Increasing evidence indicates that cancer stem cells (CSCs) and cancer stem-like cells form a special subpopulation of cells that are ubiquitous in tumors. These cells exhibit similar characteristics to those of normal stem cells in tissues; moreover, they are capable of self-renewal and differentiation, as well as high tumorigenicity and drug resistance. In prostate cancer (PCa), it is difficult to kill these cells using androgen signaling inhibitors and chemotherapy drugs. Consequently, the residual prostate cancer stem cells (PCSCs) mediate tumor recurrence and progression.

This review aims to provide a comprehensive and up-to-date overview of PCSCs, with a particular emphasis on potential therapeutic strategies targeting these cells.

After searching in PubMed and Embase databases using 'prostate cancer' and 'cancer stem cells' as keywords, studies related were compiled and examined.

In this review, we detail the origin and characteristics of PCSCs, introduce the regulatory pathways closely related to CSC survival and stemness maintenance, and discuss the link between epithelial-mesenchymal transition, tumor microenvironment and tumor stemness. Furthermore, we introduce the currently available therapeutic strategies targeting CSCs, including signaling pathway inhibitors, anti-apoptotic protein inhibitors, microRNAs, nanomedicine, and immunotherapy. Lastly, we summarize the limitations of current CSC research and mention future research directions.

A deeper understanding of the regulatory network and molecular markers of PCSCs could facilitate the development of novel therapeutic strategies targeting these cells. Previous preclinical studies have demonstrated the potential of this treatment approach. In the future, this may offer alternative treatment options for PCa patients.

Bexarotene (Bex) is a selective retinoid X receptor (RXR) agonist and is commonly used as an anti-tumor drug in the clinic to treat patients with cutaneous T-cell lymphoma (CTCL). With the widespread use of this drug, people are increasingly concerned about its side effects and safety of use. At present, the effects of bexarotene drugs on the health of organisms remain uncertain, but retinoid drugs are generally biologically active and may pose potential risks to them. Therefore, in this study, we used a zebrafish model to evaluate the effects of Bex on embryonic development. Six hours after fertilization, we exposed zebrafish embryos to 3 μg/L, 6 μg/L, and 9 μg/L bexarotene. At 96 hpf, compared with the control group, zebrafish embryos exposed to bexarotene showed obvious heart and liver development defects, including reduced hatching rate, pericardial enlargement, heart rate disorder, yolk sac edema, small liver area and abnormal photo-optical motor responses. Transcriptome and qPCR results showed abnormal expression of genes related to heart and liver development was induced by Bexarotene. Mechanistically, bexarotene induced a significant upregulation of the transcriptional expression levels of genes related to the Wnt signaling pathway, and IWR-1 was able to effectively rescue the heart and liver developmental defects of zebrafish caused by bexarotene. Therefore, our study showed that bexarotene may cause zebrafish embryonic developmental defects by upregulating the Wnt signaling pathway, revealing the side effects and associated novel mechanisms of bexarotene, and providing a theoretical basis for its safe and effective use in the treatment of clinically related diseases.

Cancer-related genes and pathways have recently been implicated in a genome-wide meta-analysis of head size. In the current study, we aimed to evaluate the association between adult head circumference and the risk of cancer.

This is a cohort study using data from the Hong Kong Osteoporosis Study, where 1,301 participants aged 27-96 years with head circumference measured between 2015 and 2019, and without a history of cancer, were followed up to 15 January 2024. Incident cancers were identified using electronic medical records from a territory-wide database. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression, adjusting for age, sex, height, weight, education, smoking, alcohol drinking, physical activity, and family history of cancer, as well as accounting for familial clustering.

The median head circumference was 53 cm (interquartile range [IQR]: 51-54) and 54 cm (IQR: 53-55) for women and men, respectively. During a median follow-up of 6.9 years, 66 individuals were diagnosed with cancer. In the adjusted model, a larger head circumference was associated with an increased risk of any cancer (HR per cm increase: 1.17; 95% CI 1.00-1.36). Results remained similar when adjusting for waist-to-hip ratio instead of weight or when additionally adjusting for serum calcium and phosphorus levels. When stratified by cancer sites, head circumference was most strongly associated with colorectal cancer (HR per cm increase: 1.81; 95% CI 1.14-2.90) and prostate cancer (HR per cm increase: 1.58; 95% CI 1.16-2.16).

Head circumference is positively associated with the risk of cancer independently of height, weight, and other cancer risk factors.

Changes in cellular physiology and proteomic homeostasis accompanied the initiation and progression of colorectal cancer. Thus, ubiquitination represents a central regulatory mechanism in proteome dynamics. However, the complexity of the ubiquitinating network involved in carcinogenesis remains unclear. This study revealed the tumor-suppressive role of the ubiquitin ligase Cullin4A (CUL4A) in the intestine. We showed that simultaneous loss of CUL4A and hyperactivation of the Wnt pathway promotes tumor development in the distal colon. This tumor development is caused by an accumulation of the inactive SMAD3, a TGF-β pathway mediator. Depletion of CUL4A resulted in stabilization of HUWE1, which attenuated SMAD3 function. We showed a correlation between the intracellular localization of CUL4A and colorectal cancer progression, where nuclear CUL4A localization correlates with advanced colorectal cancer progression. In summary, we identified CUL4A as an important regulator of SMAD3 signal transduction competence in a HUWE1-dependent manner and demonstrated a critical role for the crosstalk between ubiquitination and the Wnt/TGF-β signaling pathways in gastrointestinal homeostasis.

