Clinical analysis and literature review of two paediatric cases of anti-IgLON5 antibody-related encephalitis.

Introduction: Anti-IgLON5 antibody-related encephalitis is a rare autoimmune disorder of the central nervous system, predominantly occurring in middle-aged elderly individuals, with paediatric cases being exceptionally rare. This study aims to enhance the understanding of paediatric anti-IgLON5 antibody-related encephalitis by summarising its clinical and therapeutic characteristics. Method: A retrospective analysis was conducted on two paediatric patients diagnosed with anti-IgLON5 antibody-related encephalitis at Hunan Children's Hospital from August 2022 to November 2023. This involved reviewing their medical records and follow-up data, in addition to a literature review. Results: The study involved two patients, one male and one female, aged between 2.5 and 9.6 years, both presenting with an acute/subacute course of illness. Clinically, both exhibited movement disorders (including dystonia, involuntary movements, and ataxia), cognitive impairments, sleep disturbances, and psychiatric symptoms. Patient 1 experienced epileptic seizures, while Patient 2 exhibited brainstem symptoms and abnormal eye movements. Neither patient showed autonomic dysfunction. Patient 1 had normal cerebrospinal fluid (CSF) and Brain MRI findings, whereas Patient 2 showed moderate leukocytosis and mild protein elevation in the CSF, and Brain MRI revealed symmetrical lesions in the basal ganglia and cerebellum. Oligoclonal bands in the CSF were positive in both cases. Both patients tested negative for HLA-DQB*05:01 and HLA-DRB*10:01. They received both first-line and second-line immunotherapies, with Patient 2 showing a poor response to treatment. Discussion: Paediatric cases of anti-IgLON5 antibody-related encephalitis similarly present sleep disturbances as a core symptom, alongside various forms of movement disorders. Immunotherapy is partially effective. Compared to adult patients, these paediatric cases tend to exhibit more pronounced psychiatric symptoms, a more rapid onset, and more evident inflammatory changes in the CSF. The condition appears to have a limited association with HLA-DQB*05:01 and HLA-DRB*10:01 polymorphisms.

The causality between Type 2 diabetes and breast cancer: a bidirectional two-sample Mendelian randomization study.

Objective: Observational studies showed that Type 2 diabetes increased the risk of breast cancer, and vice versa. However, it is uncertain whether the link is causal or just due to confounding factors. Using bidirectional Mendelian randomization analysis, we assessed the bidirectional causal relationship from a genetic level. Methods: Large genome-wide association studies yielded summary-level data for Type 2 diabetes and breast cancer. Results: Genetically predicted Type 2 diabetes presented no statistically significant association with overall breast cancer or its subtypes. Similarly, genetically predicted overall breast cancer or its subtypes had no causal effect on Type 2 diabetes. Sensitivity analyses yielded similar results. Conclusion: Our bidirectional Mendelian randomization studies revealed no causal links between Type 2 diabetes and breast cancer.

Serum globulin in children with myasthenia gravis: predicting relapse and prognosis.

OBJECTIVE: Serum globulin is associated with inflammatory or immune disorders. However, it has not been established whether it is associated with myasthenia gravis (MG). We investigated the association between globulin with relapse and prognosis in children with MG. METHODS: A cohort of 148 MG cases and 150 healthy children were retrospectively enrolled from January 2015 to December 2021. Multivariate logistic and Cox regression models were used to analyze the treatment outcomes and recurrence of case group, exploring the influence of globulin. RESULTS: Compared with the control group, globulin levels in the MG group were slightly increased (t = 7.244, p < 0.001). After a mean follow-up of 2.25 ± 1.05 years, 35 cases relapsed, with a relapse rate of 23.65%. Logistic regression analysis showed that globulin levels at admission [adjusted odds ratio (OR) = 1.233, 95% confidence interval (CI) 1.028-1.472, p = 0.018] were independent risk factors for relapse. Cox regression analysis confirmed that globulin levels at admission affects relapse-free time [adjusted hazard ratio (HR) = 0.552, 95% CI 0.357-0.852, p = 0.007]. Receiver operating characteristic curve determined 25.10 as the optimal cutoff value for globulin. Cox regression showed that high globulin levels (>25.10) at admission (adjusted HR = 0.607, 95% CI 0.383-0.961, p = 0.033) were independent risk factors for poor therapeutic outcomes at follow-up. Ordinal logistic regression showed that globulin affects the treatment plan (OR = 1.445, 95% CI 1.223-1.847, p = 0.014). CONCLUSIONS: Elevated globulin levels in children with MG on admission predicts a high relapse rate and poor long-term therapeutic efficacies.

