Gastric cancer is one of the leading causes of cancer mortality worldwide, but the underlying molecular mechanisms by which gastric cancer progresses are not fully understood. While deubiquitinases have emerged as promising therapeutic targets in various cancers, a suitable target deubiquitinase for the treatment of gastric cancer has not yet been identified. Using bioinformatics analyses, we identified that upregulation of ubiquitin-specific peptidase 26 (USP26) was associated with poor patient survival in patients with gastric cancer; moreover, depletion of endogenous USP26 with short hairpin RNAs significantly suppressed the aerobic glycolysis and proliferation in tumor cells. In mechanism, USP26 was revealed to interact with and stabilize c-Myc, which is a key driver of tumor metabolism and carcinogenesis, via suppressing its polyubiquitination and degradation. In summary, these findings suggest that USP26 plays a novel oncogenic role of USP26 by forming a USP26-c-Myc regulatory axis, and that targeting USP26 may be a potential therapeutic strategy for gastric cancer.

Arrestin beta 1 (ARRB1) and ARRB2, which are multifunctional adapters in G protein-coupled receptor signaling, are highly involved in liver-related diseases. ARRB1 plays a protective role against ischemia-reperfusion injury, acute liver injury, and nonalcoholic fatty liver disease by inhibiting apoptosis and improving metabolic disorders. ARRB1 has been reported to be protective in mouse liver fibrosis models; however, it has also been shown to have pathogenic effects in human liver fibrosis. This discrepancy may be due to limitations in mouse models and species differences. In contrast, ARRB2 has dual functions in liver-related diseases. On the contrary, it reduces acute hepatitis and ischemic injury by inhibiting the NF-κB/c-Jun N-terminal kinase pathway. On the contrary, it accelerates disease progression by activating macrophages and promoting oxidative stress and collagen deposition in autoimmune hepatitis, alcoholic steatohepatitis, and fibrosis. Furthermore, the structural differences between ARRB1 and ARRB2 may determine their signal bias through nuclear output capability, nuclear input capability, and phosphorylation. In-depth analysis of the interaction between ARRBs and their signaling mechanisms is expected to provide accurate therapeutic targets for liver disease.

This essay focuses on a key host factor, the protein BIK (Bcl-2-interacting killer), that influences the severity of influenza A virus (IAV) infections. Our recent research published in Proceedings of the National Academy of Sciences describes a novel IAV-BIK-β5 axis that is critical for viral replication. The study demonstrates that BIK is essential for efficient IAV replication, and its overexpression leads to increased viral loads, lung inflammation, and heightened mortality in mouse models. We also identified a single nucleotide polymorphism (SNP), rs738276, in the BIK gene's promoter. This SNP influences the basal expression of BIK, and individuals with the high-expression AA genotype are at a higher risk for severe influenza. The molecular mechanism involves the viral nucleoprotein (NP) suppressing the proteasome's β5 subunit, which leads to BIK accumulation and promotes viral replication. These findings identify BIK as a potential therapeutic target and the rs738276 SNP as a biomarker for personalized medicine.

Dengue is the most important mosquito-borne viral infection of humans worldwide. Genetic ancestry of the host is a significant risk factor for severe dengue, but the mechanisms are not known. Recent findings using human skin explants from genetically defined donors reveal that dengue virus (DENV) replication and spread in skin increases with increasing proportion of European ancestry of the donor, associated with a strong inflammatory response and local myeloid cell infiltration, infection, and migration. In contrast, African ancestry is associated with substantially reduced cutaneous inflammation and cell infiltration following virus inoculation, resulting in reduced infection and migration of infected cells. These findings help explain the long-standing observation that individuals of African descent are relatively protected against severe dengue, while individuals of European descent are not. In this essay, we review DENV infection, focusing on human skin and the influence of genetic ancestry on the cutaneous innate response and virus spread.

