Acute myeloid leukemia (AML) represents the most prevalent malignancy within the hematologic system, characterized by refractory relapses and a scarcity of effective treatment options. Karyopherin subunit beta-1 (KPNB1) is a member of karyopherin β family, mediating the nuclear import of its cargoes. In this study, we found that elevated expression levels of KPNB1 are associated with unfavorable outcomes in patients with AML. The knockdown of KPNB1 resulted in growth inhibition and apoptosis in AML cells. Additionally, pharmacological inhibition of KPNB1 using the specific inhibitor importazole (IPZ) significantly reduced tumor burden and prolonged survival in MLL-AF9-induced AML mice. Notably, the inhibition of KPNB1 by IPZ significantly enhanced the sensitivity of both AML cell lines and patient-derived cells to venetoclax in vitro and in xenograft mice models. At the molecular level, we identified an unrecognized cargo of KPNB1, high mobility group 2 (HMGB2), which plays a crucial role in DNA damage repair. Inhibition of KPNB1 resulted in impaired nuclear import of HMGB2, eventually leading to compromised DNA damage repair in AML cells. Overall, our findings elucidate the essential roles of KPNB1 in AML cells through the HMGB2-DNA damage repair axis and highlight a promising therapeutic target for AML intervention.

Spinal cord injury in humans is a life-changing condition with no effective treatment. However, many non-mammalian vertebrates can fully regenerate their spinal cord after injury. Frogs such as Xenopus can regenerate the spinal cord at larval stages, but lose this capacity at metamorphosis. This makes them ideal models to elucidate molecular pathways underlying regenerative capacity by comparing responses to spinal cord injury in regenerative (R) and non-regenerative (NR) stages of the same species. Here we use quantitative proteomics with Isobaric Tags for Relative and Absolute Quantification (iTRAQ) followed by Ingenuity Pathway Analysis (IPA) to identify functions and pathways that were differentially regulated after spinal cord injury between R and NR stages in Xenopus laevis. We find that many embryonic pathways of neuronal development are re-activated following SCI at the R but not at the NR stage. This is accompanied by the upregulation of regulatory proteins controlling transcription and translation at the R stage, but their downregulation at the NR stage. Conversely, lipid hydrolysis and uptake as well as mitochondrial oxidative phosphorylation is downregulated at the R, but upregulated at the NR stage. Taken together this suggests that dysregulation of lipid homeostasis and augmentation of oxidative stress play a key role in the loss of regenerative capacity of the spinal cord after metamorphosis. In identifying new factors regulating regenerative capacity in the vertebrate spinal cord, our findings suggest new potential therapeutic targets for promoting neural repair in the injured adult mammalian spinal cord.

Brain endothelial cell (bEC) dysfunction is the main factor of blood-brain barrier (BBB) breakdown, which triggers a vicious cycle of aggravating traumatic brain injury (TBI) pathogenesis. Previous studies have revealed that neutrophil extracellular traps (NETs) released by neutrophils can lead to BBB disruption, but there is a lack of research on the underlying mechanisms after TBI. Here, excessive NETs were found in both contused brain tissue and circulation following TBI. We found that NETs could activate the TLR4/NF-κB pathway to induce bEC pyroptosis, which led to BBB disruption after TBI. During this process, ninjurin-1 (NINJ1) was activated in pyroptotic bECs, and it mediated the release of high mobility group box 1 protein (HMGB1) via plasma membrane rupture (PMR) to promote NET formation. NINJ1-mediated release of HMGB1 aggravated NET accumulation by forming a vicious circle following TBI. Knockdown of NINJ1 rescued NET formation, attenuated BBB leakage, and improved neurological outcomes after TBI. NINJ1 may represent a promising target for alleviating NET-induced BBB destruction and other related injuries after TBI.

Epilepsy continues to pose significant social and economic challenges on a global scale. Existing therapeutic approaches predominantly revolve around neurocentric mechanisms, and fail to control seizures in approximately one-third of patients. This underscores the pressing need for novel and complementary treatment approaches to address this gap. An increasing body of literature points to a role for glial cells, including microglia and astrocytes, in the pathogenesis of epilepsy. Notably, microglial cells, which serve as pivotal inflammatory mediators within the epileptic brain, have received increasing attention over recent years. These immune cells react to epileptogenic insults, regulate neuronal processes, and play diverse roles during the process of epilepsy development. Additionally, astrocytes, another integral non-neuronal brain cells, have garnered increasing recognition for their dynamic contributions to the pathophysiology of epilepsy. Their complex interactions with neurons and other glial cells involve modulating synaptic activity and neuronal excitability, thereby influencing the aberrant networks formed during epileptogenesis. This review explores the alterations in microglial and astrocytic function and their mechanisms of communication following an epileptogenic insult, examining their contribution to epilepsy development. By comprehensively studying these mechanisms, potential avenues could emerge for refining therapeutic strategies and ameliorating the impact of this complex neurological disease.

Cigarette smoking is a well-established risk factor for renal dysfunction. Smoking associated with renal damage bears distinct physiological correlations in conditions such as diabetic nephropathy and obesity-induced glomerulopathy. However, the cellular and molecular basis of such an association remains poorly understood. High mobility group box 1(HMGB1) is a highly conserved non-histone chromatin associated protein that largely contributes to the pathogenesis of chronic inflammatory and autoimmune diseases such as sepsis, atherosclerosis, and chronic kidney diseases. Hence, the present study tested whether HMGB1 contributes to nicotine-induced podocyte injury.

Biochemical analysis showed that nicotine treatment significantly increased the HMGB1 expression and release compared to vehicle treated podocytes. However, prior treatment with glycyrrhizin (Gly), a HMGB1 binder, abolished the nicotine-induced HMGB1 expression and release in podocytes. Furthermore, immunofluorescent analysis showed that nicotine treatment significantly decreased the expression of podocyte functional proteins- podocin and nephrin as compared to control cells. However, prior treatment with Gly attenuated the nicotine-induced nephrin and podocin reduction. In addition, nicotine treatment significantly increased desmin expression and cell permeability compared to vehicle treated podocytes. However, prior treatment with Gly attenuated the nicotine-induced desmin expression and cell permeability. Mechanistic elucidation revealed that nicotine treatment augmented the expression of toll like receptor 4 (TLR4) and pre-treatment with Gly abolished nicotine induced TLR4 upregulation. Pharmacological inhibition of TLR4 with Resatorvid, a TLR4 specific inhibitor, also attenuated nicotine induced podocyte damage.

HMGB1 is one of the important mediators of nicotine-induced podocyte injury through TLR4 activation.

