Activation of the IL-17/TRAF6/NF-κB pathway is implicated in Aß-induced neurotoxicity.

BACKGROUND: Neuroinflammation plays a critical role in Amyloid-ß (Aß) pathophysiology. The cytokine, interleukin-17A (IL-17) is involved in the learning and memory process in the central nervous system and its level was reported to be increased in Alzheimer's disease (AD) brain, while the effect of IL-17 on the course of Aß has not been well defined. METHODS: Here, we used APP/PS1 mice to detect the IL-17 expression level. Primary hippocampal neurons were treated with IL-17, and immunofluorescence was used to investigate whether IL-17 induced neuron damage. At the same time, male C57BL/6 mice were injected with Aß42 to mimic the Aß model. Then IL-17 neutralizing antibody (IL-17Ab) was used to inject into the lateral ventricle, and the Open field test, Novel Objective Recognition test, Fear condition test were used to detect cognitive function. LTP was used to assess synaptic plasticity, molecular biology technology was used to assess the IL-17/TRAF6/NF-κB pathway, and ELISA was used to detect inflammatory factors. RESULTS: Altogether, we here found that IL-17 was increased in APP/PS1 mice, and it induced neural damage by the administration to primary hippocampal neurons. Interestingly, Using Aß42 mice, the results showed that the level of IL-17 was increased in Aß42 model mice, and IL-17Ab could ameliorate Aß-induced neurotoxicity and cognitive decline in C57BL/6 mice by downregulation the TRAF6/NF-κB pathway. CONCLUSION: These findings highlight the pathogenic role of IL-17 in Aß induced-synaptic dysfunction and cognitive deficits. Inhibition of IL-17 could ameliorate Aß-induced neurotoxicity and cognitive decline in C57BL/6 mice by downregulation of the TRAF6/NF-κB pathway, which provides new clues for the mechanism of Aß-induced cognitive impairments, and a basis for therapeutic intervention.

Antibacterial-Antioxidative Thiolated Gelatin/Methacrylated Silk Fibroin Hydrogels with Nitric Oxide Release Catalyzed by Metal-Polyphenol Nanoparticles for MRSA-Infected Wound Healing.

Chronic wound infection often leads to irregular tissue closure and accompanies delayed healing and economy issues. Developing an ideal wound dressing that can control the occurrence of antibacterial infections and biological responses is highly desirable. In this study, a multifunctional hybrid hydrogel (GS@EG-Cu-CA NPs) containing synthesized thiolated gelatin, methacrylated silk fibroin, and (-)-epigallocatechin gallate-copper ionic-carrageenan nanoparticles (EG-Cu-CA NPs) was engineered by a thio-ene click reaction. The metal-polyphenol EG-Cu-CA NPs were encapsulated with kappa-carrageenan to enhance its aqueous-soluble, mechanical, and bioactive properties and endowed the hydrogel dressing with fascinating antibacterial, antioxidation, and nitric oxide (NO) generation by catalyzing. The hybrid hydrogels also illustrated a favorable cytocompatibility. Benefiting from the thio-ene click reaction, the hybrid hydrogels were injected and photocured rapidly in situ to cover an irregular wound. In an SD rat full-thickness skin-wound-infected model, the methicillin-resistant Staphylococcus aureus-infected wound covered with GS@EG-Cu-CA NPs was almost completely healed after 10 days. This study presents a facile design of hydrogel dressing incorporating metal-polyphenol nanoparticles, which demonstrates a promising potential way for dealing with effective wound infection management and other complicated wound healings.

Enhancing Idiopathic Scoliosis Patients' Outcomes Through Functional Rehabilitation Training in Combination with Orthosis.