Copper plays an essential role in numerous biological functions, requiring tight regulation to prevent toxicity and health complications. Cuproptosis is a recently discovered form of regulated cell death that occurs due to intracellular copper accumulation, with a unique mechanism distinct from other known cell death pathways. It is initiated when copper binds to lipoylated enzymes within the tricarboxylic acid (TCA) cycle, leading to enzyme aggregation, proteotoxic stress, and, ultimately, cell death. Since its identification, cuproptosis has drawn significant attention for its potential application in cancer therapy. Copper-based treatments have shown promise in suppressing tumor growth and may offer therapeutic strategies for tumors resistant to conventional chemotherapy. This article explores the underlying mechanisms of cuproptosis and the involvement of copper in various malignancies, aiming to advance targeted cancer therapies and inspire the development of novel anticancer agents that harness this pathway. Finally, important concepts of cuproptosis and issues to focus on in future studies are discussed.

Gastric cancer (GC) is the fifth most common malignancy and one of the leading causes of cancer-related death worldwide. Its histological and molecular heterogeneity make it particularly challenging to manage. The Cancer Genome Atlas classifies GC into four molecular subtypes: Epstein-Barr virus-associated GC (EBVaGC), microsatellite instability-high (MSI-H), chromosomal instability (CIN), and genomic stability (GS), each of which has distinct genetic and epigenetic characteristics. Among this biomarker diversity, non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) and long non-coding RNAs play a key role in diagnosis, prognosis, and targeted therapy. For instance, the EBVaGC subtype features PIK3CA mutations and hypermethylation of tumor suppressor genes such as , alongside ncRNAs such as EBV-encoded RNAs and H19 that enhance immunogenicity and response to programmed death-1/programmed death-ligand 1 inhibitors. MSI-H-GC is characterized by high mutational load and DNA mismatch repair defects, and ncRNAs such as MIR99AHG serve as prognostic and immunomodulatory markers. CIN-GC, the most common subtype, is associated with amplification of genes such as and ncRNAs such as miR-22 and , which exacerbate CIN and are linked to a poor prognosis may be amenable to HER2-targeted therapies. GS-GC is characterized by and mutations and epithelial-to-mesenchymal transition (EMT) features, where ncRNAs such as affect invasion and metastasis by regulating EMT. Through interactions with miRNAs and signaling pathways, these ncRNAs not only influence prognosis but also represent novel therapeutic targets. Integrating multiomics approaches and developing ncRNA-based biomarker panels are essential for advancing precision medicine in GC.

() play crucial roles in liver fibrosis (LF). We previously showed that the key is involved in LF, but its molecular mechanism remains unclear. Primary hepatic stellate cells (HSCs) were isolated from LF mice. Real-time quantitative PCR and Western blotting were used to detect the expression of , (), and (). Cell counting kit-8 and flow cytometry were used to detect the cell viability and cell cycle of the HSCs. Finally, immunofluorescence (IF) and fluorescence hybridization (FISH) were used to observe the cellular colocalization of and . In HSCs from LF mice, the expression of the was significantly reduced and negatively correlated with the expression of the HSCs activation markers () and . Overexpression of the suppressed and expression, as well as HSCs proliferation. Bioinformatics analysis and FISH experiments revealed that the has potential binding sites on mRNA and shares a common subcellular localization. Notably, overexpression of the led to marked increases in mRNA and protein levels. Further studies on the role of as a deacetylase revealed that overexpression of significantly reduced mRNA and protein levels. Importantly, overexpression also markedly decreased protein acetylation, suggesting that a mechanism exists by which is regulated via deacetylation in HSCs. The results of this study suggested that downregulation of expression reduced the expression of , leading to decreased deacetylation and promoting HSCs activation. The may be a novel therapeutic target for the diagnosis and treatment of LF.