White spot syndrome virus (WSSV) causes highly destructive infection in crustacean aquaculture, often resulting in 100% mortality within a week. However, there is lack of studies addressing the safety issues of WSSV vaccines in shrimps. In this study, WSSV VP28 mRNA vaccines were developed using codon deoptimization approach. These vaccines were administered to Litopenaeus vannamei shrimps at various dosages to access their safety and the shrimps' immune responses using quantification PCR (qPCR). The findings of this study indicate that the expression level of codon deoptimized VP28 mRNA vaccines are lower compared to the wild type VP28 vaccines, as observed through a comparison of bioinformatic predictions and experimental results. Additionally, the total haemocyte count (THC) in shrimps injected with codon deoptimized VP28 vaccine was higher than those injected with wild type VP28 vaccines. Furthermore, the expression of immune-related genes differed between codon deoptimized and wild type VP28 vaccines. In summary, the results suggest that 0.01 μg codon deoptimized VP28-D1 mRNA vaccine is the most promising WSSV mRNA vaccine, displaying low pathogenicity and expression in shrimps. To the best of our knowledge, this research represents the first attempt to attenuate WSSV using codon deoptimization method and development of a potential mRNA vaccine for shrimp purpose. The study addresses an important gap in shrimp vaccine research, offering potential solutions for WSSV control in shrimps.

Intrinsically disordered proteins (IDPs) that include one or more intrinsically disordered regions (IDRs) are abundant across all domains of life and viruses and play numerous functional roles in various cellular processes. Due to a relatively low throughput and high cost of experimental techniques for identifying IDRs, there is a growing need for fast and accurate computational algorithms that accurately predict IDRs/IDPs from protein sequences. We describe one of the leading disorder predictors, flDPnn. Results from a recent community-organized Critical Assessment of Intrinsic Disorder (CAID) experiment show that flDPnn provides fast and state-of-the-art predictions of disorder, which are supplemented with the predictions of several major disorder functions. This chapter provides a practical guide to flDPnn, which includes a brief explanation of its predictive model, descriptions of its web server and standalone versions, and a case study that showcases how to read and understand flDPnn's predictions.

Broadening of signals from atoms at interfaces can often be a limiting factor in applying solution NMR to the structure determination of complexes. Common contributors to such problems include exchange between free and bound states and the increased molecular weight of complexes relative to the free components, but another cause that can be more difficult to deal with occurs when conformational dynamics within the interface takes place at an intermediate rate on the chemical shift timescale. In this work we show how a carefully chosen mutation in the protein HMG-D rescued such a situation, making possible high-resolution structure determination of its complex with a dA2 bulge DNA ligand designed to mimic a natural DNA bend, and thereby revealing a new spatial organization of the complex.

Aging is a universal biological process characterized by a progressive, cumulative decline in homeostatic capabilities and physiological functions, which inevitably increases vulnerability to diseases. A number of molecular pathomechanisms and hallmarks of aging have been recognized, yet we miss a thorough understanding of their complex interconnectedness. This review explores the molecular and cellular mechanisms underlying human aging, with a focus on the multiple roles of high mobility group Box 1 protein (HMGB1), the archetypal damage-associated molecular pattern (DAMP) molecule. In the nucleus, this non-histone chromatin-associated protein functions as a DNA chaperone and regulator of gene transcription, influencing DNA structure and gene expression. Moreover, this versatile protein can translocate to the cytoplasm to orchestrate other processes, such as autophagy, or be unconventionally secreted into the extracellular environment, where it acts as a DAMP, combining inflammatory and regenerative properties. Notably, lower expression of HMGB1 within the cell and its heightened extracellular release have been associated with diverse age-associated traits, making it a suitable candidate as a universal biomarker of aging. In this review, we outline the evidence implicating HMGB1 in aging, also in light of an evolutionary perspective on its functional pleiotropy, and propose critical issues that need to be addressed to gauge the value of HMGB1 as a potential biomarker across age-related diseases and therapeutic target to promote healthy longevity.

High Mobility Group Box 1 (HMGB1) is a highly conserved non-histone chromatin-associated protein across species, primarily recognized for its regulatory impact on vital cellular processes, like autophagy, cell survival, and apoptosis. HMGB1 exhibits dual functionality based on its localization: both as a non-histone protein in the nucleus and as an inducer of inflammatory cytokines upon extracellular release. Pathophysiological insights reveal that HMGB1 plays a significant role in the onset and progression of a vast array of diseases, viz., atherosclerosis, kidney damage, cancer, and neurodegeneration. However, a clear mechanistic understanding of HMGB1 release, translocation, and associated signaling cascades in mediating such physiological dysfunctions remains obscure. This review presents a detailed outline of HMGB1 structure-function relationship and its regulatory role in disease onset and progression from a signaling perspective. This review also presents an insight into the status of HMGB1 druggability, potential limitations in understanding HMGB1 pathophysiology, and future perspective of studies that can be undertaken to address the existing scientific gap. Based on existing paradigm of various studies, HMGB1 is a critical regulator of inflammatory cascades and drives the onset and progression of a broad spectrum of dysfunctions. Studies focusing on HMGB1 druggability have enabled the development of biologics with potential clinical benefits. However, deeper understanding of post-translational modifications, redox states, translocation mechanisms, and mitochondrial interactions can potentially enable the development of better courses of therapy against HMGB1-mediated physiological dysfunctions.

Stress, a risk factor for major depressive disorder and Alzheimer disease, leads to the release of high-mobility group box-1 (HMGB1) protein, which in turn causes neuroinflammation. The mechanism underlying stress-induced HMGB1 release is unknown, but stress-associated glucocorticoids could be involved. Primary cultured rat cortical microglia and neurons were treated with corticosterone, a stress-associated glucocorticoid, and HMGB1 release was measured by ELISA and western blotting to test this hypothesis. With corticosterone treatment, significant HMGB1 was released in microglia but not in neuronal cell cultures. HMGB1 mRNA expression and HMGB1 protein expression in microglia were not affected by corticosterone treatment. Thus, the source of extracellular HMGB1 released into the medium is likely to be existing nuclear HMGB1 rather than newly synthesized HMGB1. Corticosterone-induced HMGB1 release in microglia culture was significantly attenuated by blocking glucocorticoid receptors but not mineralocorticoid receptors. Dexamethasone, a selective glucocorticoid receptor agonist, and dexamethasone-bovine serum albumin (BSA), a membrane-impermeable glucocorticoid receptor agonist used to confirm the membrane receptor-mediated effects of glucocorticoids, increased the release of HMGB1. Immunocytochemistry showed that HMGB1 translocated from the nucleus to the cytoplasm following dexamethasone or dexamethasone-BSA treatment through glucocorticoid receptors. The present findings suggest that glucocorticoids stimulate microglial membrane glucocorticoid receptors and trigger cytoplasmic translocation and extracellular release of nuclear HMGB1. Thus, under stress conditions, glucocorticoids induce microglial HMGB1 release, leading to a neuroinflammatory state that could mediate neurological disorders.