Breast cancer (BC) is the most prevalent cancer type in the world, with increasing incidence rates. Drug resistance is a notable factor that limits the effectiveness of BC therapy. Paclitaxel (PTX), a chemotherapeutic agent belonging to the taxane class, is commonly used in BC; however, its efficacy is often compromised by drug resistance, which is primarily attributed to genetic alterations. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and wingless-type MMTV integration site family/β-catenin signaling pathways are involved in essential cellular processes, such as proliferation, apoptosis and maintenance of homeostasis. Dysregulated activation of these pathways is strongly associated with carcinogenesis and drug resistance. In the present study, the potential effects of AKT1 (E17K/E49K/L52R) and catenin β-1 (CTNNB1; S33P/T41A/S45F) mutations on PTX resistance in BC were investigated in vitro using site-directed mutagenesis, transient transfection, MTS assay and western blot analyses. The results of the present study indicated that AKT1-E17K/E49K and CTNNB1-S45F/T41A mutations induced PTX resistance compared with AKT1-wild-type (WT) and CTNNB1-WT in MCF-7 cells, respectively. In MDA-MB-231 cells, all three AKT1 mutations (E17K/E49K/L52R) triggered PTX resistance compared with AKT1-WT, while none of the CTNNB1 mutations exhibited such an effect. In conclusion, AKT1 mutations may serve as a biomarker for PTX resistance in both estrogen receptor (ER)(+)/progesterone receptor (PR)(+)/HER2(-) and triple negative BC, while CTNNB1 mutations may be a potential biomarker for PTX resistance in ER(+)/PR(+)/HER2(-) BC.

Mammalian clathrin light chains (CLCa, CLCb) are critical players in clathrin-mediated endocytosis. However, their physiological role in contributing to specific cellular processes and early development remains elusive. To elucidate their individual functions, we generated CLC knockout mESCs. Loss of CLCa resulted in down-regulation of Wnt pathway genes along with altered secretion of Wnt3a because of impaired trafficking of its secretion mediator, WLS. Reduced Wnt signaling led to lower levels of Hip1R causing a reorganization of the actin cytoskeleton. CLCa knockout cells displayed actin patches enriched for Arp3 and cortactin, with activation of the Wnt pathway resulting in disassembly of these patches. Furthermore, we uncovered a bidirectional cross-talk between Wnt signaling and actin organization, with actin disruption resulting in lower Wnt signaling. Our data reveal a previously undiscovered role of CLCa in mediating molecular communication between actin organization and Wnt signaling.

Alu-mediated p21 transcriptional regulator (APTR) overexpression is detected in different human cancers; however, few reports have investigated APTR gene amplification conditions. Furthermore, whether APTR amplification is related to glioma malignancy and the underlying mechanism remain unknown.

APTR amplification and expression levels in 153 glioma samples were analyzed using qPCR. Correlations between APTR and patient prognosis were evaluated using Kaplan-Meier survival and COX regression analyses. Both in vitro and in vivo phenotypic assays were performed to confirm the carcinogenic effects of APTR in glioblastoma (GBM) cells. RNA-sequencing and RNA immunoprecipitation and luciferase reporter assays were performed to confirm APTR as a competing endogenous RNA (ceRNA) and to identify the downstream axis of APTR.

Our results suggest that APTR amplification and overexpression are novel independent diagnostic biomarkers for predicting poor prognosis in patients with gliomas. APTR knockdown significantly repressed the proliferation and invasion of GBM cells, both in vitro and in vivo. APTR was demonstrated to absorb miR-6734-5p and upregulate TCF7 and LEF1 expression. Taken together, these results suggest that APTR promotes the malignant phenotypes of GBM by inducing TCF7 and LEF1 expression.

We identified APTR as a novel prognostic biomarker in patients with gliomas and confirmed that APTR is a ceRNA that promotes glioma progression via the APTR/miR-6734-5p/TCF7/LEF1 axis.

Cilia are microtubule-based sensory organelles which project from the cell surface, enabling detection of mechanical and chemical stimuli from the extracellular environment. It has been shown that cilia are lost in some cancers, while others depend on cilia or ciliary signaling. Several oncogenic molecules, including tyrosine kinases, G-protein coupled receptors, cytosolic kinases, and their downstream effectors localize to cilia. The Hedgehog pathway, one of the most studied ciliary-signaling pathways, is regulated at the cilium via an interplay between Smoothened (an oncogene) and Patched (a tumor suppressor), resulting in the activation of pro-survival programs. Interestingly, cilia loss can result in resistance to Smoothened-targeting drugs and increased cancer cell survival. On the other hand, kinase inhibitor-resistant and chemoresistant cancers have increased cilia and increased Hedgehog pathway activation, and suppressing cilia can overcome this resistance. How cilia regulate cancer is therefore context dependent. Defining the signaling output of cilia-localized oncogenic pathways could identify specific targets for cancer therapy, including the cilium itself. Increasing evidence implicates cilia in supporting several hallmarks of cancer, including migration, invasion, and metabolic rewiring. While cell cycle cues regulate the biogenesis of cilia, the absence of cilia has not been conclusively shown to affect the cell cycle. Thus, a complex interplay between molecular signals, phosphorylation events and spatial regulation renders this fascinating organelle an important new player in cancer through roles that we are only starting to uncover. In this review, we discuss recent advances in our understanding of cilia as signaling platforms in cancer and the influence this plays in tumor development.

