HMGB1 in the interplay between autophagy and apoptosis in cancer.

Lysosome-mediated autophagy and caspase-dependent apoptosis are dynamic processes that maintain cellular homeostasis, ensuring cell health and functionality. The intricate interplay and reciprocal regulation between autophagy and apoptosis are implicated in various human diseases, including cancer. High-mobility group box 1 (HMGB1), a nonhistone chromosomal protein, plays a pivotal role in coordinating autophagy and apoptosis levels during tumor initiation, progression, and therapy. The regulation of autophagy machinery and the apoptosis pathway by HMGB1 is influenced by various factors, including the protein's subcellular localization, oxidative state, and interactions with binding partners. In this narrative review, we provide a comprehensive overview of the structure and function of HMGB1, with a specific focus on the interplay between autophagic degradation and apoptotic death in tumorigenesis and cancer therapy. Gaining a comprehensive understanding of the significance of HMGB1 as a biomarker and its potential as a therapeutic target in tumor diseases is crucial for advancing our knowledge of cell survival and cell death.

The hippocampal FTO-BDNF-TrkB pathway is required for novel object recognition memory reconsolidation in mice.

Memory reconsolidation refers to the process by which the consolidated memory was restored after reactivation (RA). Memory trace becomes labile after reactivation and inhibition of memory reconsolidation may disrupt or update the original memory trace, which provided a new strategy for the treatment of several psychiatric diseases, such as drug addiction and post-traumatic stress disorder. Fat mass and obesity-associated gene (FTO) is a novel demethylase of N6-methyladenosine (m6A) and it has been intensively involved in learning and memory. However, the role of FTO in memory reconsolidation has not been determined. In the present study, the function of FTO in memory reconsolidation was investigated in the novel object recognition (NOR) model in mice. The results showed that RA of NOR memory increased hippocampal FTO expression in a time-dependent manner, while FTO inhibitor meclofenamic acid (MA) injected immediately, but not 6 h after RA disrupted NOR memory reconsolidation. MA downregulated BDNF expression during NOR memory reconsolidation in the hippocampus, while the TrkB agonist 7,8-Dihydroxyflavone (7,8-DHF) reversed the disruptive effects of MA on NOR memory reconsolidation. Furthermore, overexpression of FTO increased BDNF expression via decreasing mRNA m6A in HT22 cells. Taken together, these results indicate that FTO may up-regulate the BDNF-TrkB pathway to promote NOR memory reconsolidation through m6A modification.

Liver in infections: a single-cell and spatial transcriptomics perspective.

The liver is an immune organ that plays a vital role in the detection, capture, and clearance of pathogens and foreign antigens that invade the human body. During acute and chronic infections, the liver transforms from a tolerant to an active immune state. The defence mechanism of the liver mainly depends on a complicated network of intrahepatic and translocated immune cells and non-immune cells. Therefore, a comprehensive liver cell atlas in both healthy and diseased states is needed for new therapeutic target development and disease intervention improvement. With the development of high-throughput single-cell technology, we can now decipher heterogeneity, differentiation, and intercellular communication at the single-cell level in sophisticated organs and complicated diseases. In this concise review, we aimed to summarise the advancement of emerging high-throughput single-cell technologies and re-define our understanding of liver function towards infections, including hepatitis B virus, hepatitis C virus, Plasmodium, schistosomiasis, endotoxemia, and corona virus disease 2019 (COVID-19). We also unravel previously unknown pathogenic pathways and disease mechanisms for the development of new therapeutic targets. As high-throughput single-cell technologies mature, their integration into spatial transcriptomics, multiomics, and clinical data analysis will aid in patient stratification and in developing effective treatment plans for patients with or without liver injury due to infectious diseases.

The Redox Protein High-Mobility Group Box 1 in Cell Death and Cancer.

