Pathophysiological role of ion channels and transporters in hepatocellular carcinoma.

The incidence of hepatocellular carcinoma (HCC) has continued to increase annually worldwide, and HCC has become a common cause of cancer-related death. Despite great progress in understanding the molecular mechanisms underlying HCC development, the treatment of HCC remains a considerable challenge. Thus, the survival and prognosis of HCC patients remain extremely poor. In recent years, the role of ion channels in the pathogenesis of diseases has become a hot topic. In normal liver tissue, ion channels and transporters maintain water and electrolyte balance and acid‒base homeostasis. However, dysfunction of these ion channels and transporters can lead to the development and progression of HCC, and thus these ion channels and transporters are expected to become new therapeutic targets. In this review, ion channels and transporters associated with HCC are reviewed, and potential targets for new and effective therapies are proposed.

Investigation of N-Glycan Functions in Receptor for Advanced Glycation End Products V Domain through Chemical Glycoprotein Synthesis.

The receptor for advanced glycation end products (RAGE) plays a crucial role in inflammation-related pathways and various chronic diseases. Despite the recognized significance of N-glycosylation in the ligand-binding V domain (VD) of RAGE, a comprehensive understanding of the site-activity and structure-activity relationships is lacking due to the challenges in obtaining homogeneous glycoprotein samples through biological expression. Here, we combined chemical and chemoenzymatic approaches to synthesize RAGE-VD and its congeners with Asn3-glycosylation by incorporating precise N-glycan structures. Evaluation of these samples revealed that, in comparison to other RAGE-VD forms, α2,6-sialylated N-glycosylation at the Asn3 site results in more potent inhibition of HMGB1-induced nuclear factor-κB (NF-κB) expression in RAGE-overexpressing cells. Hydrogen/deuterium exchange-mass spectrum analysis revealed a sialylated RAGE-VD-induced interaction region within HMGB1. Conversely, Asn3 N-glycosylation in VD has negligible effects on RAGE-VD/S100B interactions. This study established an approach for accessing homogeneously glycosylated RAGE-VD and explored the modulatory effects of N-glycosylation on the interactions between RAGE-VD and its ligand proteins.

Role of lactate and lactate metabolism in liver diseases (Review).

Lactate is a byproduct of glycolysis, and before the Warburg effect was revealed (in which glucose can be fermented in the presence of oxygen to produce lactate) it was considered a metabolic waste product. At present, lactate is not only recognized as a metabolic substrate that provides energy, but also as a signaling molecule that regulates cellular functions under pathophysiological conditions. Lactylation, a post­translational modification, is involved in the development of various diseases, including inflammation and tumors. Liver disease is a major health challenge worldwide. In normal liver, there is a net lactate uptake caused by gluconeogenesis, exhibiting a higher net lactate clearance rate compared with any other organ. Therefore, abnormalities of lactate and lactate metabolism lead to the development of liver disease, and lactate and lactate metabolism­related genes can be used for predicting the prognosis of liver disease. Targeting lactate production, regulating lactate transport and modulating lactylation may be potential treatment approaches for liver disease. However, currently there is not a systematic review that summarizes the role of lactate and lactate metabolism in liver diseases. In the present review, the role of lactate and lactate metabolism in liver diseases including liver fibrosis, non­alcoholic fatty liver disease, acute liver failure and hepatocellular carcinoma was summarized with the aim to provide insights for future research.

Ginsenoside compound K plays an anti-inflammatory effect without inducing glucose metabolism disorder in adjuvant-induced arthritis rats.

Ginsenoside compound K (GCK) possesses a glucocorticoid (GC)-like structure and functions as an agonist of the glucocorticoid receptor (GR), thereby exerting anti-inflammatory effects through GR activation. However, it remains unclear whether GCK leads to hyperglycemia, which is a known adverse reaction associated with classical GCs. In this study, we have successfully demonstrated that GCK exerts its anti-inflammatory effects in a rat model of adjuvant arthritis without impacting gluconeogenesis and pentose phosphate pathways, thus avoiding any glucose metabolism disorders. By employing the GR mutant plasmid, we have identified the binding site between GCK and GR as GRM560T, which differs from the binding site shared by dexamethasone (DEX) and GR. Notably, compared to DEX, GCK induces distinct levels of phosphorylation at S211 on GR upon binding to activate steroid receptor coactivator 1 (SRC1)-a co-factor responsible for mediating anti-inflammatory effects-while not engaging peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-an associated coactivator involved in gluconeogenesis.