Cardiovascular disease is the deadly disease that can result in sudden death, and inflammation plays an important role in its onset and progression. High mobility group box 1 (HMGB1) is a nuclear protein that regulates transcription, DNA replication, repair, and nucleosome assembly. HMGB1 is released passively by necrotic tissues and actively secreted by stressed cells. Extracellular HMGB1 functions as a damage associated molecular patterns molecule, producing numerous redox forms that induce a range of cellular responses by binding to distinct receptors and interactors, including tissue inflammation and regeneration. Extracellular HMGB1 inhibition reduces inflammation and is protective in experimental models of myocardial ischemia/reperfusion damage, myocarditis, cardiomyopathies caused by mechanical stress, diabetes, bacterial infection, or chemotherapeutic drugs. HMGB1 administration following a myocardial infarction followed by permanent coronary artery ligation improves cardiac function by stimulating tissue regeneration. HMGB1 inhibits contractility and produces hypertrophy and death in cardiomyocytes, while also stimulating cardiac fibroblast activity and promoting cardiac stem cell proliferation and differentiation. Maintaining normal nuclear HMGB1 levels, interestingly, protects cardiomyocytes from apoptosis by limiting DNA oxidative stress, and mice with HMGB1cardiomyocyte-specific overexpression are partially protected from cardiac injury. Finally, elevated levels of circulating HMGB1 have been linked to human heart disease. As a result, following cardiac damage, HMGB1 elicits both detrimental and helpful responses, which may be due to the formation and stability of the various redox forms, the particular activities of which in this context are mostly unknown. This review covers recent findings in HMGB1 biology and cardiac dysfunction.

Damage-associated molecular patterns (DAMPs) are endogenous molecules released in tissues upon cellular damage and necrosis, acting to initiate sterile inflammation. Constitutive DAMPs (cDAMPs) have the particularity to be present within the intracellular compartments of healthy cells, where they exert diverse functions such as regulation of gene expression and cellular homeostasis. However, after injury to the central nervous system (CNS), cDAMPs are rapidly released by stressed, damaged or dying neuronal, glial and endothelial cells, and can trigger inflammation without undergoing structural modifications. Several cDAMPs have been described in the injured CNS, such as interleukin (IL)-1α, IL-33, nucleotides (e.g. ATP), and high-mobility group box protein 1. Once in the extracellular milieu, these molecules are recognized by the remaining surviving cells through specific DAMP-sensing receptors, thereby inducing a cascade of molecular events leading to the production and release of proinflammatory cytokines and chemokines, as well as cell adhesion molecules. The ensuing immune response is necessary to eliminate cellular debris caused by the injury, allowing for damage containment. However, seeing as some molecules associated with the inflammatory response are toxic to surviving resident CNS cells, secondary damage occurs, aggravating injury and exacerbating neurological and behavioral deficits. Thus, a better understanding of these cDAMPs, as well as their receptors and downstream signaling pathways, could lead to identification of novel therapeutic targets for treating CNS injuries such as SCI, TBI, and stroke. In this review, we summarize the recent literature on cDAMPs, their specific functions, and the therapeutic potential of interfering with cDAMPs or their signaling pathways.

Sirtuins and autophagy are well-characterized agents that can promote longevity and protect individual organisms from age-associated diseases like neurodegenerative disorders. In recent years, more and more data has been obtained that discerned potential overlaps and crosstalk between Sirtuin proteins and autophagic activity. This review aims to summarize the advances within the field for each individual Sirtuin in mammalian systems. In brief, most Sirtuins have been implicated in promoting autophagy, with Sirtuin 1 and Sirtuin 6 showing the highest immediate involvement, while Sirtuin 4 and Sirtuin 5 only demonstrate occasional influence. The way Sirtuins regulate autophagy, however, is very diverse, as they have been shown to regulate gene expression of autophagy-associated genes and posttranslational modifications of proteins, with consequences for the activity and cellular localization of these proteins. They have also been shown to determine specific proteins for autophagic degradation. Overall, much data has been accumulated over recent years, yet many open questions remain. Especially although the dynamic between Sirtuin proteins and the immediate regulation of autophagic players like Light Chain 3B has been confirmed, many of these proteins have various orthologues in mammalian systems, and research so far has not exceeded the bona fide components of autophagy.

High-mobility group box 1 (HMGB1) is a highly conserved nuclear protein involved in key nuclear processes such as DNA repair, replication, and gene regulation. Beyond its established nuclear roles, HMGB1 has crucial functions in the cytoplasm and extracellular environment. When translocated to the cytoplasm, HMGB1 plays a role in autophagy, cell survival, and immune response modulation. In its extracellular form, HMGB1 acts as a damage-associated molecular pattern molecule, initiating inflammatory responses by interacting with receptors such as Receptor for advanced glycation endproducts and Toll-like receptors. Recent studies have shown its role in promoting tissue regeneration, wound healing, and angiogenesis, highlighting its dual role in both inflammation and tissue repair. Notably, the redox status of HMGB1 influences its function, with the reduced form promoting autophagy and the disulfide form driving inflammation. Dysregulation of HMGB1 contributes to the progression of various diseases, including cancer, where it influences tumor growth, metastasis, and resistance to therapy. This review provides an overview of the nuclear, cytoplasmic, and extracellular roles of HMGB1, discussing its involvement in nuclear homeostasis, rare genetic diseases, autophagy, inflammation, cancer progression, and tissue regeneration.

Aging is a universal physiological phenomenon, and chronic age-related diseases have become one of the leading causes of human mortality, accounting for nearly half of all deaths. Studies have shown that reducing the incidence of these diseases can not only extend lifespan but also promote healthy aging. In recent years, the potential role of non-histone high-mobility group proteins (HMGs) in the regulation of aging and lifespan has attracted widespread attention. HMGs play critical roles in cellular senescence and associated diseases through various pathways, encompassing multi-layered mechanisms involving protein interactions, molecular regulation, and chromatin dynamics. This review provides a comprehensive analysis of the interactions between HMG family proteins and senescence-associated secretory phenotype (SASP), chromatin structure, and histone modifications, offering a deeper exploration of the pivotal functions and impacts of HMGs in the aging process. Furthermore, we summarize recent findings on the contributions of HMG proteins to aging and age-related diseases. HMG proteins not only regulate senescence-associated inflammation through modulating the SASP but also influence genomic stability and cell fate decisions via interactions with chromatin and histones. Targeting HMG proteins holds great potential in delaying the progression of aging and its associated diseases. This review aims to provide a systematic overview of HMG proteins' roles in aging and to lay a solid foundation for future anti-aging drug development and therapeutic strategies. With the advancing understanding of the mechanisms by which HMGs regulate aging, developing therapeutic interventions targeting HMGs may emerge as a promising approach to extending lifespan and enhancing healthspan.