Serum globulin in children with myasthenia gravis: predicting relapse and prognosisFirst, the globulin in the MG children was higher than in the healthy controls, and there was some correlation between the globulin and the level of systemic inflammation.Second, globulin has been associated with relapse of MG in children. The higher the globulin, the higher the relapse rate and the shorter the time to prevent a relapse.Third, both initial and final globulin were related to the effect of MG in children, and the higher the long-term effect, the worse the long-term effect. It also influenced the change in treatment plan.

Safety, tolerability, pharmacokinetics and neutrophil elastase inhibitory effects of Sivelestat: A randomized, double-blind, placebo-controlled single- and multiple-dose escalation study in Chinese healthy subjects.

BACKGROUND AND OBJECTIVE: Neutrophil elastase has been identified as a potential therapeutic target for acute lung injury or acute respiratory distress syndrome, and Sivelestat is a selective, reversible and competitive neutrophil elastase inhibitor. This study was designed to investigate the safety, tolerability, pharmacokinetics and neutrophil elastase inhibitory effects of Sivelestat in healthy Chinese subjects. METHODS: A randomized, double-blind, placebo-controlled single- and multiple-dose escalation clinical trial was carried out. Briefly, healthy volunteers in twelve cohorts with 8 per cohort received 1.0-20.2 mg/kg/h Sivelestat or placebo in an intravenous infusion manner for two hours, and healthy volunteers in four cohorts received two hours intravenous infusion of 2.0-5.0 mg/kg/h Sivelestat or placebo with an interval of twelve hours for seven times. The safety and tolerability were evaluated and serial blood samples were collected for pharmacokinetics and neutrophil elastase inhibitory effects analysis at the specified time-point. RESULTS: A total of 128 subjects were enrolled and all participants completed the study except one. Sivelestat exhibited satisfactory safety and tolerability up to 20.2 mg/kg/h in single-dose cohorts and 5.0 mg/kg/h in multiple-dose cohorts. Even so, more attention should be paid to the safety risks when using high doses. The Cmax and AUC of Sivelestat increased in a dose dependent manner, and Tmax was similar for different dose cohorts. In multiple-dose cohorts, the plasma concentrations reached steady state 48 h after first administration and the accumulation of Cmax and AUC was not obvious. Furthermore, the Cmin_ss of 5.0 mg/kg/h dose cohort could meet the needs of clinical treatment. For some reason, the pharmacodynamics data revealed that the inhibitory effect of Sivelestat on neutrophil elastase content in healthy subjects was inconclusive. CONCLUSION: Sivelestat was safe and well tolerated with appropriate pharmacokinetic parameters, which provided support for more diverse dosing regimen in clinical application. CLINICAL TRIAL REGISTRATION: www.chinadrugtrials.org.cn identifier is CTR20210072.

Mechanism of Polygonum capitatum intervention in pulmonary fibrosis based on network pharmacology and molecular docking technology: A review.

Pulmonary fibrosis (PF) is a serious interstitial disease that includes diffuse collagen deposition of lung tissue. Polygonum capitatum Buch.-Ham. ex D. Don (THL) is a traditional vaccine that has antibacterial and anti-inflammatory effects. In this research, to investigate the mechanism of action of THL in the intervention of pulmonary fibrosis by network pharmacology and molecular docking related research methods, in order to provide a theoretical basis for expanding the scope of THL medication. A total of 49 active ingredients were analyzed and screened in Cephalus cephalusis, including 35 pulmonary fibrosis targets, and 10 key targets such as ALB, EGFR were screened after software analysis. The molecular docking results showed that there were 44 binding energies less than -3 kcal·mol-1 in the 60 docking results, indicating that most proteins had strong binding energies with compounds. The key targets of KEGG enrichment analysis were mainly enriched in 20 core action pathways, such as hemostasis-related pathway, regulation of kinase activity. This study shows that based on network pharmacology, the multicomponent-multitarget-multipathway effect of THL intervention in pulmonary fibrosis is discussed.

Multifunctional MXene/C Aerogels for Enhanced Microwave Absorption and Thermal Insulation.