Exploiting the advantages of cationic copolymers and AgBr nanoparticles to optimize the antibacterial activity of chitosan.

Recently, the chitosan (CS)-based composites have attracted increasing attention for controlling and preventing the spread of pathogenic microorganisms. Herein, an amphiphilic copolymer containing epoxy and quaternary ammonium groups (PBGDBr) was synthesized via three common acrylate monomers. The epoxy groups of this copolymer were then crosslinked with the amino groups of CS to synthesize a natural/synthetic (PBGDBr-C) composite to increase the water solubility of CS under alkaline conditions and enhance its antibacterial activity based on chemical contact-type modes. Moreover, silver bromide nanoparticles (AgBr NPs)-decorated PBGDBr-C (AgBr@PBGDBr-C) composite was prepared, which aimed to endow the final AgBr@PBGDBr-C composite with a photodynamic antibacterial mode relying on the formation of Ag/AgBr nanostructures catalyzed by visible light on AgBr NPs. The results showed that the final composite possessed satisfactory bactericidal effects at concentrations higher than 64 and 128 µg/mL against Escherichia coli and Staphylococcus aureus, respectively. Additionally, The L929 cells treated with the final composite retained high cell viability (>80 %) at a concentration of 128 µg/mL, indicating its low toxicity to L929 cells. Overall, our synthetic strategy exploits a multi-modal system that enables chemical-photodynamic synergies to treat infections caused by pathogenic bacteria while delaying the development of bacterial resistance.

Research on a new multiple-screening method for laser-induced plasma spectroscopy utilizing Lorentz.

In the field of Laser Induced Breakdown Spectroscopy (LIBS) research, the screening and extraction of complex spectra play a crucial role in enhancing the accuracy of quantitative analysis. This paper introduces a novel approach for multiple screenings of LIBS spectra using Lorentz Screening and Sensitivity and Volatility Analysis. Initially, Create symmetrical sampling standards for Lorentz fitting. Then the Lorentz fitting is used to uniformly screen the collected spectral information on both sides in order to eliminate adjacent interference peaks. Subsequently, Sensitivity and Volatility Analysis is employed to further remove overlapping peaks and select spectra with low volatility and high sensitivity. Sensitivity and Volatility Analysis is a spectral discrimination method proposed on the premise of intensity's correlation with concentration. It utilizes a Z-score method that incorporates both deviation and standard deviation for effective analysis. Furthermore, it meticulously selects spectral lines with minimal interference and volatility, thereby augmenting the precision of quantitative analysis. The quantitative accuracy (R2) for Chromium (Cr) and Nickel (Ni) elements can reach 0.9919 and 0.9768, respectively. Their average errors can be reduced to 0.0566 % and 0.1024 %. The study demonstrates that Lorentz Screening and Sensitivity and Volatility Analysis can select high-quality characteristic spectral lines to improve the performance of the model.

Targeted drug-loaded peptides induce tumor cell apoptosis and immunomodulation to increase antitumor efficacy.

Immunotherapy is an emerging approach for the treatment of solid tumors. Although chemotherapy is generally considered immunosuppressive, specific chemotherapeutic agents can induce tumor immunity. In this study, we developed a targeted, acid-sensitive peptide nanoparticle (DT/Pep1) to deliver doxorubicin (DOX) and triptolide (TPL) to breast cancer cells via the enhanced permeability and retention (EPR) effect and the breast cancer-targeting effect of peptide D8. Compared with administration of the free drugs, treatment with the DT/Pep1 system increased the accumulation of DOX and TPL at the tumor site and achieved deeper penetration into the tumor tissue. In an acidic environment, DT/Pep1 transformed from spherical nanoparticles to aggregates with a high aspect ratio, which successfully extended the retention of the drugs in the tumor cells and bolstered the anticancer effect. In both in vivo and in vitro experiments, DT/Pep1 effectively blocked the cell cycle and induced apoptosis. Importantly, the DT/Pep1 system efficiently suppressed tumor development in mice bearing 4T1 tumors while simultaneously promoting immune system activation. Thus, the results of this study provide a system for breast cancer therapy and offer a novel and promising platform for peptide nanocarrier-based drug delivery.