ROR1 and ROR2 co-receptors are transducers of non-canonical Wnt responses that promote an aggressive phenotype in several cancer types, including colon cancer. It has been demonstrated that hypoxia promotes tumor progression through the action of Hypoxia Inducible Factors (HIFs). An in silico analysis revealed that ROR2 is overexpressed in the advanced clinical stages of colon cancer. In line with this, ROR1 and ROR2 were found to be only expressed in malignant colon cells compared to non-malignant ones. The blockade of either ROR1 or ROR2 impaired colon cancer cells' colony formation abilities and the migration capacity of them. Additionally, the silencing of the ROR2 co-receptor blocked the metastatic ability of colon cancer cells in a xenografted mice model. We found that while silencing HIF-1α did not significantly reduce ROR1 or ROR2 expression, inhibiting HIF-2α and HIF-3α expression greatly decreased the protein levels of both co-receptors in colon cancer cells. The HIF-1α subunit expression is induced in acute hypoxia, whereas HIF-2α and HIF-3α show higher activity in chronic hypoxia, which may be functionally relevant since hypoxia induced a decrease in the constitutive active β-catenin transcriptional activity in SW480 cells. While both ROR1 and ROR2 stimulate proliferation and migration under normoxic conditions, the exposure of cells to hypoxia increased the expression of ROR1 or ROR2, depending on the Wnt cellular context, Thus, our results indicate that hypoxia partially represses β-catenin transcriptional activity and activates non-canonical Wnt signaling by regulating ROR1/ROR2 expression to induce an aggressive migrating and metastatic phenotype in colon cancer cells.

Sepsis-induced acute lung injury (ALI) is a critical condition characterized by excessive inflammation, with macrophage polarization playing a pivotal role in its pathogenesis. In this study, we constructed myeloid-specific Notch1 knockout mice, overexpressed the Notch intracellular domain (NICD), and inhibited β-catenin using XAV939 to investigate the impact and mechanisms of Notch1 regulation in macrophage polarization and inflammatory responses in cecal ligation and puncture (CLP)-induced septic mice. The results demonstrated that Notch1 knockout significantly reduced M1 macrophage polarization, alleviated systemic inflammation, mitigated lung injury, and improved survival in septic mice. In sepsis, Notch1 enhances β-catenin expression, which synergizes with the NF-κB pathway to promote M1 polarization and pro-inflammatory cytokine production. Specifically, NICD interacts with β-catenin in macrophages, amplifying NF-κB activation and its nuclear translocation. These results demonstrate that the Notch1 signaling pathway plays a pivotal role in regulating macrophage phenotypic switching, highlighting its potential as a therapeutic target for attenuating sepsis-associated ALI through immune homeostasis restoration.

Chromodomain Helicase DNA-binding protein 1-Like (CHD1L) is a chromatin remodeling enzyme increasingly recognized as an oncogenic factor promoting tumor progression and metastatic potential by orchestrating transcriptional programs that drive epithelial-mesenchymal transition (EMT), cytoskeletal remodeling, and metastatic dissemination. In parallel, CHD1L has emerged as a master regulator of tumor cell survival by regulating DNA damage response and repair and enforcing G1 cell cycle progression. Furthermore, CHD1L plays a key role in immune evasion pathways by regulating signaling cascades and by suppressing both apoptotic and non-apoptotic cell death. In particular, CHD1L is a key suppressor of PARthanatos, a caspase-independent mechanism triggered by poly(ADP-ribose) (PAR) polymer fragmentation and apoptosis-inducing factor (AIF) activation. By regulating SPOCK1, MDM2, and TCTP, CHD1L further supports survival under cellular stress. Its overexpression correlates with metastasis, therapy resistance, and poor prognosis across many solid tumors. This review covers CHD1L's structure, oncogenic functions, and developmental origins, and highlights emerging therapeutic strategies that target CHD1L as a druggable vulnerability in cancer.

Th17 lymphocytes are a distinct subpopulation of T cells that are characterized by the production of interleukins IL-17, IL-21, IL-22, and IL-26, and high expression of RORγt. These cells play an important role in inflammation and autoimmune diseases. Recent studies using rodent and human models have also highlighted their promising properties as agents in cellular immunotherapy for cancer. However, much less is known about the properties of canine Th17 lymphocytes, despite the domestic dog being an important model used in comparative medicine. In this study, we developed methods of activation and differentiation of canine CD4+ T lymphocytes towards the Th17 phenotype. Additionally, we targeted the Wnt/β-catenin signaling pathway to modulate the efficiency of Th17 cells differentiation. CD4+ T cells were successfully activated with magnetic EpoxyBeads, and in combination with the appropriate programming medium, they acquired the Th17 phenotype. Furthermore, indomethacin, an inhibitor of the Wnt/β-catenin pathway, significantly increased the efficiency of differentiation, causing elevated production of IL-17 and changed T cell metabolism by promoting oxidative phosphorylation. The protocol elaborated in our study provides an efficient method of canine Th17 lymphocyte differentiation. Our findings also suggested that the modification of the Wnt/β-catenin signaling pathway could be a valuable strategy for optimizing canine Th17 cell differentiation and advancing cell-based immunotherapy.

Enhancers are non-coding DNA regions that facilitate gene transcription, with a specialized subset, super-enhancers, known to exert exceptionally strong transcriptional activation effects. Super-enhancers have been implicated in oncogenesis, and their identification is achievable through histone mark chromatin immunoprecipitation followed by sequencing data using existing analytical tools. However, conventional super-enhancer detection methodologies often do not accurately reflect actual gene expression levels, and the large volume of identified super-enhancers complicates comprehensive analysis. To address these limitations, we developed the super-enhancer to gene links (SE-to-gene Links) analysis, a platform named "SEgene" which incorporates the peak-to-gene links approach-a statistical method designed to reveal correlations between genes and peak regions ( https://github.com/hamamoto-lab/SEgene ). This platform enables a targeted evaluation of super-enhancer regions in relation to gene expression, facilitating the identification of super-enhancers that are functionally linked to transcriptional activity. Here, we demonstrate the application of SE-to-gene Links analysis to public datasets, confirming its efficacy in accurately detecting super-enhancers and identifying functionally associated genes. Additionally, SE-to-gene Links analysis identified ERBB2 as a significant gene of interest in the lung adenocarcinoma dataset from the National Cancer Center Japan cohort, suggesting a potential impact across multiple patient samples. Thus, the SE-to-gene Links analysis provides an analytical tool for evaluating super-enhancers as potential therapeutic targets, supporting the identification of clinically significant super-enhancer regions and their functionally associated genes.