Introduction: Radiation-induced lung fibrosis (RILF) is a common complication of thoracic radiotherapy. Metformin has been suggested to have a radioprotective effect. Objective: This study explored the radioprotective effects of metformin on RILF and its mechanisms. Methods: C57BL/6J mice were randomly divided into control, ionizing radiation (IR), low-dose metformin (L-Met), and high-dose metformin (H-Met) groups. The IR, L-Met, and H-Met groups received 15 Gy chest irradiation. The L-Met and H-Met groups were administrated 100 or 200 mg/kg metformin from 3 days before irradiation and continued for 6 months. The mice were then sacrificed, and samples were collected for further analysis. Results: RILF was induced in the irradiated mice. Metformin improved lung pathology, inhibited collagen deposition, and reduced inflammatory factors such as high mobility group box 1 (HMGB1), interleukin-1 beta, interleukin-6, tumor necrosis factor alpha in lung tissue, lavage fluid, and serum. Western blot and quantitative real-time PCR analyses revealed that metformin downregulated HMGB1, toll-like receptor 4 (TLR4), and nuclear factor kappaB (NF-κB) expression. Additionally, metformin reversed the irradiation-induced reduction in the abundance of Lactobacillus and Lachnospiraceae at the genus level. Conclusion: Our findings indicated that metformin ameliorates RILF by downregulating the inflammatory-related HMGB1/TLR4/NF-κB pathway and improving intestinal flora disorder.

High mobility group protein B2 (HMGB2) is an abundant chromatin-associated protein with pivotal roles in transcription, cell proliferation, differentiation, inflammation, and tumorigenesis. However, its immune function in Nile tilapia (Oreochromis niloticus) remains unclear. In this study, we identified a homologue of HMGB2 from Nile tilapia (On-HMGB2) and investigated its functions in the immune response against streptococcus infection. The open reading frame (ORF) of On-HMGB2 spans 642 bp, encoding 213 amino acids, and contains two conserved HMG domains. On-HMGB2 shares over 80 % homology with other fish species and 74%-76 % homology with mammals. On-HMGB2 was widely distributed in various tissues, with its highest transcript levels in the liver and the lowest in the intestine. Knockdown of On-HMGB2 promoted the inflammatory response in Nile tilapia, increased the bacterial load in the tissues, and led to elevated mortality in Nile tilapia following Streptococcus agalactiae infection. Taken together, On-HMGB2 significantly influences the immune system of Nile tilapia in response to streptococcus infection.

The escalating incidence of breast cancer (BC) in women underscores its grave health threat. Current molecular insights into BC's post-adjuvant therapy cure remain elusive, necessitating active treatment explorations. Immunotherapy, notably chemotherapy-induced immunogenic cell death (ICD), has emerged as a promising BC therapy. ICD harnesses chemotherapeutics to activate anti-tumor immunity via DAMPs, fostering long-term T-cell memory and primary BC cure. Besides chemotherapy drugs, Nanodrugs, traditional Chinese medicine (TCM) and ICIs also induce ICD, boosting immune response. ICIs, like PD-1/PD-L1 inhibitors, revolutionize cancer treatment but face limited success in cold tumors. Thus, ICD induction combined with ICIs is studied extensively for BC immunotherapy. This article reviews the mechanism of ICD related drugs in BC and provides reference for the research and development of BC treatment, in order to explore more effective clinical treatment of BC, we hope to explore more ICD inducers and make ICIs more effective vaccines.

Saccharomyces cerevisiae HMO1 is an architectural nuclear DNA-binding protein that stimulates the activity of some remodelers and regulates the transcription of ribosomal protein genes, often binding to a DNA motif called IFHL. However, the molecular mechanism dictating this sequence specificity is unclear. Our circular dichroism spectroscopy studies show that the HMO1:DNA complex forms without noticeable changes in the structure of DNA and HMO1. Molecular modeling/molecular dynamics studies of the DNA complex with HMO1 Box B reveal two extended sites at the N-termini of helices I and II of Box B that are involved in the formation of the complex and stabilize the DNA bend induced by intercalation of the F114 side chain between base pairs. A comparison of the affinities of HMO1 for 24 bp DNA fragments containing either randomized or IFHL sequences reveals a twofold increase in the stability of the complex in the latter case, which may explain the selectivity in the recognition of the IFHL-containing promoter regions.

Bacterial biofilm communities are embedded in a protective extracellular matrix comprised of various components, with its' integrity largely owed to a 3-dimensional lattice of extracellular DNA (eDNA) interconnected by Holliday Junction (HJ)-like structures and stabilised by the ubiquitous eubacterial DNABII family of DNA-binding architectural proteins. We recently showed that the host innate immune effector High Mobility Group Box 1 (HMGB1) protein possesses extracellular anti-biofilm activity by destabilising these HJ-like structures, resulting in release of biofilm-resident bacteria into a vulnerable state. Herein, we showed that HMGB1's anti-biofilm activity was completely contained within a contiguous 97 amino acid region that retained DNA-binding activity, called 'mB Box-97'.

We engineered a synthetic version of this 97-mer and introduced a single amino acid change which lacked any post-translational modifications, and tested its activity independently and in combination with a humanised monoclonal antibody that disrupts biofilms by the distinct mechanism of DNABII protein sequestration.

mB Box-97 disrupted and prevented biofilms, including those formed by the ESKAPEE pathogens, and importantly reduced measurable proinflammatory activity normally associated with HMGB1 in a murine lung infection model.

Herein, we discuss the value of targeting the ubiquitous eDNA-dependent matrix of biofilms via mB Box-97 used singly or in a dual host-augmenting/pathogen-targeted cocktail to resolve bacterial biofilm infections.

This work was supported by NIH/NIDCD R01DC011818 to L.O.B. and S.D.G. and NIH/NIAID R01AI155501 to S.D.G.