Composite adaptive fuzzy bipartite consensus of fractional-order multiagent systems with a switched event-triggered mechanism.

This paper focuses on online recorded-data-based composite adaptive fuzzy bipartite consensus control for uncertain fractional-order multiagent systems with interconnected terms and external disturbances by employing a switched-threshold-based event-triggered mechanism (ETM) under the backstepping structure. Fuzzy logic system is used as a universal function approximation to deal with function uncertainties that are not prone to model in the system. A new composite learning adaptive parameter design scheme that synthesizes both prediction error and tracking error is developed to enhance the tracking performance, where the prediction error is raised from the utilization of online recorded data and instantaneous data. A unique switched-threshold-based ETM is introduced, in which the information transmission between the sensor and the controller is imposed on one of the individuals. One merit of this work consists in that it can automatically and rapidly switch and adjust between the fixed threshold and relative threshold ETM according to the amplitude of input signals to balance the network resources and impede the occurrence of pulse phenomenon. In addition, it is theoretically proven that the proposed scheme can ensure that all internal signals of the closed-loop system are bounded and achieve local bipartite consistent errors through the fractional Lyapunov stability criterion. Finally, a numerical example is provided to confirm the feasibility of the proposed approach.

A co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation.

Targeted degradation of proteins has emerged as a powerful method for modulating protein homeostasis. Identification of suitable degraders is essential for achieving effective protein degradation. Here, we present a non-covalent degrader construction strategy, based on a modular supramolecular co-assembly system consisting of two self-assembling peptide ligands that bind cell membrane receptors and the protein of interest simultaneously, resulting in targeted protein degradation. The developed lysosome-targeting co-assemblies (LYTACAs) can induce lysosomal degradation of extracellular protein IL-17A and membrane protein PD-L1 in several scavenger receptor A-expressing cell lines. The IL-17A-degrading co-assembly has been applied in an imiquimod-induced psoriasis mouse model, where it decreases IL-17A levels in the skin lesion and alleviates psoriasis-like inflammation. Extending to asialoglycoprotein receptor-related protein degradation, LYTACAs have demonstrated the versatility and potential in streamlining degraders for extracellular and membrane proteins.

Neuronal aerobic glycolysis exacerbates synapse loss in aging mice.

Brain consumes nearly 20% supply of energy from glucose metabolism by oxidative phosphorylation and aerobic glycolysis. Less active state of glycolytic enzymes results in a limited capacity of glycolysis in the neurons of adult brain. Here we identified that Warburg effect is enhanced in hippocampal neurons during aging. As hippocampal neurons age, lactate levels progressively increase. Notably, we observed upregulated protein levels of PFKFB3 in the hippocampus of 20-month-old mice compared to young mice, and this higher PFKFB3 expression correlated with declining memory performance in aging mice. Remarkably, in aging mice, knocking down Pfkfb3 in hippocampal neurons rescued cognitive decline and synapse loss. Conversely, Pfkfb3 overexpression in hippocampal neurons led to cognitive impairment and synapse elimination, associated with heightened glycolysis. In vitro experiments with cultured primary neurons confirmed that Pfkfb3 overexpression increased glycolysis and that glycolytic inhibition could prevent apoptotic competency in neurons. These findings underscore that glycolysis in hippocampal neurons could potentially be targeted as a therapeutic avenue to mitigate cognitive decline and preserve synaptic integrity during aging.

Tailored Zwitterionic Hemicyanine Reporters for Early Diagnosis and Prognostic Assessment of Acute Renal Failure.