The development of effective therapeutic strategies for chronic kidney disease (CKD) remains a central focus of contemporary medical research. Mesenchymal stem cells (MSCs) have emerged as a highly promising therapeutic modality for CKD, primarily due to their inherent regenerative and immunomodulatory capabilities. MSCs exert their therapeutic effects predominantly through the transfer of miRNAs via extracellular vesicles (EVs), which orchestrate key cellular pathways involved in renal repair and regeneration. However, critical challenges-including limited differentiation potential, suboptimal survival rates, and inefficient homing capacity-have significantly constrained their clinical translation. As such, enhancing the therapeutic efficacy of MSCs has become a paramount research priority. Recent investigations have demonstrated that preconditioning MSCs can markedly augment their therapeutic performance. Notably, emerging evidence has established a compelling association between herbs and the regulation of miRNA expression in MSC-derived EVs, suggesting novel synergistic interactions between herbs and MSC-based therapies. This review systematically dissects the mechanistic frameworks through which herbs and their bioactive constituents enhance the therapeutic effects of preconditioned MSCs, with a particular emphasis on EV-mediated miRNA cross-talk. The overarching goal is to provide innovative perspectives and translational strategies to facilitate the clinical implementation of preconditioned MSCs in CKD management.

We summarize recent findings on the conformational differences of chromatin fibers in immature versus mature retina cells due to different nucleosome linker length values and distributions, as revealed by cryo-electron microscopy and modeling studies, emphasizing implications to chromatin organization and epigenetic regulation broadly.

Probiotics sourced from host-adapted microbes represent a sustainable innovation in aquaculture nutrition, aiming to replace antibiotics and enhance fish health. However, studies evaluating indigenous probiotic strains specifically adapted to the gut environment of target species remain limited. In this study, an indigenous strain was isolated from common carp () intestine, PCR-authenticated via dual endoglucanase amplicons (545 and 1311 bp), formulated as a powdered feed additive, and tested at 1, 10, and 100 mg/kg against commercial Nutri-Fish®, Infloran Bio®, vitamin C, and a supplemented control in an 8-week feeding trial with ( = 126) carp. The 10 mg/kg dose significantly ( < 0.05) enhanced growth performance, producing the highest weight gain (133.27 ± 4.56 g), specific growth rate (2.59 ± 0.12% per day), and relative growth rate (43.09 ± 1.23%), along with improved feed conversion ratio (3.51 ± 0.09%), feed efficiency ratio (29.58 ± 1.45%), and protein efficiency ratio (475.95 ± 15.32%). Hematological analysis revealed neutrophilia (52%, < 0.05), a moderated neutrophil-to-lymphocyte ratio, and stable erythron parameters, indicating primed innate immunity without systemic stress. Plasma alanine aminotransferase and aspartate aminotransferase levels decreased by 30-40% relative to other groups ( < 0.05), evidencing improved hepatic integrity and lipid metabolism. Intestinal histology showed moderate mucosal fold hypertrophy at 10 mg/kg, whereas the highest dose (100 mg/kg) caused epithelial sloughing and inflammation. These results demonstrate that a precision microdose (10 mg/kg) of host-adapted can outperform multicomponent commercial supplements by significantly enhancing growth, immunity, and organ health. This probiotic strategy provides a sustainable, eco-friendly alternative for warm-water carp aquaculture, supporting circular economy principles and reducing reliance on antibiotics.

Osteoclasts, as the only cells capable of resorbing bone, play a significant role in all processes that take place at the level of bone tissue and are involved in the development of the skeleton, maintenance of its integrity, repair, and regeneration of bones. Therefore, it is not surprising that even small deviations from their normal functioning result in diseases that not only affect skeletal system but also the entire organism. There are a number of rare genetic bone diseases associated with mutations in osteoclast genes that govern their differentiation and function. Specifically, they are known as osteoclast-related diseases, and their main hallmark is either decreased or increased bone resorption. To understand the impact of osteoclast gene mutations on the course of these diseases, it is also necessary to know the cellular and molecular mechanisms underlying osteoclast development and function. Moreover, identification of specific gene mutations as potential therapeutic targets would be an important step in creating personalized gene therapies in the future.