Objective: This study aims to provide clinical evidence for the treatment of idiopathic scoliosis (IS) by assessing the therapeutic effectiveness of combining functional rehabilitation training with orthosis. Methods: We enrolled a total of 94 IS patients who were admitted to our hospital from April 2020 to February 2022. These patients were randomly assigned into two groups: a research group (RG; n=47) receiving functional rehabilitation training combined with orthosis and a control group (CG; n=47) receiving orthosis treatment alone. Clinical outcomes were evaluated one year after treatment. We also measured the Cobb angle, apical vertebral rotation (AVR), and the distance between the vertical line of the sacrum and the spinous process of the scoliosis parietal vertebra before and after treatment to determine apical vertebral translation (AVT) from the sacral midline and lumbar range of motion (ROM). Patient quality of life was assessed using the Short-Form 36 Item Health Survey (SF-36). Results: After treatment, the research group exhibited significantly lower Cobb angles, AVR, and AVT, along with a higher overall response rate and greater lumbar ROM compared to the control group (P < .05). Post-treatment SF-36 scores increased in both groups, with notably higher scores in the research group (P < .05). Conclusions: Combining functional rehabilitation training with orthosis is an effective approach for the treatment of IS and holds substantial clinical significance.

Comparison of Different Competitive Proteome Profiling Approaches in Target Identification of Covalent Inhibitors.

Competitive proteome profiling is a powerful approach for the identification of targets of small molecules. This approach usually employs an inhibitor-derived probe or a cysteine-reactive probe such as an IA-alkyne in a comparison between inhibitor-treated and untreated samples, thus enabling distinction between genuine targets and nonspecific labeling. We have developed an active probe derived from an EGFR inhibitor, afatinib, and a cysteine reactive probe, an alkyne-containing α,ß-unsaturated amide, to compare their characterization of cellular targets. In both approaches, myosin heavy chain 9 (MYH9) was identified as an off-target. Subsequent functional validation experiments suggested that MYH9 might be involved in the function of afatinib.

Mxene Reinforced Supramolecular Hydrogels with High Strength, Stretchability, and Reliable Conductivity for Sensitive Strain Sensors.

Conductive hydrogels used as electronics have received much attention due to their great flexibility and stretchability. However, the fabrication of ideal conductive hydrogels fulfilling the excellent mechanical properties and outstanding sensitivity remains a great challenge until now. Moreover, high sensitivity and broad linearity range are pivotal for the feasibility and accuracy of hydrogel sensors. In this study, a conductive supramolecular hydrogel is engineered by directly mixing the aqueous dispersion of MXene with the precursor of N-acryloyl glycinamide (NAGA) monomer and then rapidly photo cross-linked by UV irradiation. The resultant PNAGA/MXene hydrogel-sensors exhibit high mechanical strength (4.8 MPa), great stretchability (630%), and excellent durability. The conductive hydrogel-based sensor presents excellent conductivity (17.3 S m-1 ) and a wide scope of linear dependence of sensitivity on strain (0%-125%, gauge factor = 2.05). It displays reliable detection of various motions, including repeated subtle movements and large strain. It also shows good degradation in vitro and antifouling capability. This work may provide a simple and promising platform for engineering conductive supramolecular hydrogels with integrated high performance aiming for smart wearable electronics, electronic skin, soft robots, and human-machine interfacing.

Metformin attenuates sepsis-induced neuronal injury and cognitive impairment.

BACKGROUND: Sepsis is considered to be a high-risk factor for cognitive impairment in the brain. The purpose of our study is to explore whether sepsis causes cognitive impairment and try to evaluate the underlying mechanisms and intervention measures. METHODS: Here, we used cecum ligation and puncture (CLP) to simulate sepsis. Open field, Novel Objective Recognition, and Morris Water Maze Test were used to detect cognitive function, long-term potentiation was used to assess of synaptic plasticity, and molecular biological technics were used to assess synaptic proteins, ELISA kits were used to detect inflammatory factors. Metformin was injected into the lateral ventricle of SD rats, and we evaluated whether metformin alleviated CLP-mediated cognitive impairment using behavioral, electrophysiological and molecular biological technology experiments. RESULTS: Here we report hippocampal-dependent cognitive deficits and synaptic dysfunction induced by the CLP, accompanied by a significant increase in inflammatory factors. At the same time, metformin was able to improve cognitive impairment induced by CLP in adult male rats. CONCLUSION: These findings highlight a novel pathogenic mechanism of sepsis-related cognitive impairment through activation of inflammatory factors, and these are blocked by metformin to attenuate sepsis-induced neuronal injury and cognitive impairment.

Metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway.

