detected by the clone formation assay, and flow cytometry was used to detect the cell cycle and apoptosis. A nude mouse transplantation tumor model of GC cells was constructed to verify the effect of miR-328-3p overexpression on the tumorigenicity of GC cells. Tumor tissue morphology was observed by hematoxylin and eosin staining, and microtubule-associated protein light chain 3 (LC3) expression was detected by immunohistochemistry. TransmiR, STRING, and miRWalk databases were used to predict the relationship between miR-328-3p and signal transducer and activator of transcription 3 (STAT3)-related information. Expression of STAT3 mRNA and miR-328-3p was detected by quantitative polymerase chain reaction (qPCR) and the expression levels of STAT3, phosphorylated STAT3 (p-STAT3), and LC3 were detected by western blot analysis. The targeted relationship between miR-328-3p and STAT3 was detected using the dual-luciferase reporter gene system. AGS cells were infected with monomeric red fluorescent protein-green fluorescent protein-LC3 adenovirus double label. LC3 was labeled and autophagy flow was observed under a confocal laser microscope. RESULTS: The expression of miR-328-3p was significantly upregulated after 18ß-GRA intervention in AGS cells (P = 4.51E-06). Overexpression of miR-328-3p inhibited GC cell proliferation and colony formation ability, arrested the cell cycle in the G0/G1 phase, promoted cell apoptosis, and inhibited the growth of subcutaneous tumors in BALB/c nude mice (P < 0.01). No obvious necrosis was observed in the tumor tissue in the negative control group (no drug intervention or lentivirus transfection) and vector group (the blank vector for lentivirus transfection), and more cells were loose and necrotic in the miR-328-3p group. Bioinformatics tools predicted that miR-328-3p has a targeting relationship with STAT3, and STAT3 was closely related to autophagy markers such as p62. After overexpressing miR-328-3p, the expression level of STAT3 mRNA was significantly decreased (P < 0.01) and p-STAT3 was downregulated (P < 0.05). The dual-luciferase reporter gene assay showed that the luciferase activity of miR-328-3p and STAT3 3' untranslated regions of the wild-type reporter vector group was significantly decreased (P < 0.001). Overexpressed miR-328-3p combined with bafilomycin A1 (Baf A1) was used to detect the expression of LC3 II. Compared with the vector group, the expression level of LC3 II in the overexpressed miR-328-3p group was downregulated (P < 0.05), and compared with the Baf A1 group, the expression level of LC3 II in the overexpressed miR-328-3p + Baf A1 group was upregulated (P < 0.01). The expression of LC3 II was detected after intervention of 18ß-GRA in GC cells, and the results were consistent with the results of miR-328-3p overexpression (P < 0.05). Additional studies showed that 18ß-GRA promoted autophagy flow by promoting autophagosome synthesis (P < 0.001). qPCR showed that the expression of STAT3 mRNA was downregulated after drug intervention (P < 0.05). Western blot analysis showed that the expression levels of STAT3 and p-STAT3 were significantly downregulated after drug intervention (P < 0.05). CONCLUSION: 18ß-GRA promotes the synthesis of autophagosomes and inhibits GC cell proliferation by regulating the miR-328-3p/STAT3 signaling pathway.

Xuebijing injection protects sepsis induced myocardial injury by mediating TLR4/NF-κB/IKKα and JAK2/STAT3 signaling pathways.

OBJECTIVE: Compelling evidence has demonstrated that Xuebijing (XBJ) exerted protective effects against SIMI. The aims of this study were to investigate whether TLR4/IKKα-mediated NF-κB and JAK2/STAT3 pathways were involved in XBJ's cardio-protection during sepsis and the mechanisms. METHODS: In this study, rats were randomly assigned to three groups: Sham group; CLP group; XBJ group. Rats were treated with XBJ or sanitary saline after CLP. Echocardiography, myocardial enzymes and HE were used to detect cardiac function. IL-1ß, IL-6 and TNF-α in serum were measured using ELISA kits. Cardiomyocyte apoptosis were tested by TUNEL staining. The protein levels of Bax, Bcl-2, Bcl-xl, Cleaved-Caspase 3, Cleaved-Caspase 9, Cleaved-PARP, TLR4, p-NF-κB, p-IKKα, p-JAK2 and p-STAT3 in the myocardium were assayed by western blotting. And finally, immunofluorescence was used to assess the level of p-JAK2 and p-STAT3 in heart tissue. RESULTS: The results of echocardiography, myocardial enzyme and HE test showed that XBJ could significantly improve SIMI. The IL-1ß, IL-6 and TNF-α levels in the serum were markedly lower in the XBJ group than in the CLP group (p<0.05). TUNEL staining's results showed that XBJ ameliorated CLP-induced cardiomyocyte apoptosis. Meanwhile, XBJ downregulated the protein levels of Bax, Cleaved-Caspase 3, Cleaved-Caspase 9, Cleaved-PARP, TLR4, p-NF-κB, p-IKKα, p-JAK2 and p-STAT3, as well as upregulated the protein levels of Bcl-2, Bcl-xl (p <0.05). CONCLUSIONS: In here, we observed that XBJ's cardioprotective advantages may be attributable to its ability to suppress inflammation and apoptosis via inhibiting the TLR4/ IKKα-mediated NF-κB and JAK2/STAT3 pathways during sepsis.

CREB-binding protein and HIF-1α/ß-catenin to upregulate miR-322 and alleviate myocardial ischemia-reperfusion injury.

Myocardial ischemia/reperfusion injury (MIRI) is a prevalent condition associated with numerous critical clinical conditions. miR-322 has been implicated in MIRI through poorly understood mechanisms. Our preliminary analysis indicated potential interaction of CREB-binding protein (CBP), a transcriptional coactivator and acetyltransferase, with HIF-1α/ß-catenin, which might regulate miR-322 expression. We, therefore, hypothesized that CBP/HIF-1α/ß-catenin/miR-322 axis might play a role in MIRI. Rat cardiomyocytes subjected to oxygen-glucose deprivation /reperfusion (OGD/R) and Langendorff perfused heart model were used to model MIRI in vitro and in vivo, respectively. We used various techniques such as CCK-8 assay, transferase dUTP nick end labeling staining, western blotting, RT-qPCR, chromatin immunoprecipitation (ChIP), dual-luciferase assay, co-immunoprecipitation (Co-IP), hematoxylin and eosin staining, and TTC staining to assess cell viability, apoptosis, and the levels of CBP, HIF-1α, ß-catenin, miR-322, and acetylation. Our results indicate that OGD/R in cardiomyocytes decreased CBP/HIF-1α/ß-catenin/miR-322 expression, increased cell apoptosis and cytokines, and reduced cell viability. However, overexpression of CBP or miR-322 suppressed OGD/R-induced cell injury, while knockdown of HIF-1α/ß-catenin further exacerbated the damage. HIF-1α/ß-catenin bound to miR-322 promoter to promote its expression, while CBP acetylated HIF-1α/ß-catenin for stabilization. Overexpression of CBP attenuated MIRI in rats by acetylating HIF-1α/ß-catenin to stabilize their expression, resulting in stronger binding of HIF-1α/ß-catenin with the miR-322 promoter and subsequent increased miR-322 levels. Therefore, activating CBP/HIF-1α/ß-catenin/miR-322 signaling may be a potential approach to treat MIRI.