Telomerase-related advances in hepatocellular carcinoma: A bibliometric and visual analysis.

BACKGROUND: As a critical early event in hepatocellular carcinogenesis, telomerase activation might be a promising and critical biomarker for hepatocellular carcinoma (HCC) patients, and its function in the genesis and treatment of HCC has gained much attention over the past two decades. AIM: To perform a bibliometric analysis to systematically assess the current state of research on HCC-related telomerase. METHODS: The Web of Science Core Collection and PubMed were systematically searched to retrieve publications pertaining to HCC/telomerase limited to "articles" and "reviews" published in English. A total of 873 relevant publications related to HCC and telomerase were identified. We employed the Bibliometrix package in R to extract and analyze the fundamental information of the publications, such as the trends in the publications, citation counts, most prolific or influential writers, and most popular journals; to screen for keywords occurring at high frequency; and to draw collaboration and cluster analysis charts on the basis of coauthorship and co-occurrences. VOSviewer was utilized to compile and visualize the bibliometric data. RESULTS: A surge of 51 publications on HCC/telomerase research occurred in 2016, the most productive year from 1996 to 2023, accompanied by the peak citation count recorded in 2016. Up to December 2023, 35226 citations were made to all publications, an average of 46.6 citations to each paper. The United States received the most citations (n = 13531), followed by China (n = 7427) and Japan (n = 5754). In terms of national cooperation, China presented the highest centrality, its strongest bonds being to the United States and Japan. Among the 20 academic institutions with the most publications, ten came from China and the rest of Asia, though the University of Paris Cité, Public Assistance-Hospitals of Paris, and the National Institute of Health and Medical Research (INSERM) were the most prolific. As for individual contributions, Hisatomi H, Kaneko S, and Ide T were the three most prolific authors. Kaneko S ranked first by H-index, G-index, and overall publication count, while Zucman-Rossi J ranked first in citation count. The five most popular journals were the World Journal of Gastroenterology, Hepatology, Journal of Hepatology, Oncotarget, and Oncogene, while Nature Genetics, Hepatology, and Nature Reviews Disease Primers had the most citations. We extracted 2293 keywords from the publications, 120 of which appeared more than ten times. The most frequent were HCC, telomerase and human telomerase reverse transcriptase (hTERT). Keywords such as mutational landscape, TERT promoter mutations, landscape, risk, and prognosis were among the most common issues in this field in the last three years and may be topics for research in the coming years. CONCLUSION: Our bibliometric analysis provides a comprehensive overview of HCC/telomerase research and insights into promising upcoming research.

A TrkB cleavage fragment in hippocampus promotes Depressive-Like behavior in mice.

Decreased hippocampal tropomyosin receptor kinase B (TrkB) level is implicated in the pathophysiology of stress-induced mood disorder and cognitive decline. However, how TrkB is modified and mediates behavioral responses to chronic stress remains largely unknown. Here the effects and mechanisms of TrkB cleavage by asparagine endopeptidase (AEP) were examined on a preclinical murine model of chronic restraint stress (CRS)-induced depression. CRS activated IL-1ß-C/EBPß-AEP pathway in mice hippocampus, accompanied by elevated TrkB 1-486 fragment generated by AEP. Specifi.c overexpression or suppression of AEP-TrkB axis in hippocampal CaMKIIα-positive cells aggravated or relieved depressive-like behaviors, respectively. Mechanistically, in addition to facilitating AMPARs internalization, TrkB 1-486 interacted with peroxisome proliferator-activated receptor-δ (PPAR-δ) and sequestered it in cytoplasm, repressing PPAR-δ-mediated transactivation and mitochondrial function. Moreover, co-administration of 7,8-dihydroxyflavone and a peptide disrupting the binding of TrkB 1-486 with PPAR-δ attenuated depression-like symptoms not only in CRS animals, but also in Alzheimer's disease and aged mice. These findings reveal a novel role for TrkB cleavage in promoting depressive-like phenotype.

A Neutrophil Hijacking Nanoplatform Reprograming NETosis for Targeted Microglia Polarizing Mediated Ischemic Stroke Treatment.