Genome-wide studies have demonstrated regulatory roles for diverse non-coding elements, but their precise and interrelated functions have often remained enigmatic. Addressing the need for mechanistic insight, we studied their roles in expression of Lhb which encodes the pituitary gonadotropic hormone that controls reproduction. We identified a bi-directional enhancer in gonadotrope-specific open chromatin, whose functional eRNA (eRNA2) supports permissive chromatin at the Lhb locus. The central untranscribed region of the enhancer contains an iMotif (iM), and is bound by Hmgb2 which stabilizes the iM and directs transcription specifically towards the functional eRNA2. A distinct downstream lncRNA, associated with an inducible G-quadruplex (G4) and iM, also facilitates Lhb expression, following its splicing in situ. GnRH activates Lhb transcription and increased levels of all three RNAs, eRNA2 showing the highest response, while estradiol, which inhibits Lhb, repressed levels of eRNA2 and the lncRNA. The levels of these regulatory RNAs and Lhb mRNA correlate highly in female mice, though strikingly not in males, suggesting a female-specific function. Our findings, which shed new light on the workings of non-coding elements and non-canonical DNA structures, reveal novel mechanisms regulating transcription which have implications not only in the central control of reproduction but also for other inducible genes.

HMGXB4 (additionally known as HMG2L1) is a non-histone DNA-binding protein that contains a single HMG-box domain. HMGXB4 was originally described in Xenopus where it was seen to negatively regulate the Wnt/β-catenin signaling pathway.

In this study, we conducted a genetic and clinical evaluation of a single family with three affected individuals suffering from intellectual disability (ID), global developmental delay (GDD) and dysmorphic facial features.Whole genome sequencing (WGS) and Sanger sequencing were performed on the affected individuals' DNA to identify genetic variations. Additionally, a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess gene expression in both the affected and unaffected individuals in the family.

WGS identified a homozygous frameshift variant c.1193_1196del p. (Lys398Argfs × 25) in exon 5 of the HMGXB4 gene (OMIM 604702), which completely segregated the disease phenotype in the family. Furthermore, RT-qPCR revealed a substantial decrease in the HMGXB4 gene expression in the affected individuals as compared to the unaffected individuals of the family.

The current study is the first evidence linking a genetic variant in the HMGXB4 gene to ID, GDD, and dysmorphic facial features. Therefore, it is possible that HMGXB4 contributes significantly to developmental milestones and may be responsible for neurodevelopmental disorders in humans.

Eukaryotic chromatin consisting of nucleosomes connected by linker DNA is organized into higher order structures, which is facilitated by linker histone H1. Formation of chromatin compacts and protects the genome, but also hinders DNA transactions. Cells have evolved mechanisms to modify/remodel chromatin resulting in chromatin states suitable for genome functions. The high mobility group box (HMGB) proteins are non-histone chromatin architectural factors characterized by one or more HMGB motifs that bind DNA in a sequence nonspecific fashion. They play a major role in chromatin dynamics. The Saccharomyces cerevisiae (yeast hereafter) HMGB protein Hmo1 contains two HMGB motifs. However, unlike a canonical HMGB protein that has an acidic C-terminus, Hmo1 ends with a lysine rich, basic, C-terminus, resembling linker histone H1. Hmo1 exhibits characteristics of both HMGB proteins and linker histones in its multiple functions. For instance, Hmo1 promotes transcription by RNA polymerases I and II like canonical HMGB proteins but makes chromatin more compact/stable like linker histones. Recent studies have demonstrated that Hmo1 destabilizes/disrupts nucleosome similarly as other HMGB proteins in vitro and acts to maintain a common topological architecture of genes in yeast genome. This minireview reviews the functions of Hmo1 and the underlying mechanisms, highlighting recent discoveries.

Necrosis is an overarching term that describes cell death modalities caused by (extreme) adverse conditions in which cells lose structural integrity. A guaranteed consequence of necrosis is the production of necrotic cell remnants, or debris. Necrotic cell debris is a strong trigger of inflammation, and although inflammatory responses are required for tissue healing, necrotic debris may lead to uncontrolled immune responses and collateral damage. Besides local phagocytosis by recruited leukocytes, there is accumulating evidence that extracellular mechanisms are also involved in necrotic debris clearance. In this review, we focused on systemic clearance mechanisms present in the bloodstream and vasculature that often cooperate to drive the clearance of cell debris. We reviewed the contribution and cooperation of extracellular DNases, the actin-scavenger system, the fibrinolytic system and reticuloendothelial cells in performing clearance of necrotic debris. Moreover, associations of the (mis)functioning of these clearance systems with a variety of diseases were provided, illustrating the importance of the mechanisms of clearance of dead cells in the organism.

The high-mobility group box (HMGB) family consists of four DNA-binding proteins that regulate chromatin structure and function. In addition to their intracellular functions, recent studies have revealed their involvement as extracellular damage-associated molecular patterns (DAMPs), contributing to immune responses and tumor development. The HMGB family promotes tumorigenesis by modulating multiple processes including proliferation, metabolic reprogramming, metastasis, immune evasion, and drug resistance. Due to the predominant focus on HMGB1 in the literature, little is known about the remaining members of this family. This review summarizes the structural, distributional, as well as functional similarities and distinctions among members of the HMGB family, followed by a comprehensive exploration of their roles in tumor development. We emphasize the distributional and functional hierarchy of the HMGB family at both the organizational and subcellular levels, with a focus on their relationship with the tumor immune microenvironment (TIME), aiming to prospect potential strategies for anticancer therapy.

The initiation of migraine headaches and the involvement of neuroinflammatory signaling between parenchymal and meningeal cells remain unclear. Experimental evidence suggests that a cascade of inflammatory signaling originating from neurons may extend to the meninges, thereby inducing neurogenic inflammation and headache. This review explores the role of parenchymal inflammatory signaling in migraine headaches, drawing upon recent advancements. BODY: Studies in rodents have demonstrated that sterile meningeal inflammation can stimulate and sensitize meningeal nociceptors, culminating in headaches. The efficacy of relatively blood-brain barrier-impermeable anti-calcitonin gene-related peptide antibodies and triptans in treating migraine attacks, both with and without aura, supports the concept of migraine pain originating in meninges. Additionally, PET studies utilizing inflammation markers have revealed meningeal inflammatory activity in patients experiencing migraine with aura, particularly over the occipital cortex generating visual auras. The parenchymal neuroinflammatory signaling involving neurons, astrocytes, and microglia, which eventually extends to the meninges, can link non-homeostatic perturbations in the insensate brain to pain-sensitive meninges. Recent experimental research has brought deeper insight into parenchymal signaling mechanisms: Neuronal pannexin-1 channels act as stress sensors, initiating the inflammatory signaling by inflammasome formation and high-mobility group box-1 release in response to transient perturbations such as cortical spreading depolarization (CSD) or synaptic metabolic insufficiency caused by transcriptional changes induced by migraine triggers like sleep deprivation and stress. After a single CSD, astrocytes respond by upregulating the transcription of proinflammatory enzymes and mediators, while microglia are involved in restoring neuronal structural integrity; however, repeated CSDs may prompt microglia to adopt a pro-inflammatory state. Transcriptional changes from pro- to anti-inflammatory within 24 h may serve to dampen the inflammatory signaling. The extensive coverage of brain surface and perivascular areas by astrocyte endfeet suggests their role as an interface for transporting inflammatory mediators to the cerebrospinal fluid to contribute to meningeal nociception.