Garlic possesses a broad spectrum of medicinal properties, such as anti-cancer, antioxidant, anti-diabetic effects, and protective effects on the heart, nervous system, and liver. Diallyl disulfide (DADS), an oil-soluble organic sulfur-containing compound in garlic, has garnered attention in recent years for its demonstrated anti-cancer efficacy in various cancer types such as leukemia, breast cancer, hepatocellular carcinoma, stomach cancer, and prostate cancer. The anticancer properties of DADS are attributed to its ability to suppress cancer cell proliferation, impede invasion and metastasis, as well as induce apoptosis, promote differentiation, and facilitate cell cycle arrest. Although many literatures have reviewed the pharmacokinetics, molecular mechanisms of anti-cancer effects and some clinical trials of DADS, the specific mechanisms and clinical-translational therapeutic potentials have not been elucidated. This comprehensive review focuses on delineating the molecular mechanisms underlying the anticancer effects of DADS, with a particular emphasis on its potential utility as a therapeutic intervention in the clinical management of cancer, and analyzes the challenges and coping strategies faced in the application of DADS as an anti-cancer drug, pointing out the directions for scientific research.

In multicellular organisms, Wnt proteins govern stem and progenitor cell renewal and differentiation to regulate embryonic development, adult tissue homeostasis and tissue regeneration. Defects in canonical Wnt signalling, which is transduced intracellularly by β-catenin, have been associated with developmental disorders, degenerative diseases and cancers. Although a simple model describing Wnt-β-catenin signalling is widely used to introduce this pathway and has largely remained unchanged over the past 30 years, in this Review we discuss recent studies that have provided important new insights into the mechanisms of Wnt production, receptor activation and intracellular signalling that advance our understanding of the molecular mechanisms that underlie this important cell-cell communication system. In addition, we review the recent development of molecules capable of activating the Wnt-β-catenin pathway with selectivity in vitro and in vivo that is enabling new lines of study to pave the way for the development of Wnt therapies for the treatment of human diseases.

PEST-containing nuclear protein (PCNP), a short-lived small nuclear protein with 178 amino acids, is a nuclear protein containing two PEST sequences. PCNP is highly expressed in several malignant tumors such as cervical cancer, rectal cancer, and lung cancer. It is also associated with cell cycle regulation and the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) and Wnt signaling pathways during tumor growth. The present article discuss how PCNP regulates the PI3K/AKT/mTOR and Wnt signaling pathways and related proteins, and the ubiquitination of PCNP regulates tumor cell cycle as well as the progress of the application of PCNP in the pathophysiology and treatment of colon cancer, human ovarian cancer, thyroid cancer, lung adenocarcinoma and oral squamous cell carcinoma. The main relevant articles were retrieved from PubMed, with keywords such as PEST-containing nuclear protein (PCNP), cancer (tumor), and signaling pathways as inclusion/exclusion criteria. Relevant references has been included and cited in the manuscript.

Background: The RSPO gene family encodes secreted glycoproteins that are rich in cysteine, which generally serve as activators of the Wnt signaling pathway in animals. Four types of this family have been identified in a few model species. However, the evolution of the family remains unclear. Methods: In this study, we identified a total of 1496 RSPO homologs through an extensive survey of the RSPO genes in 430 animals. Gene family clustering and phylogenetic analysis identified four major subtypes of the family (RSPO1-RSPO4) and clarified their distribution of copy number in different species. Results and Conclusions: Members of the RSPO4 subfamily that were closest to ancestral forms existed in both Deuterostomes and Protostomates, and we speculate that representatives of this subfamily already existed in Urbilatera, the last common ancestor of Deuterostomes. Particularly, in some RSPO3 subtypes of Actinopterygii (ray-finned fishes), an FU repeated motif with three conserved cysteines was identified. Further conservative analysis of amino acids and alignment of tertiary protein structure revealed the potential functional sites for each subgroup. The results provide insight into the phylogenetic relationships and evolutionary patterns of conserved motifs of RSPO family genes in animal kingdoms, which will guide further studies on the biological functions of RSPO in other non-model species.

Adenomatous polyposis syndromes are hereditary conditions characterised by the development of multiple adenomas in the gastrointestinal tract, particularly in the colon and rectum, significantly increasing the risk of colorectal cancer and, in some cases, extra-colonic malignancies. These syndromes are caused by germline pathogenic variants (PVs) in genes involved in Wnt signalling and DNA repair. The main autosomal dominant adenomatous polyposis syndromes include familial adenomatous polyposis (FAP) and polymerase proofreading-associated polyposis (PPAP), caused by germline PVs in APC and the POLE and POLD1 genes, respectively. Autosomal recessive syndromes include those caused by biallelic PVs in the DNA mismatch repair genes MLH1, MSH2, MSH6, PMS2, MSH3 and probably MLH3, and in the base excision repair genes MUTYH, NTHL1 and MBD4. This review provides an in-depth discussion of the genetic and molecular mechanisms underlying hereditary adenomatous polyposis syndromes, their clinical presentations, tumour mutational signatures, and emerging approaches for the treatment of the associated cancers. Considerations for genetic testing are described, including post-zygotic mosaicism, non-coding PVs, the interpretation of variants of unknown significance and cancer risks associated with monoallelic variants in the recessive genes. Despite advances in genetic testing and the recent identification of new adenomatous polyposis genes, many cases of multiple adenomas remain genetically unexplained. Non-genetic factors, including environmental risk factors, prior oncologic treatments, and bacterial genotoxins colonising the intestine - particularly colibactin-producing Escherichia coli - have emerged as alternative pathogenic mechanisms.