Significance: As a redox-sensitive protein, high-mobility group box 1 (HMGB1) is implicated in regulating stress responses to oxidative damage and cell death, which are closely related to the pathology of inflammatory diseases, including cancer. Recent Advances: HMGB1 is a nonhistone nuclear protein that acts as a deoxyribonucleic acid chaperone to control chromosomal structure and function. HMGB1 can also be released into the extracellular space and function as a damage-associated molecular pattern protein during cell death, including during apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, alkaliptosis, and cuproptosis. Once released, HMGB1 binds to membrane receptors to shape immune and metabolic responses. In addition to subcellular localization, the function and activity of HMGB1 also depend on its redox state and protein posttranslational modifications. Abnormal HMGB1 plays a dual role in tumorigenesis and anticancer therapy (e.g., chemotherapy, radiation therapy, and immunotherapy) depending on the tumor types and stages. Critical Issues: A comprehensive understanding of the role of HMGB1 in cellular redox homeostasis is important for deciphering normal cellular functions and pathological manifestations. In this review, we discuss compartmental-defined roles of HMGB1 in regulating cell death and cancer. Understanding these advances may help us develop potential HMGB1-targeting drugs or approaches to treat oxidative stress-related diseases or pathological conditions. Future Directions: Further studies are required to dissect the mechanism by which HMGB1 maintains redox homeostasis under different stress conditions. A multidisciplinary effort is also required to evaluate the potential applications of precisely targeting the HMGB1 pathway in human health and disease. Antioxid. Redox Signal. 39, 569-590.

The redox protein HMGB1 in cell death and cancer.

SIGNIFICANCE: As a redox-sensitive protein, high-mobility group box 1 (HMGB1) is implicated in regulating stress responses to oxidative damage and cell death, which are closely related to the pathology of inflammatory diseases, including cancer. RECENT ADVANCES: HMGB1 is a non-histone nuclear protein that acts as a DNA chaperone to control chromosomal structure and function. HMGB1 can also be released into the extracellular space and function as a damage-associated molecular pattern protein during cell death, including during apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, alkaliptosis, and cuproptosis. Once released, HMGB1 binds to membrane receptors to shape immune and metabolic responses. In addition to subcellular localization, the function and activity of HMGB1 also depends on its redox state and protein posttranslational modifications. Abnormal HMGB1 plays a dual role in tumorigenesis and anticancer therapy (e.g., chemotherapy, radiation therapy, and immunotherapy) depending on tumor types and stages. CRITICAL ISSUES: A comprehensive understanding of the role of HMGB1 in cellular redox homeostasis is important for deciphering normal cellular functions and pathological manifestations. In this review, we discuss compartmental-defined roles of HMGB1 in regulating cell death and cancer. Understanding these advances may help us develop potential HMGB1-targeting drugs or approaches to treat oxidative stress-related diseases or pathological conditions. FUTURE DIRECTIONS: Further studies are required to dissect the mechanism by which HMGB1 maintains redox homeostasis under different stress conditions. A multidisciplinary effort is also required to evaluate the potential applications of precisely targeting the HMGB1 pathway in human health and disease.

A novel prognostic nomogram for older patients with acute-on-chronic liver diseases (AoCLD): a nationwide, multicentre, prospective cohort study.

BACKGROUND: the incidence of acute-on-chronic liver disease (AoCLD) is increasing. OBJECTIVE: to investigate the clinical features and risk factors of AoCLD and construct an effective prognostic nomogram model for older patients with AoCLD. METHODS: data from 3,970 patients included in the CATCH-LIFE study were used, including 2,600 and 1,370 patients in the training and validation sets, respectively. Multivariate Cox regression analyses were performed to identify predictive risk factors in older individuals, and an easy-to-use nomogram was established. Performance was assessed using area under the curve, calibration plots and decision curve analysis (DCA). RESULTS: of the 3,949 patients with AoCLD, 809 were older with a higher proportion of autoimmune-related abnormalities, hepatitis C viral infection and schistosomiasis. In the older patient group, the incidence of cirrhosis, hepatic encephalopathy (HE), infection, ascites and gastrointestinal bleeding; neutrophil-to-lymphocyte ratio (NLR), aspartate-to-alanine transaminase ratio (AST/ALT), creatinine and blood urea nitrogen levels were higher, whereas incidence of acute-on-chronic liver failure, white blood cell, platelet and haemoglobin levels; albumin, total bilirubin (TB), AST and ALT levels; international normalised ratio (INR), estimated glomerular filtration rate and blood potassium levels were lower than in the younger group. The final nomogram was developed based on the multivariate Cox analysis in training cohort using six risk factors: ascites, HE grades, NLR, TB, INR and AST/ALT. Liver transplantation-free mortality predictions were comparable between the training and validation sets. DCA showed higher net benefit for the nomograph than the treat-all or treat-none strategies, with wider threshold probabilities ranges. CONCLUSIONS: our analysis will assist clinical predictions and prognoses in older patients with AoCLD.