Extracellular vesicles (EVs) have been investigated due to their natural biocompatibility and targeting capabilities. The specific approach of combining EVs with liposomes to create hybrid nanoparticles (ELNPs) for the delivery of the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (Cas9) system for deletion of the HGF gene in stem cells, but their effectiveness in encapsulating large nucleic acids is limited due to their small size. This study aimed to knock out the HGF gene by the CRISPR/Cas9 system by ELNPs, and it was expected that the efficiency of the CRISPR/Cas9 system transfer would increase compared to the usual methods of using lipofectamine in stem cells from apical papilla (SCAPs). In this study, gRNA suitable for the HGF gene is designed first, and after insertion into the CRISPR/Cas9 vector, it enters Lipofectamine 2000. In the next step, ELNPs are prepared after collecting EVs and hybridizing them with liposomes containing CRISPR/Cas9 vector. Then, these integrated nanoparticles were presented to SCAPs, and the removal of HGF gene expression was evaluated at the level of RNA and protein. This study showed that the CRISPR/Cas9 system can be efficiently transferred to SCAP cells using ELNPs. Genomic DNA sequencing analyses of SCAP cells showed a unique pattern of mutation, highly likely mediated through EVs. Quantitative PCR and protein staining further showed a decrease in HGF gene expression in the knockout cells. Moreover, cell proliferation analysis showed a decrease in cell proliferation in KO-HGF adipose cells compared to the nonedited counterpart. In summary, this study highlights the supportive role of EVs in facilitating cell transfection and promoting a dominant DNA repair pattern, likely through an RNA-mediated mechanism, rather than the random insertions and deletions typically induced during CRISPR editing of the HGF gene in SCAPs.

Mesenchymal stromal cells (MSCs) have been widely used in clinical trials for various diseases, due to their broad differentiation potential and effective immunomodulatory effects. However, the cell death profiles of MSC subsets remain inadequately characterized. In this study, we unexpectedly identified unique differentially expressed ferroptotic genes in MSC subsets from four different tissues (adipose, bone marrow, dermis, and umbilical cord) and revealed a critical role of ferroptosis in umbilical cord derived MSCs (UC-MSCs). Furthermore, increased ferroptosis level and ferroptosis sensitivity were detected in the C1 subset of UC-MSCs, and the upregulation in the ferroptosis level and sensitivity was examined during an expansion of UC-MSCs with the treatment with an ferroptosis inducer. In addition, we detected an increase in the proportion of C1 UC-MSCs after treatment with a ferroptosis inducer (Erastin) or inhibitor (Fer-1). Overall, this study further revealed the intricate nature of MSCs and will help facilitate the use of optimal subtypes to improve their clinical efficacy in the future.

Mitochondria, originating from symbiotic ancestors, are acknowledged as the powerhouses of the cell. Their relevance to various cancer types is underscored by altered glucose metabolism (Warburg effect). Mitochondrial DNA (mtDNA) plays a crucial role in oxidative damage and is a significant contributor to cancer onset and progression. Tobacco and alcohol consumption increases reactive oxygen species generation, inducing oxidative stress that disrupts respiratory activity and mtDNA, thereby promoting carcinogenesis. This review emphasizes the link between mitochondrial dysfunction and cancer, particularly in oral squamous cell carcinoma (OSCC), highlighting the role of mtDNA mutations. This review discusses environmental factors, such as tobacco use and human papillomavirus infection, that impact mitochondrial function, stresses the importance of mitochondrial-targeted therapies, and explores the influence of microRNAs (miRNAs) on mitochondrial metabolism in cancer cells. Mitocans and miRNAs have emerged as promising therapeutic agents for OSCC. The subsequent sections delve into recent pivotal research on mitochondria, identifying mtDNA alterations as potential cancer biomarkers. These insights promise new perspectives on noninvasive cancer detection, heralding advancements in cancer therapeutics.