Colorectal cancer (CRC) is a significant global health concern, often challenging to treat effectively with conventional methods and burdened by adverse effects. Scorpion venoms offer a unique avenue for exploration, given their ability to disrupt the cell cycle, inhibit growth, and trigger apoptosis. This study delves into the impact of Mesobuthus eupeus (M. eupeus) scorpion venom on the proliferation and progression of colorectal cancer at the molecular level. The total protein concentration in the venom (607.5 µg/mL) also emphasized the rich composition and potential for therapeutic applications. The study reveals that M. eupeus venom effectively reduced the proliferation of DLD-1 and HT-29 colorectal cancer cells in a dose-dependent manner with IC50 values of 4.32 and 7.61 µg/mL, respectively. The venom also impedes cell migration, diminishes colony formation, and triggers apoptosis in the cancer cells. The venom also induced early and late apoptosis in the two cancer cell lines. The human colorectal cancer and apoptotic pathways were clarified at the molecular level using pathway panels, which revealed that 16 genes involved in colorectal cancer increased while 23 decreased. In the HT-29 cell line, 57 genes increased, and 1 decreased following venom treatment. Besides, the mRNA expression of 19 genes involved in the apoptotic pathway was increased, while 22 were reduced in DLD-1 cells. This study underscores the potential of M. eupeus venom as a natural therapeutic approach in the quest for cancer treatments.

Mesenchymal stem cells (MSCs) play a crucial role in bone formation and remodeling. Intrinsic genetic factors and extrinsic environmental cues regulate their differentiation into osteoblasts. Within the bone microenvironment, a complex network of biochemical and biomechanical signals orchestrates bone homeostasis and regeneration. In addition, the crosstalk among MSCs, immune cells, and neighboring cells-mediated by extracellular vesicles and non-coding RNAs (such as circular RNAs and micro RNAs) -profoundly influences osteogenic differentiation and bone remodeling. Recent studies have explored specific signaling pathways that contribute to effective bone regeneration, highlighting the potential of manipulating the bone microenvironment to enhance MSC functionality. The integration of advanced biomaterials, gene editing techniques, and controlled delivery systems is paving the way for more targeted and efficient regenerative therapies. Furthermore, artificial intelligence could improve bone tissue engineering, optimize biomaterial design, and enable personalized treatment strategies. This review explores the latest advancements in bone regeneration, emphasizing the intricate interplay among stem cells, immune cells, and signaling molecules. By providing a comprehensive overview of these mechanisms and their clinical implications, we aim to shed light on future research directions in this rapidly evolving field.

The molecular mechanisms regulating the zonal distribution of metabolism in liver are incompletely understood. Here we use single nuclei genomics techniques to examine the spatial transcriptional function of transcription factor 7-like 2 (TCF7L2) in mouse liver, and determine the consequences of TCF7L2 transcriptional inactivation on the metabolic architecture of the liver and the function of zonated metabolic pathways. We report that while Tcf7l2 mRNA expression is ubiquitous across the liver lobule, accessibility of the consensus TCF/LEF DNA binding motif is restricted to pericentral (PC) hepatocytes in zone 3. In mice expressing functionally inactive TCF7L2 in liver, PC hepatocyte-specific gene expression is absent, which we demonstrate promotes hepatic cholesterol accumulation, impaired bile acid synthesis, disruption to glutamine/glutamate homeostasis and pronounced dietary-induced hepatic fibrosis. In summary, TCF7L2 is a key regulator of hepatic zonal gene expression and regulates several zonated metabolic pathways that may contribute to the development of fibrotic liver disease.

The transcription factor MEIS1 belongs to the 3-amino acid loop extension (TALE) family of homeodomain proteins which plays various functions in normal and tumor cell progression. The canonical WNT/β-catenin pathway governs a plethora of biological processes including cell proliferation, differentiation, and tumor development. In the present study, the effect of MEIS1 gene silencing was assessed on WNT pathway genes in esophageal squamous cell carcinoma (ESCC) cells.

Along with the packaging plasmids, the pLKO.1-MEIS1 plasmid was cotransfected into HEK293T to generate lentiviral particles, followed by transduction of a semi-confluent KYSE-30 cell culture. After total RNA extraction and cDNA synthesis, comparative real-time PCR was applied to assess the efficiency of MEIS1 knockdown and the expression of genes related to the WNT signaling pathway.

The results revealed effective downregulation of MEIS1 in KYSE-30 cells. Interestingly, MEIS1 silencing led to a substantial overexpression of WNT pathway key components while the expression of negative regulators of this pathway was substantially decreased.

Our data suggest that MEIS1 gene probably induces WNT/β-catenin pathway deactivation in ESCC cells. Consequently, the inverse correlation of MEIS1 expression and WNT signaling pathway activation may introduce a new molecular linkage through ESCC progression and aggressiveness.

Plant extracts contain many small molecules that are less investigated. The present paper aims to study in silico physical-chemical, pharmacokinetic, medicinal chemistry and lead/drug-likeness properties and the ability to interfere with the activity of P-glycoprotein (P-gp) transporter and cytochrome P450 (CYP) oxidase system in humans of phloridzin, phloretin, 4-methylchalcone metabolic series alongside the top three compounds found in the ethanolic extract from strawberries (S), namely 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one, 2-pyrrolidinone 5-(cyclohexylmethyl) and hexadecanoic acid. The phloridzin derivatives also were studied for their inhibitory potential upon Bcl-2, TNKS1 and COX-2 molecular targets. In vitro, Caco-2 studies analyzed the cytoprotective and anti-proliferative activity of S and the three phloridzin derivatives (pure compounds) in comparison with their combination 1:1 (GAE/pure compound, w/w), in the range 1 to 50 µg active compounds per test sample. Altogether, it was concluded that phloretin (Phl) can be used alone or in combination with S to support intestinal cell health in humans. Phloridzin (Phd) and phloridzin combined with S were proven ineffective. 4-methylchalcone (4-MeCh) combined with S indicated no advantages, while the pure compound exhibited augmented inhibitory effects, becoming a candidate for combinations with anticancer drugs. Overall, in silico studies revealed possible limitations in the practical use of phloridzin derivatives due to their potential to interfere with the activity of several major CYP enzymes.