A dual watermarking scheme for identity protection.

A novel dual watermarking scheme with potential applications in identity protection, media integrity maintenance and copyright protection in both electronic and printed media is presented. The proposed watermarking scheme uses the owner's signature and fingerprint as watermarks through which the ownership and validity of the media can be proven and kept intact. To begin with, the proposed watermarking scheme is implemented on continuous-tone/greyscale images, and later extended to images achieved via multitoning, an advanced version of halftoning-based printing. The proposed watermark embedding is robust and imperceptible. Experimental simulations and evaluations of the proposed method show excellent results from both objective and subjective view-points.

The role and mechanism of tryptophan - kynurenine metabolic pathway in depression.

Major depressive disorder (MDD) is a common mental illness characterized by persistent low mood and anhedonia, normally accompanied with cognitive impairment. Due to its rising incidence and high rate of recurrence and disability, MDD poses a substantial threat to patients' physical and mental health, as well as a significant economic cost to society. However, the etiology and pathogenesis of MDD are still unclear. Chronic inflammation may cause indoleamine-2,3-dioxygenase (IDO) to become overactive throughout the body and brain, resulting in excess quinolinic acid (QUIN) and less kynuric acid (KYNA) in the brain. QUIN's neurotoxicity damages glial cells and neurons, accelerates neuronal apoptosis, hinders neuroplasticity, and causes depression due to inflammation. Therefore, abnormal TRP-KYN metabolic pathway and its metabolites have been closely related to MDD, suggesting changes in the TRP-KYN metabolic pathway might contribute to MDD. In addition, targeting TRP-KYN with traditional Chinese medicine showed promising treatment effects for MDD. This review summarizes the recent studies on the TRP-KYN metabolic pathway and its metabolites in depression, which would provide a theoretical basis for exploring the etiology and pathogenesis of depression.

An M0 macrophage-related prognostic model for hepatocellular carcinoma.

BACKGROUND: The role of M0 macrophages and their related genes in the prognosis of hepatocellular carcinoma (HCC) remains poorly characterized. METHODS: Multidimensional bioinformatic methods were used to construct a risk score model using M0 macrophage-related genes (M0RGs). RESULTS: Infiltration of M0 macrophages was significantly higher in HCC tissues than in normal liver tissues (P = 2.299e-07). Further analysis revealed 35 M0RGs that were associated with HCC prognosis; two M0RGs (OLA1 and ATIC) were constructed and validated as a prognostic signature for overall survival of patients with HCC. Survival analysis revealed the positive relationship between the M0RG signature and unfavorable prognosis. Correlation analysis showed that this risk model had positive associations with clinicopathological characteristics, somatic gene mutations, immune cell infiltration, immune checkpoint inhibitor targets, and efficacy of common drugs. CONCLUSIONS: The constructed M0RG-based risk model may be promising for the clinical prediction of prognoses and therapeutic responses in patients with HCC.

[Research Progress on Enzyme-free Blood Glucose Sensor].

Blood glucose monitoring is of great significance to diabetic patients, and the development of rapid, accurate and real-time glucose detection technology has become a research hotspot nowadays. This study introduces the concept and classification of the enzyme-free glucose sensor, expounds enzymefree glucose sensor electrode characterization methods and the application progress of different materials in enzyme-free blood glucose sensors. Meanwhile, some problems of enzyme-free glucose sensor existing in the current research and its future application prospects also will be discussed.

Emerging Roles of FTO in Neuropsychiatric Disorders.