BACKGROUND: Neuroinflammatory response is considered to be a high-risk factor for cognitive impairments in the brain. Lipopolysaccharides (LPS) is an endotoxin that induces acute inflammatory responses in injected bodies. However, the molecular mechanisms underlying LPS-associated cognitive impairments still remain unclear. METHODS: Here, primary hippocampal neurons were treated with LPS, and western blotting and immunofluorescence were used to investigate whether LPS induces neurons damage. At the same time, SD rats were injected with LPS (830 µg/Kg) intraperitoneally, and Open field test, Novel Objective Recognition test, Fear condition test were used to detect cognitive function. LTP was used to assess synaptic plasticity, and molecular biology technology was used to assess the NF-κB pathway, while ELISA was used to detect inflammatory factors. In addition, metformin was used to treat primary hippocampal neurons, and intraventricularly administered to SD rats. The same molecular technics, behavioral and electrophysiological tests were used to examine whether metformin could alleviate the LPS-associated neuronal damage, as well as synaptic plasticity, and behavioral alterations in SD rats. RESULTS: Altogether, neuronal damage were observed in primary hippocampal neurons after LPS intervention, which were alleviated by metformin treatment. At the same time, LPS injection in rat triggers cognitive impairment through activation of NF-κB signaling pathway, and metformin administration alleviates the LPS-induced memory dysfunction and improves synaptic plasticity. CONCLUSION: These findings highlight a novel pathogenic mechanism of LPS-related cognitive impairments through activation of NF-κB signaling pathway, and accumulation of inflammatory mediators, which induces neuronal pathologic changes and cognitive impairments. However, metformin attenuates LPS-induced neuronal injury and cognitive impairments by blocking NF-κB pathway.

Recombinant Tissue-Type Plasminogen Activator Study of Wake-Up Ischemic Strokes Guided by Rapid MRI.

BACKGROUND: rt-PA intravenous thrombolytic therapy and its efficacy have been widely recognized and proved for strokes. However, for patients with wake-up ischemic stroke (WUIS), they lose the opportunity to receive rt-PA intravenous thrombolytic therapy because of the difficulty of determining the onset time window. AIM: This study is aimed at investigating the intravenous thrombolytic therapy of WUIS guided by rapid MRI. METHODS: Data were collected from patients with acute ischemic stroke within 4.5 h and from WUIS patients with uncertain onset time window, who received the treatment of rt-PA intravenous thrombolytic therapy in our hospital from November 2006 to April 2018. The improved Rankin scale was used to evaluate neurological function recovery. According to the Rankin scale score, patients were divided into two groups: those with good prognosis (modified Rankin scale [mRS] score 0-1) and those with poor prognosis (mRS score 2-6). RESULTS: A total of 253 patients received rt-PA intravenous thrombolysis after head MRI evaluation; this included 177 cases of acute ischemic stroke and 76 cases of WUIS (which contains 2 death cases, 0.8% mortality; 3 cases of symptomatic bleeding, 1.2% bleeding rate; and 5 cases of aggravation, 2.0% aggravation rate). There was no statistical difference between the baseline data from the acute ischemic stroke patients with 4.5 h onset time window and the baseline data from the WUIS patients with undetermined onset time window, when the treatment was guided by rapid MRI. There were also no significant statistical differences in National Institutes of Health Stroke Scale score, Rankin scale score, symptomatic bleeding, death and aggravation of the disease between the 2 groups at 24 h, 3 days, and 7 days after admission (p < 0.05). CONCLUSION: According to the characteristic of undetermined onset time window of WUIS, more WUIS patients would be benefited from the rt-PA intravenous thrombolytic treatment when it is conducted under the guidance of rapid MRI.

Gardenamide A Protects RGC-5 Cells from H2O2-Induced Oxidative Stress Insults by Activating PI3K/Akt/eNOS Signaling Pathway.