The study of short peptides in dentistry is a particularly promising area, due to their unique biological properties, such as antibacterial and antitumor activity, the ability to modulate immune responses, tissue regeneration processes, and their potential to stimulate stem cell differentiation. This study provides a systematic review aimed at analyzing the role of short peptides in the pathogenesis and treatment of oral diseases.

A systematic search was performed according to the PRISMA statement and employed the PICO(S) approach. The search was limited to English-language articles, and in vitro study were included in the electronic search. A comprehensive search was conducted across PubMed, Embase, Web of Science and Cochrane Library databases, without timeframe limits, resulting in a total of 1085 scientific articles. After duplicate removal, 563 unique papers remained for further analysis. Following this screening process, 19 studies were identified as relevant to the topic. A final selection of 9 scientific papers was made based on their study type and the specific peptide examined. One last article was eliminated in final analysis because the laboratory methodology is now refuted by more recent scientific evidence.

8 in vitro studies dealing with different short peptides with different biological functions against oral cavity cells and tissues were included. 4 articles highlighted the ability of short peptides to positively influence the proliferation of cells in the oral cavity. 2 articles highlighted the antitumour activity of short peptides. 1 article highlighted the antimicrobial activity of the peptide DJK-15. The last paper showed that Pep-B has anti-inflammatory properties towards the cells of the oral cavity.

However, the main short peptides that have been tested in vitro and that act on cells and tissues of the oral cavity are the focus of this systematic review. It can therefore be used as a basis for a possible hypothesis of new in vitro studies to compare the different molecules, for new in vivo studies and for the investigation of potential action mechanisms and applications for new drugs to combat diseases of the oral cavity.

Not applicable.

Most molecular classifications of cancer are based on bulk-tissue profiles that measure an average over many distinct cell types. As such, cancer subtypes inferred from transcriptomic or epigenetic data are strongly influenced by cell-type composition and do not necessarily reflect subtypes defined by cell-type-specific cancer-associated alterations, which could lead to suboptimal cancer classifications.

To address this problem, we here propose the novel concept of cell-type-specific combinatorial clustering (CELTYC), which aims to group cancer samples by the molecular alterations they display in specific cell types. We illustrate this concept in the context of DNA methylation data of liver and kidney cancer, deriving in each case novel cancer subtypes and assessing their prognostic relevance against current state-of-the-art prognostic models.

In both liver and kidney cancer, we reveal improved cell-type-specific prognostic models, not discoverable using standard methods. In the case of kidney cancer, we show how combinatorial indexing of epithelial and immune-cell clusters define improved prognostic models driven by synergy of high mitotic age and altered cytokine signaling. We validate the improved prognostic models in independent datasets and identify underlying cytokine-immune-cell signatures driving poor outcome.

In summary, cell-type-specific combinatorial clustering is a valuable strategy to help dissect and improve current prognostic classifications of cancer in terms of the underlying cell-type-specific epigenetic and transcriptomic alterations.

Nuclear expression of CTNNB1 is occasionally negative in solid-pseudopapillary neoplasm (SPN) of the pancreas, leading to a missed diagnosis. In the present study, we aimed to investigate the clinical significance of CTNNB1 mutation detection for diagnosing SPN and explore the difference in clinicopathological characteristics at different ages and sex.

Patients who underwent surgery for a pathologically confirmed SPN in our institution between 2011 and 2020 were collected. Their clinicopathological data were analyzed.

The median age of the 179 patients was 31 years (6-64 years), including 34 pediatric patients (19.0%), and 32 patients were male (17.9%). We detected point mutations in exon 3 of CTNNB1 in 74.3% (133/179) of SPNs by Sanger sequencing. The main mutation sites were D32, S33, S37, G34 and T41. In the three SPNs without nuclear expression of CTNNB1, Sanger sequencing showed point mutations of CTNNB1. NGS did not detect any consistent mutation except CTNNB1 in the three cases. The tumor size, Ki-67 index, and the negative rates of CTNNB1 nuclear expression and synaptophysin expression in the pediatric group were higher than those in other groups (p < .05).

For atypical cases, testing for CTNNB1 mutations can help in the accurate diagnosis of SPN. Compared with adult patients, pediatrics with SPN may be more prone to recurrence, and their immunohistochemical phenotype is more complex, requiring additional care in the diagnosis and postoperative follow-up.

Vascular calcification contributes to increased cardiovascular morbidity and mortality in patients with chronic kidney disease, diabetes, and atherosclerosis. Currently, there are no effective therapeutic strategies to prevent or reverse vascular calcification. TRPV4 (transient receptor potential channel V4), a key Ca2+-permeable channel, plays an important role in various diseases. However, the role and mechanism of TRPV4 in vascular calcification have not yet been elucidated.

The effects of TRPV4 on vascular calcification were explored in vitro and in vivo. TRPV4 interactome assessment and molecular docking were performed to investigate the mechanism and specific therapeutic strategy for vascular calcification.