Precise and efficient regulation of microglia is vital for ischemic stroke therapy and prognosis. The infiltration of neutrophils into the brain provides opportunities for regulatory drugs across the blood-brain barrier, while hindered by neutrophil extracellular traps (NETs) and targeted delivery of intracerebral drugs to microglia. This study reports an efficient neutrophil hijacking nanoplatform (referred to as APTS) for targeted A151 (a telomerase repeat sequence) delivery to microglia without the generation of NETs. In the middle cerebral artery occlusion (MCAO) mouse model, the delivery efficiency to ischemic stroke tissues increases by fourfold. APTS dramatically reduces the formation of NETs by 2.2-fold via reprogramming NETosis to apoptosis in neutrophils via a reactive oxygen species scavenging-mediated citrullinated histone 3 inhibition pathway. Noteworthy, A151 within neutrophils is repackaged into apoptotic bodies following the death pattern reprogramming, which, when engulfed by microglia, polarizes microglia to an anti-inflammatory M2 phenotype. After four times treatment, the cerebral infarction area in the APTS group decreases by 5.1-fold. Thus, APTS provides a feasible, efficient, and practical drug delivery approach for reshaping the immune microenvironment and treating brain disorders in the central nervous system.

Crystal Facet Engineering on SrTiO3 Enhances Photocatalytic Overall Water Splitting.

Single-crystal semiconductor-based photocatalysts exposing unique crystallographic facets show promising applications in energy and environmental technologies; however, crystal facet engineering through solid-state synthesis for photocatalytic overall water splitting is still challenging. Herein, we develop a novel crystal facet engineering strategy through solid-state recrystallization to synthesize uniform SrTiO3 single crystals exposing tailored {111} facets. The presynthesized low-crystalline SrTiO3 precursors enable the formation of well-defined single crystals through kinetically improved crystal structure transformation during solid-state recrystallization process. By employing subtle Al3+ ions as surface morphology modulators, the crystal surface orientation can be precisely tuned to a controlled percentage of {111} facets. The photocatalytic overall water splitting activity increases with the exposure percentage of {111} facets. Owing to the outstanding crystallinity and favorable anisotropic surface structure, the SrTiO3 single crystals with 36.6% of {111} facets lead to a 3-fold enhancement of photocatalytic hydrogen evolution rates up to 1.55 mmol·h-1 in a stoichiometric ratio of 2:1 than thermodynamically stable SrTiO3 enclosed with isotropic {100} facets.

Effect of levosimendan on ventricular remodelling in patients with left ventricular systolic dysfunction: a meta-analysis.

Heart failure is the final stage of several cardiovascular diseases, and the key to effectively treating heart failure is to reverse or delay ventricular remodelling. Levosimendan is a novel inotropic and vasodilator agent used in heart failure, whereas the impact of levosimendan on ventricular remodelling is still unclear. This study aims to investigate the impact of levosimendan on ventricular remodelling in patients with left ventricular systolic dysfunction. Electronic databases were searched to identify eligible studies. A total of 66 randomized controlled trials involving 7968 patients were included. Meta-analysis results showed that levosimendan increased left ventricular ejection fraction [mean difference (MD) = 3.62, 95% confidence interval (CI) (2.88, 4.35), P < 0.00001] and stroke volume [MD = 6.59, 95% CI (3.22, 9.96), P = 0.0001] and significantly reduced left ventricular end-systolic volume [standard mean difference (SMD) = -0.52, 95% CI (-0.67, -0.37), P < 0.00001], left ventricular end-diastolic volume index [SMD = -1.24, 95% CI (-1.61, -0.86), P < 0.00001], and left ventricular end-systolic volume index [SMD = -1.06, 95% CI (-1.43, -0.70), P < 0.00001]. In terms of biomarkers, levosimendan significantly reduced the level of brain natriuretic peptide [SMD = -1.08, 95% CI (-1.60, -0.56), P < 0.0001], N-terminal pro-brain natriuretic peptide [SMD = -0.99, 95% CI (-1.41, -0.56), P < 0.00001], and interleukin-6 [SMD = -0.61, 95% CI (-0.86, -0.35), P < 0.00001]. Meanwhile, levosimendan may increase the incidence of hypotension [risk ratio (RR) = 1.24, 95% CI (1.12, 1.39), P < 0.0001], hypokalaemia [RR = 1.57, 95% CI (1.08, 2.28), P = 0.02], headache [RR = 1.89, 95% CI (1.50, 2.39), P < 0.00001], atrial fibrillation [RR = 1.31, 95% CI (1.12, 1.52), P = 0.0005], and premature ventricular complexes [RR = 1.86, 95% CI (1.27, 2.72), P = 0.001]. In addition, levosimendan reduced all-cause mortality [RR = 0.83, 95% CI (0.74, 0.94), P = 0.002]. In conclusion, our study found that levosimendan might reverse ventricular remodelling when applied in patients with left ventricular systolic dysfunction, especially in patients undergoing cardiac surgery, decompensated heart failure, and septic shock.