Gardenamide A (GA) protects the rat retinal ganglion (RGC-5) cells against cell apoptosis induced by H2O2. The protective effect of GA was completely abrogated by the specific phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the specific protein kinase B (Akt) inhibitor Akt VIII respectively, indicating that the protective mechanism of GA is mediated by the PI3K/Akt signaling pathway. The specific extracellular signal-regulated kinase (ERK1/2) inhibitor PD98059 could not block the neuroprotection of GA. GA attenuated the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) induced by H2O2. Western blotting showed that GA promoted the phosphorylation of ERK1/2, Akt and endothelial nitric oxide synthase (eNOS), respectively, and effectively reversed the H2O2-inhibited phosphorylation of these three proteins. LY294002 completely inhibited the GA-activated phosphorylation of Akt, while only partially inhibiting eNOS. This evidence implies that eNOS may be activated directly by GA. PD98059 attenuated only partially the GA-induced phosphorylation of ERK1/2 with/without the presence of H2O2, indicating that GA may activate ERK1/2 directly. All these results put together confirm that GA protects RGC-5 cells from H2O2 insults via the activation of PI3K/Akt/eNOS signaling pathway. Whether the ERK1/2 signaling pathway is involved requires further investigations.

[Different ratio of hormone effects on Fritillaria cirrhosa bulb induction].

OBJECTIVE: To study the effects of different hormone induced bulb of Fritillaria cirrhosa seedling leaves, in order to provide an effective way to expant Fritillaria cirrhosa source. METHODS: Fritillaria cirrhosa seedling leaves were used as explants, orthogonal test was carried out to study the medium consisting of 6-BA, NAA, 2, 4-D and KT, and proliferation induced by direct bulb. Induction rate and average number of bulb producing was treated as the assessment indices, and the content of alkaloid of bulb was determined. RESULTS: The best medium formula for Fritillaria cirrhosa tissue culture seedling was MS+6-BA 2.0 mg/L +NAA 1.0mg/L +KT 1.0mg/L, the bulb induction rate was 83.37% and the average number of bulb was 17.27. The alkaloid content of induced bulb was 0.389%, which was 1.64 times that of wild Fritillaria cirrhosa bulb. CONCLUSION: This study provides a simple and rapid mehod for the production of tissue culture of Fritillaria cirrhosa bulb. It is useful for reasonable development and utilization of Fritillaria cirrhosa resources, as well as improvement of the quality of medicinal materials.

Clinical significance and immune characteristics analysis of miR-221-3p and its key target genes related to epithelial-mesenchymal transition in breast cancer.

BACKGROUND: MicroRNA-221-3p (miR-221-3p) facilitates the advancement of breast cancer (BC) through the induction of epithelial-mesenchymal transition (EMT). Our research aimed to utilize bioinformatics to discover possible EMT-related target genes (ETGs) of miR-221-3p and examine their roles in breast cancer. METHODS: We employed bioinformatics techniques to identify ten key ETGs of miR-221-3p. Subsequently, we conducted an extensive analysis of both miR-221-3p and the ten ETGs, including clinical significance and immune characteristics. RESULTS: The expression of miR-221-3p was notably higher in Basal-like BC compared to other subtypes and adjacent normal tissue. Our pathway analysis suggested that miR-221-3p might regulate EMT through the MAPK signaling pathway by targeting its ETGs. Among the ETGs, seven core genes (EGFR, IGF1, KDR, FGF2, KIT, FGFR1, and FGF1) exhibited downregulation in BC. Conversely, ERBB2, SDC1, and MMP14 showed upregulation in BC and displayed potential diagnostic value. The analysis of prognostication indicated that increased levels of SDC1 and MMP14 were correlated with an unfavorable prognosis, whereas elevated expression of KIT was associated with a more favorable prognosis. The infiltration of various immune cells and the expression of immune checkpoint genes (ICGs) exhibited positive correlations with most ETGs and miR-221-3p. SDC1 exhibited a greater tumor mutational burden (TMB) score, while ERBB2, KDR, FGF2, KIT, FGFR1, and FGF1 showed lower TMB scores. Furthermore, decreased ERBB2 and KDR expression levels were correlated with elevated microsatellite instability (MSI) scores. Elevated expression of ETGs was linked to decreased mRNA stemness indices (mRNAsi), whereas miR-221-3p displayed the opposite pattern. Most ETGs and miR-221-3p expression exhibited a negative correlation with IC50 values for drugs. Among the ETGs, amplification was the most significant genetic alteration, except for IGF1. CONCLUSION: In conclusion, miR-221-3p acts as a unique indicator for Basal-like BC. The examination revealed ten essential ETGs of miR-221-3p, some of which show potential as diagnostic and prognostic markers. The in-depth examination of these ten ETGs and miR-221-3p indicates their participation in the development of BC, emphasizing their promise as innovative targets for therapy in BC patients.