Two-dimensional transition metal carbides and nitrides (MXene) have emerged as promising candidates for microwave absorption (MA) materials. However, they also have some drawbacks, such as poor impedance matching, high self-stacking tendency, and high density. To tackle these challenges, MXene nanosheets were incorporated into polyacrylonitrile (PAN) nanofibers and subsequently assembled into a three-dimensional (3D) network structure through PAN carbonization, yielding MXene/C aerogels. The 3D network effectively extends the path of microcurrent transmission, leading to enhanced conductive loss of electromagnetic (EM) waves. Moreover, the aerogel's rich pore structure significantly improves the impedance matching while effectively reducing the density of the MXene-based absorbers. EM parameter analysis shows that the MXene/C aerogels exhibit a minimum reflection loss (RLmin) value of - 53.02 dB (f = 4.44 GHz, t = 3.8 mm), and an effective absorption bandwidth (EAB) of 5.3 GHz (t = 2.4 mm, 7.44-12.72 GHz). Radar cross-sectional (RCS) simulations were employed to assess the radar stealth effect of the aerogels, revealing that the maximum RCS reduction value of the perfect electric conductor covered by the MXene/C aerogel reaches 12.02 dB m2. In addition to the MA performance, the MXene/C aerogel also demonstrates good thermal insulation performance, and a 5-mm-thick aerogel can generate a temperature gradient of over 30 °C at 82 °C. This study provides a feasible design approach for creating lightweight, efficient, and multifunctional MXene-based MA materials.

Nanodrugs systems for therapy and diagnosis of esophageal cancer.

With the increasing incidence of esophageal cancer, its diagnosis and treatment have become one of the key issues in medical research today. However, the current diagnostic and treatment methods face many unresolved issues, such as low accuracy of early diagnosis, painful treatment process for patients, and high recurrence rate after recovery. Therefore, new methods for the diagnosis and treatment of esophageal cancer need to be further explored, and the rapid development of nanomaterials has brought new ideas for solving this problem. Nanomaterials used as drugs or drug delivery systems possess several advantages, such as high drug capacity, adjustably specific targeting capability, and stable structure, which endow nanomaterials great application potential in cancer therapy. However, even though the nanomaterials have been widely used in cancer therapy, there are still few reviews on their application in esophageal cancer, and systematical overview and analysis are deficient. Herein, we overviewed the application of nanodrug systems in therapy and diagnosis of esophageal cancer and summarized some representative case of their application in diagnosis, chemotherapy, targeted drug, radiotherapy, immunity, surgery and new therapeutic method of esophageal cancer. In addition, the nanomaterials used for therapy of esophageal cancer complications, esophageal stenosis or obstruction and oesophagitis, are also listed here. Finally, the challenge and the future of nanomaterials used in cancer therapy were discussed.

Association between blood eosinophil count and Duchenne muscular dystrophy severity and prognosis: a retrospective cohort study.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a rare hereditary muscular disease. The role of eosinophils in DMD has not been clarified. This study aims to evaluate the association between peripheral blood eosinophil count and severity and prognosis of DMD. METHODS: A retrospective cohort study was performed for 145 DMD patients between January 2012 and December 2020. Clinical data of 150 healthy children were collected as a control group. Logistic regression and Cox regression analyses were used to explore the influences of eosinophil count on DMD severity and prognosis. RESULTS: Eosinophil count in DMD group was lower than the control group (Z = 2.163, P = 0.031). It was negatively correlated with Vignos scale score, Spearman correlation coefficient was p = 0.245, P = 0.040 (at admission), p = 0.137, P = 0.032 (at follow-up); was a protective factor for high Vignos scale score at admission [odds ratio (OR) = 0.038, 95%CI: 0.002-0.752, P = 0.032] and follow-up (OR = 0.033,95%CI: 0.001-0.121, P = 0.039). The Cox regression analysis indicated that elevated eosinophil count was correlated with better therapeutic efficacy for DMD patients [hazard ratio (HR) = 2.218, 95%CI: 1.154-3.924, P = 0.016]. CONCLUSION: Eosinophil count in peripheral blood was correlated with the severity of DMD. It could indicate the therapeutic efficacy and prognosis of DMD patients to a certain extent. Eosinophils may be a potentially valuable biomarker or therapeutic target for DMD.

Highly absorbent bio-sponge based on carboxymethyl chitosan/poly-γ-glutamic acid/platelet-rich plasma for hemostasis and wound healing.