FTO (fat mass and obesity associated) is a recently discovered gene related to obesity and expressed in various tissues of the human body, especially with high expression in the brain. Earlier studies have found that FTO is involved in several biological processes, including brain development and function. In particular, recent studies have found that FTO is a demethylase of N6-methyladenosine (m6A) and it can affect neurological function through the m6A modification of mRNA. At present, a number of studies have shown that FTO is associated with many neuropsychiatric disorders. This paper reviews the discovery, structure, function, and tissue expression of FTO followed by discussing the relationship between FTO and neuropsychiatric diseases. In addition, the potential roles of FTO gene in drug addiction, major depression (MDD), and schizophrenia (SCZ) through regulating m6A modification of dopamine related genes were also highlighted.

Deep Brain Stimulation in Drug Addiction Treatment: Research Progress and Perspective.

Drug addiction is a chronic psychiatric disorder characterized by compulsive drug-seeking and drug-using behavior, and a tremendous socioeconomic burden to society. Current pharmacological and psychosocial methods have shown limited treatment effects for substance abuse. Deep Brain Stimulation (DBS) is a novel treatment for psychiatric disease and has gradually gained popularity in the treatment of addiction. Addiction is characterized by neuroplastic changes in the nucleus accumbens (NAc), a key structure in the brain reward system, and DBS in this region has shown promising treatment effects. In this paper, the research progress on DBS for drug addiction has been reviewed. Specifically, we discuss the mechanism of NAc DBS for addiction treatment and summarize the results of clinical trials on DBS treatment for addiction to psychoactive substances such as nicotine, alcohol, cocaine, opioids and methamphetamine/amphetamine. In addition, the treatment effects of DBS in other brain regions, such as the substantia nigra pars reticulata (SNr) and insula are discussed.

The Versatile Gasdermin Family: Their Function and Roles in Diseases.

The gasdermin (GSDM) family, a novel group of structure-related proteins, consists of GSDMA, GSDMB, GSDMC, GSDMD, GSDME/DNFA5, and PVJK/GSDMF. GSDMs possess a C-terminal repressor domain, cytotoxic N-terminal domain, and flexible linker domain (except for GSDMF). The GSDM-NT domain can be cleaved and released to form large oligomeric pores in the membrane that facilitate pyroptosis. The emerging roles of GSDMs include the regulation of various physiological and pathological processes, such as cell differentiation, coagulation, inflammation, and tumorigenesis. Here, we introduce the basic structure, activation, and expression patterns of GSDMs, summarize their biological and pathological functions, and explore their regulatory mechanisms in health and disease. This review provides a reference for the development of GSDM-targeted drugs to treat various inflammatory and tissue damage-related conditions.

Analysis of the Efficacy and Safety of PEGylated Interferon-α2b Treatment in Inactive Hepatitis B Surface Antigen Carriers.

INTRODUCTION: Hepatitis B virus (HBV) infection is associated with the onset of several major liver diseases. Inactive hepatitis B surface antigen (HBsAg) carriers (IHCs) may be successfully treated with PEGylated interferon-α2b (PEG-IFNα2b)-based antiviral therapy; however, studies on this treatment have been insufficient. In this study, we evaluated the efficacy and safety of PEG-IFNα2b treatment in IHCs. METHODS: Nineteen IHCs were treated with subcutaneous PEG-IFNα2b (180 µg/week) for 48 weeks (treatment group). Patients were followed up for 24 weeks after treatment discontinuation. Twenty untreated control patients were observed for 72 weeks (control group). HBsAg clearance (HBsAg < 0.05 IU/mL), HBsAg seroconversion, and alanine aminotransferase levels were monitored. RESULTS: Of the 19 patients treated with PEG-IFNα2b, 16 showed HBsAg loss (84.2%), and 13 showed HBsAg seroconversion (68.4%) at 72 weeks. All patients in the treatment group exhibited virological response (serum HBV DNA level < 10 IU/mL) at the time of drug withdrawal. In the control group, no patients experienced HBsAg loss during the observational period. There were no serious adverse events during treatment, and the therapy was well tolerated. CONCLUSIONS: Short PEG-IFNα2b therapy in IHCs produced a high functional cure rate and good safety profile, suggesting that PEG-IFNα2b treatment may be the best choice for clinical cure of some IHCs.