Drug-induced renal failure (DIRF) poses a serious medical complication with high mortality risk. However, early diagnosis or prognosis of DIRF remain challenging, as current methods rely on detecting late-stage biomarkers. Herein we present a library of zwitterionic unimolecular hemicyanines (ZCs) available for constructing activatable reporters to detect DIRF since its initial stage. Zwitterionic properties of these probes are achieved through interspersedly integrating alkyl sulfonates and quaternary ammonium cations onto hemicyanine skeleton, which result in record low plasma protein binding (<5 %) and remarkable renal clearance efficiencies (≈96 %). An activatable reporter ZCRR is further developed by masking the optimal candidate ZC6 with a tetrapeptide specifically cleavable by caspase-8, an initiating indicator of apoptosis. In living mice with cisplatin-induced DIRF, systematically administered ZCRR efficiently accumulates in kidneys and responds to elevated caspase-8 for near-infrared fluorescence signals 'turn-on', enabling sensitive detection of intrarenal apoptosis 60 h earlier than clinical methods, and precise evaluation of apoptosis remediation effects by different medications on DIRF mice. As it's urinary excretable, ZCRR also allows for remote detection of DIRF and predicting renoprotective efficacy through in vitro optical urinalysis. This study thus presents unimolecular renal clearable scaffolds that are applicable to developing versatile activatable reporters for renal diseases management.

A Flexible Wearable Supernumerary Robotic Limb for Chronic Stroke Patients.

In this study, we present a flexible wearable supernumerary robotic limb that helps chronic stroke patients with finger rehabilitation and grasping movements. The design of this innovative limb draws inspiration from bending pneumatic muscles and the unique characteristics of an elephant's trunk tip. It places a strong emphasis on crucial factors such as lightweight construction, safety, compliance, waterproofing, and achieving a high output-to-weight/pressure ratio. The proposed structure enables the robotic limb to perform both envelope and fingertip grasping. Human-robot interaction is facilitated through a flexible bending sensor, detecting the wearer's finger movements and connecting them to motion control via a threshold segmentation method. Additionally, the system is portable for versatile daily use. To validate the effectiveness of this innovation, real-world experiments involving six chronic stroke patients and three healthy volunteers were conducted. The feedback received through questionnaires indicates that the designed mechanism holds immense promise in assisting chronic stroke patients with their daily grasping activities, potentially improving their quality of life and rehabilitation outcomes.

Ginsenoside compound K exerts anti-inflammatory effects through transcriptional activation and transcriptional inhibition of glucocorticoid receptor in rheumatoid arthritis fibroblast-like synoviocytes.

Ginsenoside compound K (GCK) has anti-inflammatory and immunoregulatory effects, and glucocorticoid receptor (GR) has been considered as its potential target. But the mechanism by which GCK exerts its anti-inflammatory effects after GR activation remains unclear. In this study, molecular docking, isothermal titration calorimetry, siRNA of GR and GRA458T mutation were used to confirm the anti-inflammatory mechanism of GCK targeting GR in fibroblast-like synoviocytes (FLS). The results showed that the key binding sites of GR and GCK were identified as ASN564, MET560 and ASN638, with binding levels at the µm level. In addition, the inhibitory effect of GCK on the proliferation of FLS and the secretion of inflammatory cytokines (IL-6, IL-8, and IL-1ß) were mediated by transcriptional activation of GR, but on the migration, invasion, and TNF-α secretion of FLS were mediated by transcriptional inhibition of GR. These actions exert anti-inflammatory effects through indirect and direct inhibition of NF-κB transcriptional activity, respectively. In conclusion, this study elucidates that GCK can directly bind to and activate GR. Furthermore, after activation, GR mediates the anti-inflammatory effects of GCK through two mechanisms: transcriptional activation and transcriptional inhibition.

Patients' expectancy scale of acupuncture: Development and clinical performance test.