N-homocysteinylation of DJ-1 promotes neurodegeneration in Parkinson's disease.

DJ-1, also known as Parkinson's disease protein 7 (Park7), is a multifunctional protein that regulates oxidative stress and mitochondrial function. Dysfunction of DJ-1 is implicated in the pathogenesis of Parkinson's disease (PD). Hyperhomocysteinemia is associated with an increased risk of PD. Here we show that homocysteine thiolactone (HTL), a reactive thioester of homocysteine (Hcy), covalently modifies DJ-1 on the lysine 182 (K182) residue in an age-dependent manner. The N-homocysteinylation (N-hcy) of DJ-1 abolishes its neuroprotective effect against oxidative stress and mitochondrial dysfunction, exacerbating cell toxicity. Blocking the N-hcy of DJ-1 restores its protective effect. These results indicate that the N-hcy of DJ-1 abolishes its neuroprotective effect and promotes the progression of PD. Inhibiting the N-hcy of DJ-1 may exert neuroprotective effect against PD.

A tau fragment links depressive-like behaviors and cognitive declines in Alzheimer's disease mouse models through attenuating mitochondrial function.

Introduction: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease characterized by extracellular senile plaques including amyloid-ß peptides and intracellular neurofibrillary tangles consisting of abnormal Tau. Depression is one of the most common neuropsychiatric symptoms in AD, and clinical evidence demonstrates that depressive symptoms accelerate the cognitive deficit of AD patients. However, the underlying molecular mechanisms of depressive symptoms present in the process of AD remain unclear. Methods: Depressive-like behaviors and cognitive decline in hTau mice were induced by chronic restraint stress (CRS). Computational prediction and molecular experiments supported that an asparagine endopeptidase (AEP)-derived Tau fragment, Tau N368 interacts with peroxisome proliferator-activated receptor delta (PPAR-δ). Further behavioral studies investigated the role of Tau N368-PPAR-δ interaction in depressive-like behaviors and cognitive declines of AD models exposed to CRS. Results: We found that mitochondrial dysfunction was positively associated with depressive-like behaviors and cognitive deficits in hTau mice. Chronic stress increased Tau N368 and promoted the interaction of Tau N368 with PPAR-δ, repressing PPAR-δ-mediated transactivation in the hippocampus of mice. Then we predicted and identified the binding sites of PPAR-δ. Finally, inhibition of AEP, clearance of Tau N368 and pharmacological activation of PPAR-δ effectively alleviated CRS-induced depressive-like behaviors and cognitive decline in mice. Conclusion: These results demonstrate that Tau N368 in the hippocampus impairs mitochondrial function by suppressing PPAR-δ, facilitating the occurrence of depressive-like behaviors and cognitive decline. Therefore, our findings may provide new mechanistic insight in the pathophysiology of depression-like phenotype in mouse models of Alzheimer's disease.

Light-driven micro/nanomotors in biomedical applications.

Nanotechnology brings hope for targeted drug delivery. However, most current drug delivery systems use passive delivery strategies with limited therapeutic efficiency. Over the past two decades, research on micro/nanomotors (MNMs) has flourished in the biomedical field. Compared with other driven methods, light-driven MNMs have the advantages of being reversible, simple to control, clean, and efficient. Under light irradiation, the MNMs can overcome several barriers in the body and show great potential in the treatment of various diseases, such as tumors, and gastrointestinal, cardiovascular and cerebrovascular diseases. Herein, the classification and mechanism of light-driven MNMs are introduced briefly. Subsequently, the applications of light-driven MNMs in overcoming physiological and pathological barriers in the past five years are highlighted. Finally, the future prospects and challenges of light-driven MNMs are discussed as well. This review will provide inspiration and direction for light-driven MNMs to overcome biological barriers in vivo and promote the clinical application of light-driven MNMs in the biomedical field.