Guanidinylated bioactive chitosan-based injectable hydrogels with pro-angiogenic and mechanical properties for accelerated wound closure.

Wound healing is a complex process involving the concerted action of many genes and signaling pathways, with angiogenesis being crucial for expediting wound closure. Dressings that possess pro-angiogenic properties are increasingly recognized as attractive candidates for wound care. Drawing inspiration from the active closure of wounds in embryos, we have developed a thermo-responsive hydrogel with mechanoactive properties, combining vascular regeneration and skin wound contraction to accelerate healing. The significant improvement in vascular reconstruction is attributed to the synergistic effect of arginine and deferoxamine (DFO) released from the hydrogels. Additionally, the contraction force of the hydrogel actively promotes skin closure in wounds. Remarkably, groups treated with hydroxybutyl chitosan methacrylate combined with arginine (HBC_m_Arg/DFO) exhibited increased vascularization, and greater wound maturity, leading to enhanced healing. These results highlight the synergistic impact of pro-angiogenic and mechanical properties of the HBC_m_Arg/DFO hydrogel in accelerating wound healing in rats.

Modulation of macrophage polarization by secondary cross-linked hyaluronan-dopamine hydrogels.

The inflammatory response plays a critical role in standard tissue repair processes, wherein active modulation of macrophage polarization is necessary for wound healing. Dopamine, a mussel-inspired bioactive material, is widely involved in wound healing, neural/bone/myocardial regeneration, and more. Recent studies indicated that dopamine-modified biomaterials can potentially alter macrophages polarization towards a pro-healing phenotype, thereby enhancing tissue regeneration. Nevertheless the immunoregulatory activity of dopamine on macrophage polarization remains unclear. This study introduces a novel interpenetrating hydrogel to bridge this research gap. The hydrogel, combining varying concentrations of oxidized dopamine with hyaluronic acid hydrogel, allows precise regulation of mechanical properties, antioxidant bioactivity, and biocompatibility. Surprisingly, both in vivo and in vitro outcomes demonstrated that dopamine concentration modulates macrophage polarization, but not linearly. Lower concentration (2 mg/mL) potentially decrease inflammation and facilitate M2 type macrophage polarization. In contrast, higher concentration (10 mg/mL) exhibited a pro-inflammatory tendency in the late stages of implantation. RNA-seq analysis revealed that lower dopamine concentrations induced the M1/M2 transition of macrophages by modulating the NF-κB signaling pathway. Collectively, this research offers valuable insights into the immunoregulation effects of dopamine-integrated biomaterials in tissue repair and regeneration.

Prognostic implication of novel immune-related signature in breast cancer.

Checkpoint inhibitor therapy has become increasingly important and has been endorsed as a treatment regimen in breast cancer. But benefits were limited to a small proportion of patients. We aimed to develop an improved signature on the basis of immune genes for detection of potential benefit from immunotherapy. Gene expression data of patients with breast cancer initially extracted from The Cancer Genome Atlas were analyzed. Ten genes were selected from the interaction of differentially expressed genes as well as immune-related genes to develop a survival signature. We compared the high-risk and low-risk groups by gene set enrichment analysis, immune infiltration, checkpoint molecule expression and immunophenoscore. Ten genes were extracted from interactions of differentially expressed and immune-related genes. The immune risk score was determined on the basis of the Cox regression coefficient of hub genes and validated with the GSE96058 dataset. Immune cell infiltrates, including CD8 + T cells, plasma cells, follicular helper T cells, CD4 + memory T cells, M1 macrophages, regulatory T cells and resting NK cells, were more highly infiltrated in the high-risk group as compared to the low-risk group. Checkpoint molecules, including CTLA-4, PD-L1, TIM-3, VISTA, ICOS, PD-1, and PD-L2, were expressed at markedly lower levels in the high-risk group as compared to the low-risk group. Immunophenoscores, as a surrogate of response to immune checkpoint therapy, was observed significant lower in the high-risk group. The 10-gene prognostic signature could identify patients' survival and was correlated with the biomarkers of immune checkpoint inhibitor therapy, which may guide precise therapeutic decisions in clinical practice.