Glucose homeostasis is an essential physiological process to ensure a stable energy supply to all tissues while preventing the harmful consequences of hypo- or hyperglycemia. The endocrine pancreas plays a central role in maintaining this process, where β-cells and α-cells secrete insulin and glucagon to coordinate systemic glucose metabolism, storage, and production. In this context, β-cells act as the main glucose sensors, closely linking extracellular glucose fluctuations to insulin release. This sensing is dependent on glucose transporters (GLUTs), which regulate cellular glucose uptake through their dynamic trafficking to the plasma membrane. The resultant increase in ATP links metabolism to electrical activity and exocytosis of insulin granules. β-cells maintain plasma glucose within the physiological range of 4-5.5 mM by integrating glucose uptake with metabolic signaling, thereby lowering elevated postprandial concentrations to ∼7.8 mM. In type 2 diabetes, defects in GLUT regulation reduce β-cell responsiveness, impair insulin secretion, and destabilize glucose homeostasis, highlighting GLUT dynamics as a target to maintain normoglycemia.

Cuproptosis is a regulated cell death mechanism that has recently been identified and is distinct from other known cell death mechanisms (e.g., apoptosis, Ferroptosis, necrotic apoptosis, etc.). Cuproptosis causes oligomer formation through the abnormal accumulation of intracellular copper ions that target binding to lipocytosed proteins, especially those involved in the tricarboxylic acid cycle. At the same time, it can destabilize iron-containing sulfur proteins, thereby inducing proteotoxic stress, leading to triggered cell death. It has also been shown that cuproptosis is also associated with oxidative stress activation and inhibition of the ubiquitin-proteasome system. Genes linked to cuproptosis were screened, and knocking out seven genes reversed cuproptosis: reductase-ferredoxin 1; the three genes of the lipoic acid pathway-lipoyltransferase 1, lipoyl synthase, and dihydrolipoamide dehydrogenase; and the acylated protein targets-dihydrolipoyl transacetylase (DLAT), pyruvate dehydrogenase complex component A1 (PDHA1), and pyruvate dehydrogenase complex component B (PDHB). Among them, the β subunit of pyruvate dehydrogenase, encoded by the PDHB gene, can form a tetramer with the α subunit and irreversibly catalyze the physiological function of converting pyruvate to acetyl-CoA since DLAT provides structural support and also exhibits enzymatic activity within the pyruvate dehydrogenase complex (PDC). Furthermore, within the PDC, the primary target of cuproptosis is DLAT rather than PDHB or PDHA1. Consequently, the involvement of PDHB in the inactivation of PDC caused by cuproptosis is more likely a secondary consequence. In this review, the characteristics of the cuproptosis-associated gene PDHB and its role in the biological function and pathogenesis of the disease are discussed.

The 6-methyladenine (m6A) modification plays a major role in various diseases. Serine protease 8 () contributes to the initiation and progression of liver fibrosis (LF). However, the mechanism by which the m6A modification of induces hepatic stellate cells (HSCs) activation in the LF is unclear. This study focused on exploring the contribution of m6A modification to the pathogenesis of LF. First, primary hepatic parenchymal cells (hepatocytes) and HSCs were isolated from a mouse model of LF, and a coculture of these two types of cells was used as the object of study. Then, real-time fluorescence quantitative PCR, methylated RNA immunoprecipitation, and Western blotting were used to test the expression levels of mRNA and protein, m6A modification, , , and . Finally, the expression levels of inflammatory markers were measured via an enzyme-linked immunosorbent assay. Compared with the control group, the model group presented significantly lower mRNA and protein levels in hepatocytes but greater levels of m6A modification; moreover, the expression of HSC activation markers and the , , and proteins was significantly elevated. Mutation of the m6A modification site led to upregulation of mRNA and protein and decreased levels of m6A modification, , , and . Furthermore, mutation of the m6A modification site increased the stability of mRNA. Rescue experiments confirmed the regulatory link between m6A modification and . Overall, m6A modification decreases the stability of its mRNA, promoting -mediated inflammatory cascades and leading to excessive activation of HSCs. Targeting m6A modification is a promising therapeutic strategy for LF.