We propose that neuronal stress induced by CSD or synaptic activity-energy mismatch may initiate a parenchymal inflammatory signaling cascade, transmitted to the meninges, thereby triggering lasting headaches characteristic of migraine, with or without aura. This neuroinflammatory interplay between parenchymal and meningeal cells points to the potential for novel targets for migraine treatment and prophylaxis.

The HMGB1 protein typically serves as a DNA chaperone that assists DNA-repair enzymes and transcription factors but can translocate from the nucleus to the cytoplasm or even to extracellular space upon some cellular stimuli. One of the factors that triggers the translocation of HMGB1 is its phosphorylation near a nuclear localization sequence by protein kinase C (PKC), although the exact modification sites on HMGB1 remain ambiguous. In this study, using spectroscopic methods, we investigated the HMGB1 phosphorylation and its impact on the molecular properties of the HMGB1 protein. Our nuclear magnetic resonance (NMR) data on the full-length HMGB1 protein showed that PKC specifically phosphorylates the A-box domain, one of the DNA binding domains of HMGB1. Phosphorylation of S46 and S53 was particularly efficient. Over a longer reaction time, PKC phosphorylated some additional residues within the HMGB1 A-box domain. Our fluorescence-based binding assays showed that the phosphorylation significantly reduces the binding affinity of HMGB1 for DNA. Based on the crystal structures of HMGB1-DNA complexes, this effect can be ascribed to electrostatic repulsion between the negatively charged phosphate groups at the S46 side chain and DNA backbone. Our data also showed that the phosphorylation destabilizes the folding of the A-box domain. Thus, phosphorylation by PKC weakens the DNA-binding affinity and folding stability of HMGB1.

HMGB3 protein belongs to the group of HMGB proteins from the superfamily of nuclear proteins with high electrophoretic mobility. HMGB proteins play an active part in almost all cellular processes associated with DNA-repair, replication, recombination, and transcription-and, additionally, can act as cytokines during infectious processes, inflammatory responses, and injuries. Although the structure and functions of HMGB1 and HMGB2 proteins have been intensively studied for decades, very little attention has been paid to HMGB3 until recently. In this review, we summarize the currently available data on the molecular structure, post-translational modifications, and biological functions of HMGB3, as well as the possible role of the ubiquitin-proteasome system-dependent HMGB3 degradation in tumor development.

Proteomic analysis of injured human peripheral nerves, particularly focusing on events occurring in the proximal and distal nerve ends, remains relatively underexplored. This study aimed to investigate the molecular patterns underlying a digital nerve injury, focusing on differences in protein expression between the proximal and distal nerve ends.

A total of 26 human injured digital nerve samples (24 men; 2 women; median age 47 [30-66] years), harvested during primary nerve repair within 48 h post-injury from proximal and distal nerve ends, were analyzed using mass spectrometry.

A total of 3,914 proteins were identified, with 127 proteins showing significant differences in abundance between the proximal and the distal nerve ends. The downregulation of proteins in the distal nerve end was associated with synaptic transmission, autophagy, neurotransmitter regulation, cell adhesion and migration. Conversely, proteins upregulated in the distal nerve end were implicated in cellular stress response, neuromuscular junction stability and muscle contraction, neuronal excitability and neurotransmitter release, synaptic vesicle recycling and axon guidance and angiogenesis.

Investigation of proteins, with functional annotations analysis, in proximal and the distal ends of human injured digital nerves, revealed dynamic cellular responses aimed at promoting tissue degeneration and restoration, while suppressing non-essential processes.

Chromatin condensation state is the key for retrieving genetic information. High-mobility group protein (HMG) proteins exhibit DNA-binding and bending activities, playing an important role in the regulation of chromatin structure. We have shown that nucleosomes tightly packaged into heterochromatin undergo considerable dynamic histone H2A-H2B maintenance via the direct interaction between HP1/Swi6 and facilitate chromatin transcription (FACT), which is composed of the Spt16/Pob3 heterodimer and Nhp6. In this study, we analyzed the role of Nhp6, an HMG box protein, in the FACT at heterochromatin. Pob3 mutant strains showed derepressed heterochromatin-dependent gene silencing, whereas Nhp6 mutant strains did not show significant defects in chromatin regulation or gene expression, suggesting that these two modules play different roles in chromatin regulation. We expressed a protein fusing Nhp6 to the C-terminus of Pob3, which mimics the multicellular FACT component Ssrp1. The chromatin-binding activity of FACT increased with the number of Nhp6 fused to Pob3, and the heterochromatin formation rate was promoted more strongly. Furthermore, we demonstrated that this promotion of heterochromatinization inhibited the heterochromatic variegation caused by epe1+ disruption. Heterochromatic variegation can be observed in a variety of regulatory steps; however, when it is caused by fluctuations in chromatin arrangement, it can be eliminated through the strong recruitment of the FACT complex.

Childhood epilepsy affects up to 1 % of children. It has been shown that 30 % of patients are resistant to drug treatments, making further investigation of other potential treatment strategies necessary. One such approach is the ketogenic diet (KD) showing promising results and potential benefits beyond the use of current antiepileptic drugs. This study aims to investigate the effects of KD on inflammation and oxidative stress, as one of the main suggested mechanisms of neuroprotection, in children with epilepsy. This narrative review was conducted using the Medline and Google Scholar databases, and by searching epilepsy, drug-resistant epilepsy, child, children, ketogenic, ketogenic diet, diet, ketogenic, keto, ketone bodies (BHB), PUFA, gut microbiota, inflammation, inflammation mediators, neurogenic inflammation, neuroinflammation, inflammatory marker, adenosine modulation, mitochondrial function, MTOR pathway, Nrf2 pathway, mitochondrial dysfunction, PPARɣ, oxidative stress, ROS/RNS, and stress oxidative as keywords. Compelling evidence underscores inflammation and oxidative stress as pivotal factors in epilepsy, even in cases with genetic origins. The ketogenic diet effectively addresses these factors by reducing ROS and RNS, enhancing antioxidant defenses, improving mitochondrial function, and regulating inflammatory genes. Additionally, KD curbs pro-inflammatory cytokine and chemokine production by dampening NF-κB activation, inhibiting the NLRP3 inflammasome, increasing brain adenosine levels, mTOR pathway inhibition, upregulating PPARɣ expression, and promoting a healthy gut microbiota while emphasizing the consumption of healthy fats. KD could be considered a promising therapeutic intervention in patients with epilepsy particularly in drug-resistant epilepsy cases, due to its targeted approach addressing oxidative stress and inflammatory mechanisms.