Study on effects of partial ossicular replacement prostheses with different materials on hearing restoration.

Numerical simulation method was used in this paper to study the effects of partial ossicular replacement prostheses (PORPs) with different materials on hearing restoration, from the biomechanical point of view. According to the CT scan imagery of the right ear from a normal human body, the CT data was digitalized and imported into PATRAN to establish a three dimension finite element model by self-compiling program, and then a frequency response analysis was made for the model. The calculated results were compared with experiment data to verify the correctness of the numerical model. Based on this, human numerical model of PORPs was established to make dynamic calculation of sound conduction and analyse the effects of PORPs with different materials on hearing restoration. The following conclusions are obtained : From the angle of dynamical behaviors in sound conduction process of human ear, in different frequency bands of the same sound pressure, PORPs with different materials have different effects on hearing restoration. A better sound transmission in low frequencies is obtained by PORPs with hydroxyapatite ceramics, stainless steel. In high frequencies, better sound transmission is gained by PORPs with porous polyethylene. In the 500-3,000 Hz range which is clinicians typically measure and pay attention to, better sound transmission is gained by PORPs with alumina ceramics, hydroxyapatite ceramics, EH composite materials and porous polyethylene. There are three materials which has an obvious potential to provide more hearing restoration than another between 500 and 3,000 Hz. The hearing restoration value of hydroxyapatite ceramics is 7.1 dB larger than that of stainless steel. The hearing restoration value of titanium is 4.9 dB larger than that of stainless steel. Hydroxyapatite ceramics has better effects on sound transmission than titanium and other materials.

Oxidant-Induced Bioconjugation for Protein Labeling in Live Cells.

Chemical proteomics is a powerful technology that can be used in the studies of the functions of uncharacterized proteins in the human proteome. It relies on a suitable bioconjugation strategy for protein labeling. This could be either a UV-responsive photo-crosslinker or an electrophilic warhead embedded in chemical probes that can form covalent bonds with target proteins. Here, we report a new protein-labeling strategy in which a nitrile oxide, a highly reactive intermediate that reacts with proteins, can be efficiently generated by the treatment of oximes with a water-soluble and a minimally toxic oxidant, phenyliodine bis (trifluoroacetate) (PIFA). The resulting intermediate can rapidly bioconjugate with amino acid residues of target proteins, thus enabling target identification of oxime-containing bioactive molecules. Excellent chemoselectivity of cysteine residues by the nitrile oxide was observed, and over 4000 reactive and/or accessible cysteines, including KRAS G12C, have been successfully characterized by quantitative chemical proteomics. Some of these residues could not be detected by conventional cysteine reagents, thus demonstrating the complementary utility of this method.

Effect of Transport Properties of Crystalline Transition Metal (Oxy)hydroxides on Oxygen Evolution Reaction.

Electronic transport plays a pivotal role in the electrolysis of semiconducting electrocatalysts for oxygen evolution reaction (OER), while it is mostly underestimated and largely unexplored. Here, by investigating the electronic transport behavior of seven archetypical crystalline Co/Ni/Fe-based (oxy)hydroxides (unary, binary, and ternary) under OER potential, we study how and the extent to which it affects the apparent catalytic performances. The electronic transports of unary metal (oxy)hydroxides follow the order of Co > Ni > Fe, and their binary or ternary compounds can generally impose one order of magnitude higher electrical conductivity. By studying the dependence of catalytic performances on electrical conductivities, we further unveil that charge transportability not only determines the electronic accessibility of catalytic nanoparticles but also, to our surprise, regulates the reaction kinetics of the electronically accessible active sites. Remarkably, the regulation extent of reaction kinetics correlates with the electrical conductivities of electrocatalysts, suggesting that the electrocatalytic process is strongly coupled with electronic transport. The work presents an overview of electronic transports of crystalline (oxy)hydroxides under OER potentials and highlights their pivotal role in unfolding catalytic potential, holding both fundamental and technical implications for the screen and design of efficient electrocatalysts.