Liver Failure of Wilson's Disease With Manifestations Similar to Porphyria and Uncommon ATP7B Gene Mutation: A Case Report and Literature Review.

Background: Wilson's disease (WD) is a rare condition; its diagnosis is challenging owing to a wide spectrum of ATP7B genotypes and variable clinical phenotypes, along with environmental factors. Few cases of WD with presentation of skin lesions and acute neurovisceral symptoms have been reported in the literature. To our knowledge, this is the first reported case of WD with an uncommon ATP7B gene mutation and rare symptoms of photosensitivity, sensation abnormality, and skin eruption occurring in a 19-year-old woman. Case presentation: We report the case of a 19-year-old woman with WD presenting with liver failure, skin manifestations, and acute neurovisceral symptoms.The rare mutation in intron 1 of ATP7B (c.51+2T > G) was further confirmed by gene sequencing. The patients' symptoms improved after administration of penicillamine and zinc therapy combined with plasma exchange. She received long-term penicillamine treatment, and her liver function was within the normal range at 1 year after discharge. However, she underwent liver transplantation at 1.5 years after discharge. Conclusions: We present a case of WD with a novel ATP7B gene mutation that may serve as a reference to generalists and specialists in hepatology or neurology of the rare clinical characteristics of WD, to prevent misdiagnosis and aid in the early diagnosis and treatment of the condition.

Causal effects of gallstone disease on risk of gastrointestinal cancer in Chinese.

BACKGROUND: Gallstone disease (GSD) is associated with a higher risk of gastrointestinal (GI) cancer. However, it is unclear whether the associations are causal. METHODS: The prospective China Kadoorie Biobank (CKB) recorded 17,598 cases of GI cancer among 510,137 participants without cancer at baseline during 10 years of follow-up. Cox regression was used to estimate hazard ratios (HRs) for specific cancer by GSD status and duration. Mendelian randomisation was conducted to assess the genetic associations of GSD with specific cancer. RESULTS: Overall 6% of participants had symptomatic GSD at baseline. Compared with those without GSD, individuals with symptomatic GSD had adjusted HRs of 1.13 (1.01-1.29) for colorectal, 2.01 (1.78-2.26) for liver, 3.70 (2.88-4.87) for gallbladder, 2.31 (1.78-3.07) for biliary tract, and 1.38 (1.18-1.74) for pancreatic cancer. Compared with participants without GSD, the risks of colorectal, liver, gallbladder, biliary tract, and pancreatic cancer were highest during 0 to <5 years following disease diagnosis. There was evidence of genetic associations of GSD with these cancers, with odds ratios per 1-SD genetic score of 1.08 (1.05-1.11) for colorectal, 1.22 (1.19-1.25) for liver, 1.56 (1.49-1.64) for gallbladder, 1.39 (1.31-1.46) for biliary tract, and 1.16 (1.10-1.22) for pancreatic cancer. When meta-analysing the genetic estimates in CKB and UK Biobank, there was evidence of causal associations of GSD with colon cancer, gallbladder and biliary tract cancer (GBTC), and total GI cancer (RR per 1-SD: 1.05 [0.99-1.11], 2.00 [1.91-2.09], and 1.09 [1.05-1.13]). CONCLUSIONS: GSD was associated with higher risks of several GI cancers, warranting future studies on the underlying mechanisms.

Safety and Efficacy of Tenofovir Alafenamide Fumarate in Early-Middle Pregnancy for Mothers With Chronic Hepatitis B.