Stopping bleeding at an early stage and promoting wound healing are of great significance for efficient wound management. In this study, a carboxymethyl chitosan (CMCS)/poly-γ-glutamic acid (γ-PGA)/platelet-rich plasma (PRP) hydrogel (CP-PRP hydrogel) was firstly prepared by crosslinking of CMCS with γ-PGA and the enzymatic coagulation of PRP. Then, the CP-PRP hydrogel was freeze-dried and transformed into a sponge (CP-PRP sponge). A series of safety experiments with cells, blood, and tissues proved the biocompatibility of the CP-PRP sponge. Importantly, the CP-PRP sponge was able to adhere and condense red blood cells, which accelerated blood clotting. Therefore, the CP-PRP sponge showed an enhanced hemostasis effect compared to SURGIFLO® Hemostatic Matrix. Moreover, in vitro and in vivo experiments showed that the sponge was able to release epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF). Thus, in a mouse model of full-thickness skin defects, the wounds of the sponge-treated mice were significantly healed within two weeks. These results proved the transforming potential of the CP-PRP sponge as a novel bioactive wound dressing.

Durability of Plant Fiber Composites for Structural Application: A Brief Review.

Environmental sustainability and eco-efficiency stand as imperative benchmarks for the upcoming era of materials. The use of sustainable plant fiber composites (PFCs) in structural components has garnered significant interest within industrial community. The durability of PFCs is an important consideration and needs to be well understood before their widespread application. Moisture/water aging, creep properties, and fatigue properties are the most critical aspects of the durability of PFCs. Currently, proposed approaches, such as fiber surface treatments, can alleviate the impact of water uptake on the mechanical properties of PFCs, but complete elimination seems impossible, thus limiting the application of PFCs in moist environments. Creep in PFCs has not received as much attention as water/moisture aging. Existing research has already found the significant creep deformation of PFCs due to the unique microstructure of plant fibers, and fortunately, strengthening fiber-matrix bonding has been reported to effectively improve creep resistance, although data remain limited. Regarding fatigue research in PFCs, most research focuses on tension-tension fatigue properties, but more attention is required on compression-related fatigue properties. PFCs have demonstrated a high endurance of one million cycles under a tension-tension fatigue load at 40% of their ultimate tensile strength (UTS), regardless of plant fiber type and textile architecture. These findings bolster confidence in the use of PFCs for structural applications, provided special measures are taken to alleviate creep and water absorption. This article outlines the current state of the research on the durability of PFCs in terms of the three critical factors mentioned above, and also discusses the associated improvement methods, with the hope that it can provide readers with a comprehensive overview of PFCs' durability and highlight areas worthy of further research.

[Genetic analysis of a child with early onset neurodevelopmental disorder with involuntary movement and a literature review].

OBJECTIVE: To explore the clinical phenotype and genetic basis of a child with early onset neurodevelopmental disorder with involuntary movement (NEDIM). METHODS: A child who presented at Department of Neurology of Hunan Children's Hospital on October 8, 2020 was selected as the study subject. Clinical data of the child were collected. Genomic DNA was extracted from peripheral blood samples of the child and his parents. Whole exome sequencing (WES) was carried out for the child. Candidate variant was verified by Sanger sequencing and bioinformatic analysis. Relevant literature was searched from the CNKI, PubMed and Google Scholar databases to summarize the clinical phenotypes and genetic variants of the patients. RESULTS: This child was a 3-year-and-3-month boy with involuntary trembling of limbs and motor and language delay. WES revealed that the child has harbored a c.626G>A (p.Arg209His) variant of the GNAO1 gene. Sanger sequencing confirmed that neither of his parents has carried the same variant. The variant had been reported in HGMD and ClinVar databases, but not in the dbSNP, ExAC and 1000 Genomes databases. Prediction with SIFT, PolyPhen-2, and Mutation Taster online software suggested that the variant may be deleterious to the protein function. By UniProt database analysis, the encode amino acid is highly conserved among various species. Prediction with Modeller and PyMOL software indicated that the variant may affect the function of GαO protein. Based on the guideline of the American College of Medical Genetics and Genomics (ACMG), the variant was rated as pathogenic. CONCLUSION: The GNAO1 gene c.626G>A (p.Arg209His) variant probably underlay the NEDIM in this child. Above finding has expanded the phenotypic spectrum of GNAO1 gene c.626G>A (p.Arg209His) variant and provided a reference for clinical diagnosis and genetic counseling.