Integrated pan-cancer analysis and experimental verification of the roles of tropomyosin 4 in gastric cancer.

Objective: To investigate the function of tropomyosin 4 (TPM4) using pan-cancer data, especially in gastric cancer (GC), using comprehensive bioinformatics analysis and molecular experiments. Methods: We used UCSC Xena, The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx), TIMER2.0, GEPIA, cBioPortal, Xiantao tool, and UALCAN websites and databases for the extraction of pan-cancer data on TPM4. TPM4 expression was investigated with respect to prognosis, genetic alterations, epigenetic alterations, and immune infiltration. RNA22, miRWalk, miRDB, Starbase 2.0, and Cytoscape were used for identifying and constructing the regulatory networks of lncRNAs, miRNAs, and TPM4 in GC. Data from GSCALite, drug bank databases, and Connectivity Map (CMap) were used to analyze the sensitivity of drugs dependent on TPM4 expression. Gene Ontology (GO), enrichment analyses of the Kyoto Encyclopedia of Genes and Genomes (KEGG), wound healing assays, and (Matrigel) transwell experiments were used to investigate the biological functions of TPM4 in GC. Result: The findings of the comprehensive pan-cancer analysis revealed that TPM4 has a certain diagnostic and prognosis value in most cancers. Alterations in the expression of TPM4, including duplications and deep mutations, and epigenetic alterations revealed that TPM4 expression is related to the expression of DNA methylation inhibitors and RNA methylation regulators at high concentrations. Besides, TPM4 expression was found to correlate with immune cell infiltration, immune checkpoint (ICP) gene expression, the tumor mutational burden (TMB), and microsatellite instability (MSI). Neoantigens (NEO) were also found to influence its response to immunotherapy. A lncRNA-miRNA -TPM4 network was found to regulate GC development and progression. TPM4 expression was related to docetaxel,5-fluorouracil, and eight small molecular targeted drugs sensitivity. Gene function enrichment analyses revealed that genes that were co-expressed with TPM4 were enriched within the extracellular matrix (ECM)-related pathways. Wound-healing and (Matrigel) transwell assays revealed that TPM4 promotes cell migration and invasion. TPM4, as an oncogene, plays a biological role, perhaps via ECM remodeling in GC. Conclusions: TPM4 is a prospective marker for the diagnosis, treatment outcome, immunology, chemotherapy, and small molecular drugs targeted for pan-cancer treatment, including GC treatment. The lncRNA-miRNA-TPM4network regulates the mechanism underlying GC progression. TPM4 may facilitate the invasion and migration of GC cells, possibly through ECM remodeling.

Inactivation of ERK1/2-CREB Pathway Is Implicated in MK801-induced Cognitive Impairment.

OBJECTIVE: Schizophrenia (SZ) is associated with cognitive impairment, and it is known that the activity of cAMP response element binding protein (CREB) decreases in the brain of SZ patients. The previous study conducted by the investigators revealed that the upregulation of CREB improves the MK801-related SZ cognitive deficit. The present study further investigates the mechanism on how CREB deficiency is associated with SZ-related cognitive impairment. METHODS: MK-801 was used to induce SZ in rats. Western blotting and immunofluorescence were performed to investigate CREB and the CREB-related pathway implicated in MK801 rats. The long-term potentiation and behavioral tests were performed to assess the synaptic plasticity and cognitive impairment, respectively. RESULTS: The phosphorylation of CREB at Ser133 decreased in the hippocampus of SZ rats. Interestingly, among the upstream kinases of CREB, merely ERK1/2 was downregulated, while CaMKII and PKA remained unchanged in the brain of MK801-related SZ rats. The inhibition of ERK1/2 by PD98059 reduced the phosphorylation of CREB-Ser133, and induced synaptic dysfunction in primary hippocampal neurons. Conversely, the activation of CREB attenuated the ERK1/2 inhibitor-induced synaptic and cognitive impairment. CONCLUSION: These present findings partially suggest that the deficiency of the ERK1/2-CREB pathway is involved in MK801-related SZ cognitive impairment. The activation of the ERK1/2-CREB pathway may be therapeutically useful for treating SZ cognitive deficits.