IL-18 is a member of the IL-1 family of cytokines, which is highly expressed in intestinal epithelial cells (IECs). Upon barrier breach, IL-18 is matured to its bioactive form as a result of inflammasome activation, released from the cell via Gasdermin D pores, and sensed by IL-18 receptor 1-positive (IL18R1) immune cells to initiate an inflammatory response. In addition to this epithelial-out signaling network, we recently uncovered an epithelial-intrinsic IL-18 signaling pathway in the murine small intestine and identified enterochromaffin cells and revival stem cells (revSC) as IL18R1 bearing IEC populations in the recovering crypt. Here, we discuss the mechanism, and physiological relevance, as well as some of the open questions presented by this discovery in relation to intestinal health and disease.

-Methyladenosine (mA) is a reversible RNA modification that regulates tumorigenesis. KIAA1429, a critical component of the mA methyltransferase complex, has an unclear role in clear cell renal cell carcinoma (ccRCC). Here, we investigated the role of KIAA1429 in ccRCC tumorigenesis. The expressions of KIAA1429 and thymosin beta-10 (TMSB10) in ccRCC samples were evaluated using quantitative real-time PCR (qRT-PCR). The malignant features of ccRCC cells were assessed via CCK-8, colony formation, transwell migration, and invasion assays, as well as tumor xenograft models. The relationship between KIAA1429 and TMSB10 was verified via Pearson correlation analysis, methylated RNA immunoprecipitation, qRT-PCR, and Western blotting assays. Functional rescue experiments further confirmed their interaction. We found that KIAA1429 was highly expressed in ccRCC, and its silencing significantly suppressed cell proliferation, migration, invasion, and tumor growth , while overexpression had the opposite effect. Bioinformatics and mechanistic analyses identified TMSB10 as a downstream target of KIAA1429, whose expression was upregulated in an mA-dependent manner. Furthermore, overexpressing TMSB10 partially reversed the inhibitory effects of KIAA1429 silencing on ccRCC cells. Moreover, TMSB10 overexpression partially reversed the inhibitory effects of KIAA1429 knockdown. Taken together, our findings demonstrate that KIAA1429 promotes ccRCC tumorigenesis by enhancing TMSB10 expression via mA modification, suggesting it as a potential prognostic biomarker and therapeutic target. However, the lack of clinical validation limits the immediate translational impact of these findings.

Tegumentary leishmaniasis (TL) is a neglected tropical disease that affects approximately one million new patients living in endemic areas with a lack of health service infrastructure. In many countries, including Brazil, public referral centers provide diagnostic support using high-sensitivity and high-specificity tests. In this context, PCR has been increasingly used for diagnosis and other downstream applications, employing different clinical specimens and types of storage. However, new protocols must be developed to enable the use of PCR in specific tissue processing methods, such as those involving glycol methacrylate (GMA). This study aimed to evaluate the applicability of GMA-embedded biopsies as clinical specimens for diagnosis of TL by PCR. Thirty-five 3-µm sections were incubated at 55°C for 12 h in Tris-EDTA-NaCl buffer containing NP-40 detergent and proteinase K for DNA extraction. Twenty-five patients with clinical suspicion of TL were included. PCR detected the kinetoplast DNA (kDNA) in 19 out of 23 (82.6%) patients with cutaneous lesions. Additionally, 13 out of 15 (81.2%) patients with cutaneous lesions displaying a histopathological pattern compatible with TL were also kDNA PCR positive. Only two patients with mucosal lesions were evaluated, and both tested positive by PCR. Our results demonstrate that GMA-embedded samples are suitable for diagnosis of TL by kDNA PCR, highlighting their potential for clinical applications.