SERS-Based Optical Nanobiosensors for the Detection of Alzheimer's Disease.

Alzheimer's disease (AD) is a leading cause of dementia, impacting millions worldwide. However, its complex neuropathologic features and heterogeneous pathophysiology present significant challenges for diagnosis and treatment. To address the urgent need for early AD diagnosis, this review focuses on surface-enhanced Raman scattering (SERS)-based biosensors, leveraging the excellent optical properties of nanomaterials to enhance detection performance. These highly sensitive and noninvasive biosensors offer opportunities for biomarker-driven clinical diagnostics and precision medicine. The review highlights various types of SERS-based biosensors targeting AD biomarkers, discussing their potential applications and contributions to AD diagnosis. Specific details about nanomaterials and targeted AD biomarkers are provided. Furthermore, the future research directions and challenges for improving AD marker detection using SERS sensors are outlined.

High spindle and kinetochore-associated complex subunit-3 expression predicts poor prognosis and correlates with adverse immune infiltration in hepatocellular carcinoma.

BACKGROUND: Spindle and kinetochore-associated complex subunit 3 (SKA3) is a malignancy-associated gene that plays a critical role in the regulation of chromosome separation and cell division. However, the molecular mechanism through which SKA3 regulates tumor cell proliferation in hepatocellular carcinoma (HCC) has not been fully elucidated. AIM: To investigate the molecular mechanisms underlying the role of SKA3 in HCC. METHODS: SKA3 expression, clinicopathological, and survival analyses were performed using multiple public database platforms, and the results were verified by Western blot and immunohistochemistry staining using collected clinical samples. Functional enrichment analyses were performed to evaluate the biological functions and molecular mechanisms of SKA3 in HCC. Furthermore, the Tumor Immune Estimation Resource and single-sample Gene Set Enrichment Analysis (ssGSEA) algorithms were utilized to investigate the abundance of tumor-infiltrating immune cells in HCC. The response to chemotherapeutic drugs was evaluated by the R package "pRRophetic". RESULTS: We found that upregulated SKA3 expression was significantly correlated with poor prognosis in patients with HCC. Multivariable Cox regression analysis indicated that SKA3 was an independent risk factor for survival. GSEA revealed that SKA3 expression may facilitate proliferation and migratory processes by regulating the cell cycle and DNA repair. Moreover, patients with high SKA3 expression had significantly decreased ratios of CD8+ T cells, natural killer cells, and dendritic cells. Drug sensitivity analysis showed that the high SKA3 group was more sensitive to sorafenib, sunitinib, paclitaxel, doxorubicin, gemcitabine, and vx-680. CONCLUSION: High SKA3 expression led to poor prognosis in patients with HCC by enhancing HCC proliferation and repressing immune cell infiltration surrounding HCC. SKA3 may be used as a biomarker for poor prognosis and as a therapeutic target in HCC.

Bacteroides Fragilis in the gut microbiomes of Alzheimer's disease activates microglia and triggers pathogenesis in neuronal C/EBPß transgenic mice.

Gut dysbiosis contributes to Alzheimer's disease (AD) pathogenesis, and Bacteroides strains are selectively elevated in AD gut microbiota. However, it remains unknown which Bacteroides species and how their metabolites trigger AD pathologies. Here we show that Bacteroides fragilis and their metabolites 12-hydroxy-heptadecatrienoic acid (12-HHTrE) and Prostaglandin E2 (PGE2) activate microglia and induce AD pathogenesis in neuronal C/EBPß transgenic mice. Recolonization of antibiotics cocktail-pretreated Thy1-C/EBPß transgenic mice with AD patient fecal samples elicits AD pathologies, associated with C/EBPß/Asparaginyl endopeptidase (AEP) pathway upregulation, microglia activation, and cognitive disorders compared to mice receiving healthy donors' fecal microbiota transplantation (FMT). Microbial 16S rRNA sequencing analysis shows higher abundance of proinflammatory Bacteroides fragilis in AD-FMT mice. Active components characterization from the sera and brains of the transplanted mice revealed that both 12-HHTrE and PGE2 activate primary microglia, fitting with poly-unsaturated fatty acid (PUFA) metabolites enrichment identified by metabolomics. Strikingly, recolonization with live but not dead Bacteroides fragilis elicited AD pathologies in Thy1-C/EBPß transgenic mice, so did 12-HHTrE or PGE2 treatment alone. Collectively, our findings support a causal role for Bacteroides fragilis and the PUFA metabolites in activating microglia and inducing AD pathologies in Thy1- C/EBPß transgenic mice.