[Analysis of clinical phenotype and genetic variants in a child with mitochondrial F-S disease due to variants of FDXR gene].

OBJECTIVE: To analyze the clinical phenotype and genetic variants of a child suspected for mitochondrial F-S disease. METHODS: A child with mitochondrial F-S disease who visited Department of Neurology, Hunan Provincial children's Hospital on November 5, 2020 was selected as research subject of this study. Clinical data of the child was collected. The child was subjected to whole exome sequencing (WES). Bioinformatics tools were used to analyze the pathogenic variants. Candidate variants were verified by Sanger sequencing of the child and her parents. RESULTS: WES revealed that the child has harbored compound heterozygous variants of the FDXR gene, namely c.310C>T (p.R104C) and c.235C>T (p.R79C), which were inherited from her father and mother, respectively. Neither variant has been reported in HGMD, PubMed, 1000 Genomes, and dbSNP databases. Both of the variants have been suggested as deleterious according to the prediction results from different bioinformatics analysis software. CONCLUSION: Mitochondrial diseases should be suspected for patients with multiple system involvement. The compound heterozygous variants of the FDXR gene probably underlay the disease in this child. Above finding has enriched the spectrum of FDXR gene mutations underlying mitochondrial F-S disease. WES can facilitate the diagnosis of mitochondrial F-S disease at the molecular level.

Glucose oxidase-loaded colloidal stable WS2 nanobowls for combined starvation/photothermal therapy of colorectal tumors.

Glucose is used as an important nutrient to support cell growth. The glucose oxidase (GOx) can transform glucose into gluconic acid and toxic H2O2, which can be used for tumor starvation therapy. However, the leakage of GOx may cause severe side effects to the normal tissue. To prevent the accidental leakage of GOx, this study proposes the chemical modification of GOx on the photothermal transducing agent surface, to realize the safe and combined starvation and photothermal therapy of colorectal tumors. Polyvinylpyrrolidone (PVP)-modified WS2 nanobowls (WS2-PVP) as a photothermal transducing agent were produced using a one-pot preparation method. Then, α-lipoic acid (LA) molecules were immobilized at the sulfur-deficient sites on the surface of WS2 nanobowls to afford the chemical loading of GOx through amide bonds. Under the irradiation of a near-infrared laser (808 nm), thermal energy is generated by WS2 to kill colorectal cancer cells locally. The photothermal conversion efficiency of WS2-PVP-LA was 27.2%. This study is anticipated to open up an alternative avenue for the rational design of multifunctional nanotherapeutics for tumor therapy.

A conductive gelatin methacrylamide hydrogel for synergistic therapy of osteosarcoma and potential bone regeneration.

In this study, a methacrylic gelatin/oxidized dextran/montmorillonite­strontium/polypyrrole (GOMP) hydrogel was prepared. The GOMP hydrogel had dual network structure which was formed through photoinitiator-initiated double bond polymerization and Schiff base reaction. The network structure led to a sustained release of the antitumor drug, doxorubicin (DOX). Polypyrrole introduced the conductivity and high photothermal conversion capacity to the GOMP hydrogel, which showed a photothermal conversion efficiency of 31.61 % under 808 nm laser radiation. The GOMP hydrogel had good swelling properties in solvents. Further study showed that the GOMP hydrogel had good biocompatibility and excellent biodegradability in vitro and in vivo. The experiments of in vitro tumor therapy and in vivo anti-tumor recurrence indicated that the DOX-loaded GOMP hydrogel had synergistic effects on tumor cell apoptosis based on chemotherapy and photothermal therapy. In addition, montmorillonite­strontium (MMT-Sr) doped in the hydrogel not only improved the mechanical properties of the hydrogel but also promoted potential bone regeneration. The multifunctional DOX-loaded GOMP hydrogel with bone regeneration, photothermal therapy, and chemotherapy functions has great potential application for treating osteosarcoma.

Lightweight and flexible PAN@PPy/MXene films with outstanding electromagnetic interference shielding and Joule heating performance.