TRPV4 was substantially upregulated in high inorganic phosphate-induced calcified vascular smooth muscle cells (SMCs) and calcified aortas from cholecalciferol (vitamin D3)-overloaded mice. TRPV4 overexpression increased the expression of the osteochondrogenic markers Runx2 (runt-related transcription factor 2), Msx2 (Msh homeobox 2), and Sox9 (SRY-box transcription factor 9) and exacerbated high inorganic phosphate-induced vascular SMC calcification in a Ca2+ influx-dependent manner. In contrast, TRPV4 deficiency or inactivation significantly inhibited vascular SMC calcification under high inorganic phosphate conditions. Moreover, compared with that in control littermates, SMC-specific TRPV4 deficiency in mice alleviated vitamin D3-induced and 5/6 nephrectomy-induced vascular calcification. Mechanistically, TRPV4 interacted with β-catenin and activated β-catenin/TCF (T-cell factor) transcriptional activity via Ca2+/ASK1 (apoptosis signal regulating kinase 1)/p38 signaling. β-Catenin knockdown abolished the effects of TRPV4 overexpression on vascular SMC calcification. TRPV4/β-catenin interaction is pivotal for maintaining TRPV4/Ca2+-induced ASK1/p38/β-catenin activation. Hesperidin, a natural product found in citrus fruits, effectively disrupted TRPV4/β-catenin interaction, thereby inhibiting ASK1/p38/β-catenin activity and preventing vascular calcification.

Our study identified TRPV4 as a new pathogenic factor for vascular calcification that directly associates with and activates β-catenin. Blocking the TRPV4/β-catenin interaction through hesperidin suppressed the progression of vascular calcification and may be an effective precision strategy to address vascular calcification.

Glioblastoma (GBM) is recognized as the most lethal primary malignant tumor of the central nervous system. Although traditional treatments can somewhat prolong patient survival, the overall prognosis remains grim. Immunotherapy has become an effective method for GBM treatment. Oncolytic virus, checkpoint inhibitors, CAR T cells and tumor vaccines have all been applied in this field. Moreover, the combining of immunotherapy with traditional radiotherapy, chemotherapy, or gene therapy can further improve the treatment outcome. This review systematically summarizes the features of GBM, the recent progress of immunotherapy in overcoming GBM.

Cardiac fibroblasts (CFs) are the essential cell type for heart morphogenesis and homeostasis. In addition to maintaining the structural integrity of the heart tissue, muscle fibroblasts are involved in complex signaling cascades that regulate cardiomyocyte proliferation, migration, and maturation. While CFs serve as the primary source of extracellular matrix proteins (ECM), tissue repair, and paracrine signaling, they are also responsible for adverse pathological changes associated with cardiovascular disease. Following activation, fibroblasts produce excessive ECM components that ultimately lead to fibrosis and cardiac dysfunction. Decades of research have led to a much deeper understanding of the role of CFs in cardiogenesis. Recent studies using the single-cell genomic approach have focused on advancing the role of CFs in cellular interactions, and the mechanistic implications involved during cardiovascular development and disease. Arguably, the unique role of fibroblasts in development, tissue repair, and disease progression categorizes them into the friend or foe category. This brief review summarizes the current understanding of cardiac fibroblast biology and discusses the key findings in the context of development and pathophysiological conditions.

Cancer remains a significant global health challenge, with current chemotherapeutic strategies frequently limited by the emergence of resistance. In this context, natural compounds with the potential to overcome resistance have garnered considerable attention. Among these, sesquiterpene lactones, primarily derived from plants in the Asteraceae family, stand out for their potential anticancer properties. This review specifically focuses on five key signaling pathways: PI3K/Akt/mTOR, NF-κB, Wnt/β-catenin, MAPK/ERK, and STAT3, which play central roles in the mechanisms of cancer resistance. For each of these pathways, we detail their involvement in both cancer development and the emergence of drug resistance. Additionally, we investigate how sesquiterpene lactones modulate these pathways to overcome resistance across diverse cancer types. These insights highlight the potential of sesquiterpene lactones to drive the advancement of novel therapies that can effectively combat both cancer progression and drug resistance.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and a leading cause of cancer-related mortality worldwide. Genetic alterations play a critical role in hepatocarcinogenesis, with mutations in the telomerase reverse transcriptase promoter (TERTp) and CTNNB1 exon 3 representing two of the most frequently reported somatic events in HCC. However, the frequency and distribution of these mutations vary across geographic regions and viral etiologies, particularly hepatitis B virus (HBV) and hepatitis C virus (HCV). This study aimed to assess the global distribution and etiological associations of TERTp and CTNNB1 exon 3 mutations in HCC through a comprehensive literature review. Our analysis, encompassing over 4000 HCC cases, revealed that TERTp mutations were present in 49.2% of tumors, with C228T being the predominant variant (93.3% among mutated cases). A striking contrast was observed between viral etiologies: TERTp mutations were detected in 31.6% of HBV-related HCCs, compared to 66.2% in HCV-related cases. CTNNB1 exon 3 mutations were identified in 23.1% of HCCs, showing a similar association with viral etiology, being more common in HCV-related cases (30.7%) than in HBV-related tumors (12.8%). Geographically, both mutations exhibited comparable patterns, with higher frequencies in Europe, Japan, and the USA, while lower rates were observed in China, Taiwan, and South Korea. Our findings underscore the distinct molecular profiles of HCC according to viral etiology and geographic origin, highlighting the need for region- and etiology-specific approaches to HCC prevention, diagnosis, and targeted therapy.

Congenital heart defects are structural anomalies present at birth that can affect the function of the heart. Aneuploidy is a significant risk factor for congenital heart defects. Mosaic variegated aneuploidy syndrome, caused by mutations in Bub1b (encoding BubR1, a mitotic checkpoint protein), leads to congenital heart defects such as septal defects. However, the molecular rationale for how Bub1b mutations promote congenital heart defects associated with mosaic variegated aneuploidy syndrome remains unresolved.

To study morphological, structural, and cellular consequences of BubR1 deletion in the heart, we crossed mice carrying conditional alleles of Bub1b with Nkx2.5-cre mice. Single-cell RNA sequencing was carried out to determine differentially expressed genes and biological processes in various cell types present in the developing heart. Trajectory analysis was carried out to determine the differentiation trajectory of BubR1 knockout embryonic hearts. Finally, CellChat analysis provided details on the major signaling interactions that were either absent or hyperactive in the BubR1 knockout heart.