PURPOSE: This study aims to develop and validate a concise tool for evaluating acupuncture expectancy that is easy to understand and conforms to acupuncture characteristics. MATERIALS AND METHODS: A draft was created using the Delphi consensus method. Reliability, validity, discrimination, and feasibility tests were conducted at the item and scale levels. RESULTS: The scale themes were defined as disease-related, treatment-related, process-related, and outcome-related. After two rounds of Delphi surveys with good experts' reliability (authority coefficients of experts were 0.86 and 0.87 in the two rounds) and agreement (Kendall's concordance coefficient of the participants were 0.33 and 0.15 in the two rounds, P < 0.05), 11 items (the mean score for item importance, full mark ratios, and coefficient of variation of items were ≥3.5, ≥25%, and ≤0.30, respectively) were included in the draft. A total of 145 individuals were recruited to test the draft. Reliability was assessed by Cronbach's α coefficient (0.90), split-half reliability coefficient (0.89), and test-retest reliability (Pearson's coefficient = 0.74, P < 0.05). Content validity was assessed by the content validity index (Item-CVI ≥ 0.78 and Scale-CVI/Ave = 0.92), and a confirmatory factor analysis was performed to assess the construct validity. The discrimination of scale items was evaluated by the critical ratio (CR > 3.00) and the homogeneity test (item-total correlations >0.40). Feasibility was assessed through the acceptance rate (recovery rate = 98.60%, response rate = 100%), completion rate (100%), and completion time (4.99 ± 6.80 min). CONCLUSION: The patients' expectancy scale of acupuncture (PESA) consists of 11 items with four themes, disease-related, treatment-related, process-related, and outcome-related. It has great reliability, validity, discrimination, and feasibility and has the potential to evaluate acupuncture expectancy in clinical trials.

Intracellular chloride channel 1 and tumor.

As the major intracellular anion, chloride plays an important role in maintaining intracellular and extracellular ion homeostasis, osmotic pressure, and cell volume. Intracellular chloride channel 1, which has the physiological role of forming membrane proteins in the lipid bilayer and playing ion channels, is a hot research topic in recent years. It has been found that CLIC1 does not only act as an ion channel but also participates in cell cycle regulation, apoptosis, and intracellular oxidation; thus, it participates in the proliferation, invasion, and migration of various tumor cells in various systems throughout the body. At the same time, CLIC1 is highly expressed in tumor cells and is associated with malignancy and a poor prognosis. This paper reviews the pathological mechanisms of CLIC1 in systemic diseases, which is important for the early diagnosis, treatment, and prognosis of systemic diseases associated with CLIC1 expression.

The S100 calcium-binding protein A6 plays a crucial role in hepatic steatosis by mediating lipophagy.

BACKGROUND: S100 calcium-binding protein A6 (S100A6) is a calcium-binding protein that is involved in a variety of cellular processes, such as proliferation, apoptosis, and the cellular response to various stress stimuli. However, its role in NAFLD and associated metabolic diseases remains uncertain. METHODS AND RESULTS: In this study, we revealed a new function and mechanism of S100A6 in NAFLD. S100A6 expression was upregulated in human and mouse livers with hepatic steatosis, and the depletion of hepatic S100A6 remarkably inhibited lipid accumulation, insulin resistance, inflammation, and obesity in a high-fat, high-cholesterol (HFHC) diet-induced murine hepatic steatosis model. In vitro mechanistic investigations showed that the depletion of S100A6 in hepatocytes restored lipophagy, suggesting S100A6 inhibition could alleviate HFHC-induced NAFLD. Moreover, S100A6 liver-specific ablation mediated by AAV9 alleviated NAFLD in obese mice. CONCLUSIONS: Our study demonstrates that S100A6 functions as a positive regulator of NAFLD, targeting the S100A6-lipophagy axis may be a promising treatment option for NAFLD and associated metabolic diseases.

Anti-Tumor Immunity Induced by a Ternary Membrane System Derived From Cancer Cells, Dendritic Cells, and Bacteria.