Lightweight and flexible multifunctional materials with excellent electromagnetic interference (EMI) shielding and Joule heating performances are highly demanded for smart and wearable electronics. In this work, polyacrylonitrile (PAN) nanofiber films are prepared by electrospinning and then coated with polypyrrole (PPy) via vapor deposition, yielding a continuous three-dimensional (3D) conductive network of PAN@PPy. Ti3C2Tx MXene nanosheets with high electrical conductivity are sprayed on the PAN@PPy film to enhance its EMI shielding performance. The as-prepared PAN@PPy/MXene films (55 µm thick) exhibit a high EMI shielding effectiveness (SE) of 32 dB, achieving an extraordinarily high normalized surface-specific SE (SSE/t) of up to 17 534.5 dB cm2 g-1 from 8.2 to 12.4 GHz; simultaneously, the temperatures of PAN@PPy/MXene films can be driven up to 170.5 °C at an input voltage of 4 V, and exhibit fast-response, stable, and long-term Joule heating performance. The high SSE/t and efficient Joule heating ability of the films bode potential applications in smart and wearable devices.

Nabais Sa-de Vries syndrome in a Chinese infant associated with a novel SPOP mutation: A clinical study and genetic report.

BACKGROUND: Nabais Sa-de Vries syndrome (NSDVS) is a newly identified neurodevelopmental disorder (NDD), characterized by mutations in the SPOP gene, which encodes the speckle-type BTB/POZ protein. It is divided into two disease subtypes, according to patient facial features, which could be related to altered SPOP protein function. Few studies have documented this syndrome and little is known about its pathophysiology. Herein, we present an unexplained infant case of NDD, possibly the first Asian NSDVS case report. METHODS: A 7-month-old boy presented with an enlarged head circumference, widened eye distance, and a protruding nose. Trio-whole exome sequencing of the patient's family was performed, and a variant was identified by bioinformatics analysis and further verified by Sanger sequencing. This variant was then identified by molecular dynamics analysis. Finally, a plasmid was constructed in vitro to transfect the human 293 T cells. qPCR and western blotting (WB) experiments were subsequently performed. These analyses verified the variant's transcription and protein expression. RESULTS: Trio-whole exome sequencing was used to identify the SPOP mutation c.67 T > C (p.Cys23Arg). Crystal structure simulations suggest that this single-residue substitution alters hydrogen bonding with nearby residues. Analysis via qPCR and WB experiments indicated decreased mutant mRNA and protein expression levels. CONCLUSION: Our findings suggest that genetic testing should be performed as soon as possible for children with NDD showing low phenotypic specificity. Prompt testing will provide more accurate diagnoses, which in turn offers evidence to assist in the formulation of rehabilitation training plans, and genetic counseling for patients' families.

ML323, a USP1 inhibitor triggers cell cycle arrest, apoptosis and autophagy in esophageal squamous cell carcinoma cells.

Esophageal squamous cell carcinoma (ESCC) is a common digestive cancer with high mortality rate due to late diagnosis and drug resistance. It is important to identify new molecular target and develop new anticancer strategy. ML323 is a novel USP1 inhibitor and exhibits anticancer activity against several cancers. Herein, we investigated whether ML323 has some cytotoxity effect on ESCC cells and explored the underlying mechanisms. Results revealed that ML323 impeded esophageal cancer cell viability and colony formation. Meanwhile, ML323 blocked cells at G0/G1 phase concomitant with the reduced protein level of c-Myc, cyclin D1, CDK4 and CDK6. ML323 treatment also triggered DNA damage and active p53. Then, ML323 induced apoptosis by p53-Noxa. Additionally, it stimulated protective autophagy. Co-treatment with CQ or BafA1, two classical autophagy inhibitors, enhanced the cytotoxity of ML323. These findings suggested that USP1 inhibitor (ML323) could be used as a viable anti-ESCC approach.

Exploring the molecular mechanism of action of Polygonum capitatum Buch-Ham. ex D. Don for the treatment of bacterial prostatitis based on network pharmacology and experimental verification.