The prevention and early diagnosis of liver cancer remains a global medical challenge. During the malignant transformation of hepatocytes, a variety of oncogenic cellular signalling molecules, such as novel high mobility group-Box 3, angiopoietin-2, Golgi protein 73, glypican-3, Wnt3a (a signalling molecule in the Wnt/β-catenin pathway), and secretory clusterin, can be expressed and secreted into the blood. These signalling molecules are derived from different signalling pathways and may not only participate in the malignant transformation of hepatocytes but also become early diagnostic indicators of hepatocarcinogenesis or specific targeted molecules for hepatocellular carcinoma therapy. This article reviews recent progress in the study of several signalling molecules as sensitive biomarkers for monitoring hepatocarcinogenesis.

Late diagnosis of cancer in advanced stages due to the lack of screening methods is considered as the main cause of poor prognosis and high mortality rate among these patients. Therefore, it is necessary to investigate the molecular tumor biology in order to introduce biomarkers that can be used in cancer screening programs and early diagnosis. MicroRNAs (miRNAs) have key roles in regulation of the cellular pathophysiological processes. Due to the high stability of miRNAs in body fluids, they are widely used as the non-invasive tumor markers. According to the numerous reports about miR-505 deregulation in a wide range of cancers, we investigated the role of miR-505 during tumor progression. It was shown that miR-505 mainly has the tumor suppressor functions through the regulation of signaling pathways, chromatin remodeling, and cellular metabolism. This review has an effective role in introducing miR-505 as a suitable marker for the early cancer diagnosis.

Deregulation of cell death is a common characteristic of cancer, and resistance to this process often occurs in lung cancer. Understanding the molecular mechanisms underlying an aberrant cell death is important. Recent studies have emphasized the involvement of calmodulin-regulated spectrin-associated protein 3 (CAMSAP3) in lung cancer aggressiveness, its influence on cell death regulation remains largely unexplored.

CAMSAP3 was knockout in lung cancer cells using CRISPR-Cas9 system. Cell death and autophagy were evaluated using MTT and autophagic detection assays. Protein interactions were performed by proteomic analysis and immunoprecipitation. Protein expressions and their cytoplasmic localization were analyzed through immunoblotting and immunofluorescence techniques.

This study reveals a significant correlation between low CAMSAP3 expression and poor overall survival rates in lung cancer patients. Proteomic analysis identified high mobility group box 1 (HMGB1) as a candidate interacting protein involved in the regulation of cell death. Treatment with trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs) resulted in increased HMGB1 acetylation and its translocation to the cytoplasm and secretion, thereby inducing autophagic cell death. However, this process was diminished in CAMSAP3 knockout lung cancer cells. Mechanistically, immunoprecipitation indicated an interaction between CAMSAP3 and HMGB1, particularly with its acetylated form, in which this complex was elevated in the presence of TSA.

CAMSAP3 is prerequisite for TSA-mediated autophagic cell death by interacting with cytoplasmic acetylated HMGB1 and enhancing its release.

This finding provides molecular insights into the role of CAMSAP3 in regulating cell death, highlighting its potential as a therapeutic target for lung cancer treatment.

High-mobility group B (HMGB) proteins are a class of non-histone proteins associated with eukaryotic chromatin and are known to regulate a variety of biological processes in plants. However, the functions of HMGB genes in tomato (Solanum lycopersicum) remain largely unexplored. Here, we identified 11 members of the HMGB family in tomato using BLAST. We employed genome-wide identification, gene structure analysis, domain conservation analysis, cis-acting element analysis, collinearity analysis, and qRT-PCR-based expression analysis to study these 11 genes. These genes were categorized into four groups based on their unique protein domain structures. Despite their structural diversity, all members contain the HMG-box domain, a characteristic feature of the HMG superfamily. Syntenic analysis suggested that tomato SlHMGBs have close evolutionary relationships with their homologs in other dicots. The promoter regions of SlHMGBs are enriched with numerous cis-elements related to plant growth and development, phytohormone responsiveness, and stress responsiveness. Furthermore, SlHMGB members exhibited distinct tissue-specific expression profiles, suggesting their potential roles in regulating various aspects of plant growth and development. Most SlHMGB genes respond to a variety of abiotic stresses, including salt, drought, heat, and cold. For instance, SlHMGB2 and SlHMGB4 showed positive responses to salt, drought, and cold stresses. SlHMGB1, SlHMGB3, and SlHMGB8 were involved in responses to two types of stress: SlHMGB1 responded to drought and heat, while SlHMGB3 and SlHMGB8 responded to salt and heat. SlHMGB6 and SlHMGB11 were solely regulated by drought and heat stress, respectively. Under various treatment conditions, the number of up-regulated genes significantly outnumbered the down-regulated genes, implying that the SlHMGB family may play a crucial role in mitigating abiotic stress in tomato. These findings lay a foundation for further dissecting the precise roles of SlHMGB genes.

Single-cell expression dynamics, from differentiation trajectories or RNA velocity, have the potential to reveal causal links between transcription factors (TFs) and their target genes in gene regulatory networks (GRNs). However, existing methods either overlook these expression dynamics or necessitate that cells be ordered along a linear pseudotemporal axis, which is incompatible with branching trajectories. We introduce Velorama, an approach to causal GRN inference that represents single-cell differentiation dynamics as a directed acyclic graph of cells, constructed from pseudotime or RNA velocity measurements. Additionally, Velorama enables the estimation of the speed at which TFs influence target genes. Applying Velorama, we uncover evidence that the speed of a TF's interactions is tied to its regulatory function. For human corticogenesis, we find that slow TFs are linked to gliomas, while fast TFs are associated with neuropsychiatric diseases. We expect Velorama to become a critical part of the RNA velocity toolkit for investigating the causal drivers of differentiation and disease.

High-mobility group B1 (HMGB1) is both a DNA binding nuclear factor modulating transcription and a crucial cytokine that mediates the response to both infectious and noninfectious inflammation such as autoimmunity, cancer, trauma, and ischemia reperfusion injury. HMGB1 has been proposed to control ribosome biogenesis, similar as the other members of a class of HMGB proteins.