BACKGROUND: Tenofovir alafenamide fumarate has been used in late pregnancy; however, no data exist regarding its safety and effectiveness in early and middle pregnancy for mothers with hepatitis B virus infection. AIMS: To design a prospective study to investigate the efficacy and safety of TAF in pregnant women with chronic HBV infection during early-middle pregnancy. METHODS: Pregnant women with active chronic hepatitis B who received tenofovir alafenamide fumarate during early and middle pregnancy were enrolled and followed up until 6 months postpartum. Infants received immunoprophylaxis. The primary endpoint was the safety of mothers and infants. The secondary endpoints were maternal hepatitis B virus DNA reduction at delivery and mother-to-child transmission rate. RESULTS: Among 98 mothers enrolled, 31 initiated tenofovir alafenamide fumarate in early pregnancy, and 57 in middle pregnancy. The mean (± standard deviation) age was 29.00 (±3.81) years. At delivery, 100% (98/98) of the mothers achieved hepatitis B virus DNA levels <200,000 IU/L. Ninety-eight infants were born, and none had congenital defects or malformations. All infants received hepatitis B virus immunoprophylaxis. The mother-to-child transmission rate was 0%. Growth parameters including body weight, height, and head circumference were comparable to the national standards for physical development. No severe adverse effects were reported in either mothers or infants. No severe liver function damage occurred in any of the mothers. CONCLUSIONS: Initiating tenofovir alafenamide fumarate in early and middle pregnancy appears safe for both mothers and infants, and it is effective for controlling maternal disease as well as interrupting mother-to-child transmission.

BDNF and nicotine dependence: associations and potential mechanisms.

Smoking is the leading preventable cause of death worldwide and tobacco addiction has become a serious public health problem. Nicotine is the main addictive component of tobacco, and the majority of people that smoke regularly develop nicotine dependence. Nicotine addiction is deemed to be a chronic mental disorder. Although it is well known that nicotine binds to the nicotinic acetylcholine receptors (nAChRs) and activates the mesolimbic dopaminergic system (MDS) to generate the pleasant and rewarding effects, the molecular mechanisms of nicotine addiction are not fully understood. Brain-derived neurotrophic factor (BDNF) is the most prevalent growth factor in the brain, which regulates neuron survival, differentiation, and synaptic plasticity, mainly through binding to the high affinity receptor tyrosine kinase receptor B (TrkB). BDNF gene polymorphisms are associated with nicotine dependence and blood BDNF levels are altered in smokers. In this review, we discussed the effects of nicotine on BDNF expression in the brain and summarized the underlying signaling pathways, which further indicated BDNF as a key regulator in nicotine dependence. Further studies that aim to understand the neurobiological mechanism of BDNF in nicotine addcition would provide a valuable reference for quitting smoking and developing the treatment of other addictive substances.

Insomnia symptoms and risk of cardiovascular diseases among 0.5 million adults: A 10-year cohort.

OBJECTIVE: To examine the associations of individual insomnia symptoms with risks of incident cardio-cerebral vascular diseases (CVD) and possible moderating factors among Chinese adults. METHODS: The China Kadoorie Biobank is a prospective cohort study that recruited participants from 10 areas across China. Data from 487,200 adults 30 to 79 years of age who were free of stroke, coronary heart disease, and cancer at baseline were analyzed. Three insomnia symptoms were assessed with self-reported difficulties in initiating or maintaining sleep, early morning awakening, and daytime dysfunction for at least 3 d/wk at baseline. Incidences of CVD were followed up through disease registries and national health insurance databases until 2016. RESULTS: During a median of 9.6 years of follow-up, 130,032 cases of CVD were documented. Cox regressions showed that 3 insomnia symptoms were associated with increased risk of total CVD, with respective adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of 1.09 (95% CI 1.07-1.11), 1.07 (95% CI 1.05-1.09), and 1.13 (95% CI 1.09-1.18). Participants with individual symptoms also had higher risks of ischemic heart disease (IHD; HR 1.13, 1.09, and 1.17) and ischemic stroke but not hemorrhagic stroke. Participants with all 3 symptoms were at an 18%, 22%, or 10% higher risk of CVD, IHD, or ischemic stroke compared to nonsymptomatic adults. Associations between 3 symptoms and CVD incidence were consistently stronger in younger adults or those without baseline hypertension (p for interaction <0.05). CONCLUSIONS: Individual and coexisting insomnia symptoms are independent risk factors for CVD incidence, especially among young adults or adults who have not developed hypertension.