Simultaneous Solar-Thermal Desalination and Catalytic Degradation of Wastewater Containing Both Salt Ions and Organic Contaminants.

Although solar steam generation is promising in generating clean water by desalinating seawater, it is powerless to totally degrade organic contaminants in the seawater. Herein, solar steam generation and catalytic degradation are integrated to generate clean water by simultaneous solar-driven desalination and catalytic degradation of wastewater containing both salt ions and organic contaminants. Stepwise decoration of three-dimensional nickel foam with polypyrrole, reduced graphene oxide (RGO), and cobalt phosphate is realized to obtain polypyrrole/RGO/cobalt phosphate/nickel foam (PGCN) hybrids for solar-driven desalination and catalytic degradation of wastewater containing antibiotics and salt ions. The oxygen-containing groups of the RGO integrated with the porous nickel foam make the porous PGCN hybrid hydrophilic and ensure the upward transport of water to the evaporation surface, and the oxygen vacancies of the cobalt phosphate allow the PGCN to generate abundant highly active singlet oxygen that could still exhibit excellent catalytic degradation performances in the high salinity and highly alkaline environment of seawater. In addition to the high solar light absorbance and satisfactory solar-thermal conversion efficiency of polypyrrole and RGO, the thermally conductive nickel foam skeleton can effectively transfer the heat generated by the solar-thermal energy conversion to the adjacent cobalt phosphate catalyst and nearby wastewater, achieving a solar-thermal-promoted catalytic degradation of organic contaminants. Therefore, a high pure water evaporation rate of 2.08 kg m-2 h-1 under 1 sun irradiation and 100% catalytic degradation of Norfloxacin and dyes are achieved. The PGCN hybrid is highly efficient in purifying seawater containing 10 ppm Norfloxacin and simultaneously achieves a high purification efficiency of 100 kg m-2 h-1.

Inhibition of miR-543 alleviates cardiac fibroblast-to-myofibroblast transformation and collagen expression in insulin resistance via targeting PTEN.

BACKGROUND: Myocardial interstitial fibrosis is an important manifestation of diabetic heart disease, and insulin resistance is one of the mechanisms of myocardial interstitial fibrosis. Some studies have found that miR-543 is associated with insulin resistance, but whether it plays a role in diabetic myocardial interstitial fibrosis remains unclear. This study aimed to investigate the role of miR-543 in diabetic myocardial interstitial fibrosis. METHODS: The combination of high glucose and high insulin was used to establish an insulin-resistant myocardial fibroblast model. The expression levels of miR-543, α-SMA, collagen Ⅰ, collagen Ⅲ and PTEN were detected. Cell proliferation and migration were detected. Luciferase reporter gene assay was used to verify the targeting relationship between miR-543 and PTEN. RESULTS: The expression of miR-543 was up-regulated in myocardial fibroblasts with insulin resistance, which was consistent with the results of bioinformatics analysis. The proliferation and migration levels of myocardial fibroblasts in insulin-resistant states were increased, and the expression levels of α-SMA, collagen Ⅰ and collagen Ⅲ were also increased. Inhibition of miR-543 expression could reverse the above changes. Target gene prediction and dual luciferase reporter assay demonstrated that miR-543 could bind to the 3'UTR region of PTEN. Moreover, the effect of miR-543 on insulin-resistant myocardial fibroblasts is mediated by targeting PTEN. CONCLUSIONS: Inhibition of miR-543 can reduce myocardial fibroblast-myofibroblast transformation and collagen expression in insulin-resistant states by targeting PTEN.

Recent progress of micro/nanomotors to overcome physiological barriers in the gastrointestinal tract.