ETHNOPHARMACOLOGY RELEVANCE: Polygonum capitatum Buch-Ham. ex D. Don (CNPC2009), a traditional Miao-national herbal medicine, has been widely used with considerable therapeutic efficacy in the treatment of various urologic disorders including prostatitis. However, the molecular mechanism of action (MOA) remains unclear. AIM OF THE STUDY: In this study, UPLC-Q-Exactive-MS and Network pharmacological methods were used to explore the underlying molecular MOA of Polygonum capitatum Buch-Ham. Ex D. Don (P.capitatum) for the treatment bacterial prostatitis (BP). MATERIALS AND METHODS: The UPLC-Q-Exactive-MS technique was used to identify the chemical components of P. capitatum. Databases such as SwissTargetPrediction, Gene Cards, and OMIM were used to predict the targets of P. capitatum for the treatment of BP. The Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) was used to analyze the protein-protein interaction (PPI) and construct a PPI network, and the Metascape was used for Gene Ontology (GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. In addition, experimental treatment of Escherichia coli (E.coli)-induced BP was verified. RESULTS: A total of 31 molecular components were identified by UPLC-Q-Exactive-MS. Network pharmacology revealed that P. capitatum may act on the AKT1, PI3K, MTO, EGFR and other targets through active components such as Gallic acid, Quercetin, Luteolin, Protocatechuic Acid, Kaempferol and thereby regulate PI3K-AKT, ErbB, AMPK, HIF-1, and other signaling pathways to intervene in the pathological mechanism of BP. Verification through experimental results showed that compared with the model group, treatment with P. capitatum could significantly inhibit bacterial growth in prostate tissues, lowered the prostate index, down-regulated the levels of inflammatory mediators(IL-1ß, IL-6, and TNF-α) in prostate tissues, and down-regulate the protein expression and mRNA expression levels of AKT and PI3K. CONCLUSION: This study preliminarily revealed the MOA of P. capitatum for treating BP with multiple components, multiple targets, and multiple pathways, especially affecting the PI3K-AKT signaling pathways.

Screening and identification of HLA-A2-restricted neoepitopes for immunotherapy of non-microsatellite instability-high colorectal cancer.

Colorectal cancer has one of the highest mortality rates among malignant tumors, and most patients with non-microsatellite instability-high (MSI-H) colorectal cancer do not benefit from targeted therapy or immune checkpoint inhibitors. Identification of immunogenic neoantigens is a promising strategy for inducing specific antitumor T cells for cancer immunotherapy. Here, we screened potential high-frequency neoepitopes from non-MSI-H colorectal cancer and tested their abilities to induce tumor-specific cytotoxic T cell responses. Three HLA-A2-restricted neoepitopes (P31, P50, and P52) were immunogenic and could induce cytotoxic T lymphocytes in peripheral blood mononuclear cells from healthy donors and colorectal cancer patients. Cytotoxic T lymphocytes induced in HLA-A2.1/Kb transgenic mice could recognize and lyse mutant neoepitope-transfected HLA-A2+ cancer cells. Adoptive transfer of cytotoxic T lymphocytes induced by the peptide pool of these three neoepitopes effectively inhibited tumor growth and increased the therapeutic effects of anti-PD-1 antibody. These results revealed the potential of high-frequency mutation-specific peptide-based immunotherapy as a personalized treatment approach for patients with non-MSI-H colorectal cancer. The combination of adoptive T cell therapy based on these neoepitopes with immune checkpoint inhibitors, such as anti-PD-1, could provide a promising treatment strategy for non-MSI-H colorectal cancer.

Forsythiaside A alleviates methotrexate-induced intestinal mucositis in rats by modulating the NLRP3 signaling pathways.

Most chemotherapeutic drugs can kill the tumor cells, but also cause a vast damage to body, such as intestinal mucositis (IM). The present study was design to find out the effect of Forsythiaside A (FTA) on chemotherapeutic-induced IM in rats. Briefly, for 3 consecutive days, male Sprague-Dawley rats were treated with 7 mg / kg methotrexate (MTX) to establish IM and simultaneously administered with 40 or 80 mg / kg FTA for 7 days. Our results showed that the final body weight and daily food intake were increased, and the disease activity index was reduced in the MTX group after FTA treatment. The MTX group showed the pathological alterations like the inflammatory cells infiltration, the mucosal layer destruction, glands expansion, intestinal villi structure disorder and goblet cells reduction, while we found that 80 mg / kg FTA treatment displayed evident reversal effects. ELISA further suggested that TNF-α, IL-1ß and IL-18 levels in serum in MTX-induced rats were reduced after 80 mg / kg FTA treatment. Moreover, FTA decreased the number of leukocytes, neutrophils and lymphocytes in peripheral blood. Western blot and immunofluorescence results indicated that the expression levels of NLRP3, cleaved caspase 1, cleaved IL-1ß and CD68 positive rate were down-regulated in MTX-induced rats after 80 mg / kg FTA intervention. The findings of the current study suggested that FTA effectively inhibited MTX-induced IM in rats by attenuating the activation of the NLRP3 signaling pathways.