Here, we report that HMGB1 selectively promotes transcription of genes involved in the regulation of transcription, osteoclast differentiation and apoptotic process. Improved RNA immunoprecipitation by UV cross-linking and deep sequencing (iRIP-seq) experiment revealed that HMGB1 selectively bound to mRNAs functioning not only in signal transduction and gene expression, but also in axon guidance, focal adhesion, and extracellular matrix organization. Importantly, HMGB1-bound reads were strongly enriched in specific structured RNAs, including the domain II of 28S rRNA, H/ACA box snoRNAs including snoRNA63 and scaRNAs. RTL-P experiment showed that overexpression of HMGB1 led to a decreased methylation modification of 28S rRNA at position Am2388, Cm2409, and Gm2411. We further showed that HMGB1 overexpression increased ribosome RNA expression levels and enhanced protein synthesis.

Taken together, our results support a model in which HMGB1 binds to multiple RNA species in human cancer cells, which could at least partially contribute to HMGB1-modulated rRNA modification, protein synthesis function of ribosomes, and differential gene expression including rRNA genes. These findings provide additional mechanistic clues to HMGB1 functions in cancers and cell differentiation.

Liver regeneration is a well-orchestrated compensatory process that is regulated by multiple factors. We recently reported the importance of the chromatin protein, a high-mobility group box 2 (HMGB2) in mouse liver regeneration. However, the molecular mechanism remains unclear. In this study, we aimed to study how HMGB2 regulates hepatocyte proliferation during liver regeneration. Seventy-percent partial hepatectomy (PHx) was performed in wild-type (WT) and HMGB2-knockout (KO) mice, and the liver tissues were used for microarray, immunohistochemistry, quantitative polymerase chain reaction (qPCR), and Western blotting analyses. In the WT mice, HMGB2-positive hepatocytes colocalized with cell proliferation markers. In the HMGB2-KO mice, hepatocyte proliferation was significantly decreased. Oil Red O staining revealed the transient accumulation of lipid droplets at 12-24 hr after PHx in the WT mouse livers. In contrast, decreased amount of lipid droplets were found in HMGB2-KO mouse livers, and it was preserved until 36 hr. The microarray, immunohistochemistry, and qPCR results demonstrated that the expression of lipid metabolism-related genes was significantly decreased in the HMGB2-KO mouse livers. The in vitro experiments demonstrated that a decrease in the amount of lipid droplets correlated with decreased cell proliferation activity in HMGB2-knockdown cells. HMGB2 promotes de novo lipogenesis to accelerate hepatocyte proliferation during liver regeneration.

Pyroptosis, an inflammatory programmed cell death process, has recently garnered significant attention due to its pivotal role in various neurological diseases. This review delves into the intricate molecular signaling pathways governing pyroptosis, encompassing both caspase-1 dependent and caspase-1 independent routes, while emphasizing the critical role played by the inflammasome machinery in initiating cell death. Notably, we explore the Nucleotide-binding domain leucine-rich repeat (NLR) containing protein family, the Absent in melanoma 2-like receptor family, and the Pyrin receptor family as essential activators of pyroptosis. Additionally, we comprehensively examine the Gasdermin family, renowned for their role as executioner proteins in pyroptosis. Central to our review is the interplay between pyroptosis and various central nervous system (CNS) cell types, including astrocytes, microglia, neurons, and the blood-brain barrier (BBB). Pyroptosis emerges as a significant factor in the pathophysiology of each cell type, highlighting its far-reaching impact on neurological diseases. This review also thoroughly addresses the involvement of pyroptosis in specific neurological conditions, such as HIV infection, drug abuse-mediated pathologies, Alzheimer's disease, and Parkinson's disease. These discussions illuminate the intricate connections between pyroptosis, chronic inflammation, and cell death in the development of these disorders. We also conducted a comparative analysis, contrasting pyroptosis with other cell death mechanisms, thereby shedding light on their unique aspects. This approach helps clarify the distinct contributions of pyroptosis to neuroinflammatory processes. In conclusion, this review offers a comprehensive exploration of the role of pyroptosis in various neurological diseases, emphasizing its multifaceted molecular mechanisms within various CNS cell types. By elucidating the link between pyroptosis and chronic inflammation in the context of neurodegenerative disorders and infections, it provides valuable insights into potential therapeutic targets for mitigating these conditions.

A significant portion of human cancers are caused by oncoviruses (12%-25%). Oncoviruses employ various strategies to promote their replication and induce tumourigenesis in host cells, one of which involves modifying the gene expression patterns of the host cells, leading to the rewiring of genes and resulting in significant changes in cellular processes and signalling pathways. In recent studies, a specific mode of gene regulation known as circular RNA (circRNA)-mediated competing endogenous RNA (ceRNA) networks has emerged as a key player in this context. CircRNAs, a class of non-coding RNA molecules, can interact with other RNA molecules, such as mRNAs and microRNAs (miRNAs), through a process known as ceRNA crosstalk. This interaction occurs when circRNAs, acting as sponges, sequester miRNAs, thereby preventing them from binding to their target mRNAs and modulating their expression. By rewiring the host cell genome, oncoviruses have the ability to manipulate the expression and activity of circRNAs, thereby influencing the ceRNA networks that can profoundly impact cellular processes such as cell proliferation, differentiation, apoptosis, and immune responses. This review focuses on a comprehensive evaluation of the latest findings on the involvement of virus-induced reprogramming of host circRNA-mediated ceRNA networks in the development and pathophysiology of human viral cancers, including cervical cancer, gastric cancer, nasopharyngeal carcinoma, Kaposi's sarcoma, hepatocellular carcinoma, and diffuse large B cell lymphoma. Understanding these mechanisms can improve our knowledge of how oncoviruses contribute to human tumourigenesis and identify potential targets for developing optimised therapies and diagnostic tools for viral cancers.

Determining the post-mortem interval (PMI) is one of forensic pathology's primary objectives and one of its most challenging tasks. Numerous studies have demonstrated the accuracy of histomorphology and immunohistochemical investigations in determining the time of death. Nevertheless, the skin, a robust and easy-to-remove tissue, has only been partially analyzed so far. By studying 20 adult male mice, we tried to determine whether post-mortem immunohistochemical detection in the skin of HMGB1 proteins and associated components (Beclin1 and RAGE) could be used for this purpose. We discovered that nuclear HMGB1 overexpression indicates that death occurred within the previous 12 h, nuclear HMGB1 negativization with high cytoplasmic HMGB1 intensity indicates that death occurred between 12 and 36 h earlier and cytoplasmic HMGB1 negativization indicates that more than 48 h have passed since death. RAGE and Beclin1 levels in the cytoplasm also decreased with time. The latter proteins' negativization might indicate that more than 24 and 36 h, respectively, have passed from the time of death. These indicators might potentially be helpful in forensic practice for determining the PMI using immunohistochemistry.