Oral administration is a convenient administration route for gastrointestinal disease therapy with good patient compliance. But the nonspecific distribution of the oral drugs may cause serious side effects. In recent years, oral drug delivery systems (ODDS) have been applied to deliver the drugs to the gastrointestinal disease sites with decreased side effects. However, the delivery efficiency of ODDS is tremendously limited by physiological barriers in the gastrointestinal sites, such as the long and complex gastrointestinal tract, mucus layer, and epithelial barrier. Micro/nanomotors (MNMs) are micro/nanoscale devices that transfer various energy sources into autonomous motion. The outstanding motion characteristics of MNMs inspired the development of targeted drug delivery, especially the oral drug delivery. However, a comprehensive review of oral MNMs for the gastrointestinal diseases therapy is still lacking. Herein, the physiological barriers of ODDS were comprehensively reviewed. Afterward, the applications of MNMs in ODDS for overcoming the physiological barriers in the past 5 years were highlighted. Finally, future perspectives and challenges of MNMs in ODDS are discussed as well. This review will provide inspiration and direction of MNMs for the therapy of gastrointestinal diseases, pushing forward the clinical application of MNMs in oral drug delivery.

Plasma lipid profiles and homocysteine levels in anti-N-methyl-D-aspartate receptor encephalitis.

Introduction: We aimed to investigate whether lipid profiles and homocysteine levels in patients with anti-N-methyl-D-aspartate receptor encephalitis are related to clinical presentation and prognosis, which may contribute to further research on the pathogenesis and treatment of this disease. Methods: This study included a total of 43 patients with anti-N-methyl-D-aspartate receptor encephalitis and 43 sex-age-matched healthy controls. Baseline demography, clinical data, patient outcomes, and ancillary examination results were recorded. Patients were followed up every 2-3 months during the first year. The modified Rankin Scale score was used to evaluate the therapeutic effect and clinical outcome. Results: Among the 43 patients included in this study, 55.81% were male, the mean age of onset was 27 years old, and the median modified Rankin Scale score on admission was 3.0. Apolipoprotein A-1 was significantly lower in patients with anti-N-methyl-D-aspartate receptor encephalitis compared with healthy controls (p = 0.004). Compared with healthy controls, homocysteine (p = 0.002), apolipoprotein B (p = 0.004), Lpa (p = 0.045), and apolipoprotein B/apolipoprotein A-1 (p = 0.001) were significantly increased in patients with anti-N-methyl-D-aspartate receptor encephalitis. According to the modified Rankin Scale scores, 6 months after discharge, 72.09% of patients had a good prognosis and 27.91% had a poor prognosis. In the good prognosis group, age (p = 0.031), lipoprotein a (p = 0.023), apolipoprotein A-1 (p = 0.027) at baseline, and the modified Rankin Scale score on admission (p = 0.019) were significantly higher than those in the poor prognosis group. Conclusion: This study suggests the possibility that serum lipid profile and homocysteine play an important role in the pathogenesis of anti-N-methyl-D-aspartate receptor encephalitis, providing support for lipid-lowering treatment of anti-N-methyl-D-aspartate receptor encephalitis patients.

Circuit- and laminar-specific regulation of medial prefrontal neurons by chronic stress.

BACKGROUND: Chronic stress exposure increases the risk of mental health problems such as anxiety and depression. The medial prefrontal cortex (mPFC) is a hub for controlling stress responses through communicating with multiple limbic structures, including the basolateral amygdala (BLA) and nucleus accumbens (NAc). However, considering the complex topographical organization of the mPFC neurons in different subregions (dmPFC vs. vmPFC) and across multiple layers (Layer II/III vs. Layer V), the exact effects of chronic stress on these distinct mPFC output neurons remain largely unknown. RESULTS: We first characterized the topographical organization of mPFC neurons projecting to BLA and NAc. Then, by using a typical mouse model of chronic restraint stress (CRS), we investigated the effects of chronic stress on the synaptic activity and intrinsic properties of the two mPFC neuronal populations. Our results showed that there was limited collateralization of the BLA- and NAc-projecting pyramidal neurons, regardless of the subregion or layer they were situated in. CRS significantly reduced the inhibitory synaptic transmission onto the BLA-projecting neurons in dmPFC layer V without any effect on the excitatory synaptic transmission, thus leading to a shift of the excitation-inhibition (E-I) balance toward excitation. However, CRS did not affect the E-I balance in NAc-projecting neurons in any subregions or layers of mPFC. Moreover, CRS also preferentially increased the intrinsic excitability of the BLA-projecting neurons in dmPFC layer V. By contrast, it even caused a decreasing tendency in the excitability of NAc-projecting neurons in vmPFC layer II/III. CONCLUSION: Our findings indicate that chronic stress exposure preferentially modulates the activity of the mPFC-BLA circuit in a subregion (dmPFC) and laminar (layer V) -dependent manner.