Cancer vaccines generally are limited by insufficient tumor-specific cellular immunogenicity. Herein, a potent "ABC" ternary membrane-derived vaccine system blended from antigen-presenting mature dendritic cell membranes ("A"), bacterial E. coli cytoplasmic membranes ("B"), and cancer cell membranes ("C") is developed using a block-copolymer micelle-enabled approach. The respective ABC membrane components provide for a source of cellular immune communication/activation and enhanced accumulation in lymph nodes (A), immunological adjuvant (B), and tumor antigens (C). The introduction of dendritic cell (DC) membranes enables multiple cell-to-cell communication and powerful immune activation. ABC activates dendritic cells and promotes T-cell activation and proliferation in vitro. In vivo, ABC is 14- and 304-fold more immunogenic than binary (BC) and single (C) membrane vaccines, and immunization with ABC enhances the frequency of tumor-specific cytotoxic T lymphocytes, leading to an 80% cure rate in tumor-bearing mice. In a surgical resection and recurrence model, ABC prevents recurrence with vaccination from autologous cancer membranes, and therapeutic effects are observed in a lung metastasis model even with heterologous cancer cell membranes. ABCs formed from human cancer patient-derived tumor cells activate human monocyte-derived dendritic cells (moDC). Taken together, the ternary ABC membrane system provides the needed functional components for personalized cancer immunotherapy.

Myofascial acupuncture versus routine acupuncture for mechanical neck pain: a protocol for a multicentre randomised controlled trial.

INTRODUCTION: Mechanical neck pain (MNP) is defined as pain in the area of the neck and/or neck-shoulder provoked by body mechanics and which adversely affects physical, psychological and social function. The treatments for MNP are limited. Previous studies and clinical experience have indicated that myofascial acupuncture might be a better treatment option for MNP, but the efficacy is controversial. Therefore, our aim is to compare the efficacy of myofascial acupuncture and routine acupuncture for MNP. METHODS AND ANALYSIS: The study is a multicentre, prospective randomised clinical trial. Patients will be recruited from four tertiary hospitals in China. A total of 438 participants with MNP will be randomly assigned into two groups, namely the 'Sancai-Tianbu' myofascial acupuncture group and the routine acupuncture group, at a ratio of 1:1. Each group will receive the acupuncture treatment twice a week for 21 days, totalling six sessions. The primary outcome will be the Visual Analogue Scale score. The secondary outcomes will be the Neck Disability Index, the cervical range of motion and the MOS 36-Item Short Form Health Survey. The assessments will be performed at baseline (immediately after allocation), pretreatment (5 min before every treatment), post-treatment (within 10 min after every treatment), postcourse (within 1 day after the course), and at 1, 3 and 6 months after the course. All patients will be included in the intent-to-treat analysis. Repeated-measure analysis of covariance will be used to determine the effects of the intervention on the outcome measures. ETHICS AND DISSEMINATION: Ethics approval was obtained from China Aerospace Science & Industry Corporation 731 Hospital, with permission number 2022-0204-01. Written informed consent will be obtained from the enrolled patients. Trial results will be disseminated in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ChiCTR2200061453.

Novel roles of karyopherin subunit alpha 2 in hepatocellular carcinoma.

Hepatocellular carcinoma is the most common type of liver cancer and associated with a high fatality rate. This disease poses a major threat to human health worldwide. A considerable number of genetic and epigenetic factors are involved in the development of hepatocellular carcinoma. However, the molecular mechanism underlying the progression of hepatocellular carcinoma remains unclear. Karyopherin subunit alpha 2 (KPNA2), also termed importin α1, is a member of the nuclear transporter family. In recent years, KPNA2 has been gradually linked to the nuclear transport pathway for a variety of tumor-associated proteins. Furthermore, it promotes tumor development by participating in various pathophysiological processes such as cell proliferation, apoptosis, immune response, and viral infection. In hepatocellular carcinoma, it has been found that KPNA2 expression is significantly higher in liver cancer tissues versus paracancerous tissues. Moreover, it has been identified as a marker of poor prognosis and early recurrence in patients with hepatocellular carcinoma. Nevertheless, the role of KPNA2 in the development of hepatocellular carcinoma remains to be determined. This review summarizes the current knowledge on the pathogenesis and role of KPNA2 in hepatocellular carcinoma, and provides new directions and strategies for the diagnosis, treatment, and prediction of prognosis of this disease.