Stimulation of soluble guanylate cyclase by vericiguat reduces skeletal muscle atrophy of mice following chemotherapy.

Background: The chemotherapeutic doxorubicin (DOX) promotes severe skeletal muscle atrophy, which induces skeletal muscle weakness and fatigue. Soluble guanylate cyclase (sGC) contributes to a variety of pathophysiological processes, but whether it is involved in DOX-induced skeletal muscle atrophy is unclear. The present study aimed to stimulate sGC by vericiguat, a new oral sGC stimulator, to test its role in this process. Methods: Mice were randomly divided into four groups: control group, vericiguat group, DOX group, and DOX + vericiguat group. Exercise capacity was evaluated before the mice were sacrificed. Skeletal muscle atrophy was assessed by histopathological and molecular biological methods. Protein synthesis and degradation were monitored in mice and C2C12 cells. Results: In this study, a significant decrease in exercise capacity and cross-sectional area (CSA) of skeletal muscle fibers was found in mice following DOX treatment. Furthermore, DOX decreased sGC activity in mice and C2C12 cells, and a positive correlation was found between sGC activity and CSA of skeletal muscle fibers in skeletal muscle. DOX treatment also impaired protein synthesis, shown by puromycin detection, and activated ubiquitin-proteasome pathway. Following sGC stimulation, the CSA of muscle fibers was elevated, and exercise capacity was enhanced. Stimulation of sGC also increased protein synthesis and decreased ubiquitin-proteasome pathway. In terms of the underlying mechanisms, AKT/mTOR and FoxO1 pathways were impaired following DOX treatment, and stimulation of sGC restored the blunted pathways. Conclusion: These results unravel sGC stimulation can improve skeletal muscle atrophy and increase the exercise capacity of mice in response to DOX treatment by enhancing protein synthesis and inhibiting protein degradation. Stimulation of sGC may be a potential treatment of DOX-induced skeletal muscle dysfunction.

Cytokines/chemokines and immune checkpoint molecules in anti-leucine-rich glioma-inactivated 1 encephalitis.

OBJECTIVE: We aimed to investigate levels of cytokines/chemokines and immune checkpoint molecules in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis. METHODS: The study recruited 12 patients with anti-LGI1 encephalitis and six non-inflammatory controls from the Qilu Hospital of Shandong University treated between January 2019 and December 2020. Serum levels of 30 cytokines/chemokines and 10 checkpoint molecules were measured in participants of both the groups. RESULTS: In contrast to those in the control group, 24 cytokines/chemokines and 5 immune checkpoint molecules were differentially expressed in patients with anti-LGI1 encephalitis, with 14 cytokines being upregulated and 10 being downregulated. There were 1033 enriched biological processes and 61 enriched Kyoto Encyclopedia of Genes and Genomes signaling pathways. CONCLUSION: A wide range of cytokines/chemokines and immune checkpoint molecules are implicated in immune regulation in anti-LGI1 encephalitis, indicating that they may serve as important targets in the development and treatment of the disease.

Increased formation of neutrophil extracellular traps in patients with anti-N-methyl-d-aspartate receptor encephalitis.

Background: Neutrophil extracellular traps (NETs) have been found to play an important role in several nervous system diseases. However, their role in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis remains unclear. The purpose of this study was to examine the possible role of NETs in anti-NMDAR encephalitis. Materials and methods: Eleven patients with anti-NMDAR encephalitis and ten healthy participants were enrolled. Plasma NETs levels were detected using an immunofluorescence assay and enzyme-linked immunosorbent assay. Additionally, we examined 10 plasma cytokines in patients with anti-NMDAR encephalitis and analyzed the correlation between citrullinated histone 3 levels and cytokine release. Results: Peripheral blood neutrophils from patients with anti-NMDAR encephalitis were more susceptible to NET generation. When compared with controls, cases of anti-NMDAR encephalitis showed elevated levels of IL-1 α, IL-6, IL-8, IL-13, MCP-1, and TNF-α (p < 0.05). Moreover, IL-6, IL-8, and TNF-α levels were positively correlated with H3Cit levels. Conclusion: We provide evidence that NETs may play a role in anti-NMDAR encephalitis, providing clues for elucidation of the pathogenesis of this disease.