Here, we show that cardiac-specific BubR1 deletion causes embryonic lethality due to developmental stalling after cardiac looping with defects in cardiac maturation including chamber wall thickness, septation, and trabeculation. Single-cell transcriptomic profiling further revealed that the differentiation trajectory of cardiomyocytes is severely impacted with suppression of critical cardiogenesis genes. Hyperactivation of Wnt signaling in BubR1 knockout hearts indicated a disturbed homeostasis in cellular pathways essential for proper tissue morphogenesis of the heart.

Taken together, these findings reveal that BubR1 is a crucial regulator of cardiac development in vivo, which ensures the proper timing of heart morphogenesis.

Poly-ADP-ribosylation (PARylation) is a post-translational modification in which ADP-ribose is added to substrate proteins. PARylation is mediated by a superfamily of ADP-ribosyl transferases known as PARPs and influences a wide range of cellular functions, including genome integrity maintenance, and the regulation of proliferation and differentiation. We and others have recently reported that PARylation of SH3 domain-binding protein 2 (3BP2) plays a role in bone metabolism, immune system regulation, and cytokine production. Additionally, PARylation has recently gained attention as a target for cancer treatment. In this review, we provide an overview of PARylation, its involvement in several signaling pathways related to cancer immunity, and the potential of combination therapies with PARP inhibitors and immune checkpoint inhibitors.

Aberrant Wnt pathway activation is a key driver of colorectal cancer (CRC) and is essential to sustain tumour growth and progression. Although the downstream protein-coding target genes of the Wnt cascade are well known, the long non-coding transcriptome has not yet been fully resolved.

In this study, we aim to comprehensively reveal the Wnt-regulated long non-coding transcriptome and exploit essential molecules as novel therapeutic targets.

We used global run-on sequencing to define β-catenin-regulated long non-coding RNAs (lncRNAs) in CRC. CRISPRi dropout screens were subsequently used to establish the functional relevance of a subset of these lncRNAs for long-term expansion of CRC.

We uncovered that LINC02418 is essential for cancer cell clonogenic outgrowth. Mechanistically, LINC02418 regulates MYC expression levels to promote CRC stem cell functionality and prevent terminal differentiation. Furthermore, we developed effective small interfering RNA (siRNA)-based therapeutics to target LINC02418 RNA in vivo.

We propose that cancer-specific Wnt-regulated lncRNAs provide novel therapeutic opportunities to interfere with the Wnt pathway, which has so far defied effective pharmacological inhibition.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, necessitating the continuous evolution of therapeutic approaches. Despite advancements in early detection and localized treatments, metastatic colorectal cancer (mCRC) poses significant challenges due to low survival rates and resistance to conventional therapies. This review highlights the current landscape of CRC treatment, focusing on chemotherapy and targeted therapies. Chemotherapeutic agents, including 5-fluorouracil, irinotecan, and oxaliplatin, have significantly improved survival but face limitations such as systemic toxicity and resistance. Targeted therapies, leveraging mechanisms like VEGF, EGFR, and Hedgehog pathway inhibition, offer promising alternatives, minimizing damage to healthy tissues while enhancing therapeutic precision. Furthermore, future directions in CRC treatment include exploring innovative targets such as Wnt/β-catenin, Notch, and TGF-β pathways, alongside IGF/IGF1R inhibition. These emerging strategies aim to address drug resistance and improve patient outcomes. This review emphasizes the importance of integrating molecular insights into drug development, advocating for a more personalized approach to combat CRC's complexity and heterogeneity.

Amino acid transporters are essential for supplying nutrients to cells and are implicated in tumor progression. L-type amino acid transporter 1 (LAT1) is reported to be overexpressed in various cancers, affecting tumor development. However, the exact mechanisms by which LAT1 affects colorectal cancer (CRC) arising from a chronic inflammatory background are not yet fully understood. This study aimed to explore the role of LAT1 in CRC. Mice with intestinal epithelium-specific deletions of LAT1 (LAT1fl/fl; vil-cre) were treated with azoxymethane (AOM)/dextran sulfate sodium (DSS) in a colitis-associated cancer (CAC) model. Our results demonstrated that LAT1 was detected in normal colon crypts and highly expressed in AOM/DSS-induced tumor tissue. During the chronic colitis phase, weight loss was more prominent in LAT1fl/fl; vil-cre mice, compared with that in LAT1fl/fl mice. IL-1β and IL-6 expressions significantly increased in LAT1-deleted tumors; however, no overall difference in colon tumor number or size was observed between LAT1fl/fl and LAT1fl/fl; vil-cre mice. Accordingly, cell proliferation and apoptotic cell number were similar when comparing LAT1-deleted tumors with those with sufficient LAT1. Our findings indicated that LAT1 might not phenotypically affect overall colonic tumor development in this model; however, it affected the chronic colitis phase and inflammatory status within the tumors. These findings suggest that severe inflammation in tumors might have compensated for tumor growth in defects of amino acid supplementation through LAT1 deficiency, and provide insights into the potential of LAT1-targeted therapies for clinical CRC treatment.

Cancer drug resistance, encompassing both acquired and intrinsic chemoresistance, remains a significant challenge in the clinical management of tumors. While advancements in drug discovery and the development of various small molecules and anti-cancer compounds have improved patient responses to chemotherapy, the frequent and prolonged use of these drugs continues to pose a high risk of developing chemoresistance. Therefore, understanding the primary mechanisms underlying drug resistance is crucial. Wnt proteins, as secreted signaling molecules, play a pivotal role in transmitting signals from the cell surface to the nucleus. Aberrant expression of Wnt proteins has been observed in a variety of solid and hematological tumors, where they contribute to key processes such as proliferation, metastasis, stemness, and immune evasion, often acting in an oncogenic manner. Notably, the role of the Wnt signaling pathway in modulating chemotherapy response in human cancers has garnered significant attention. This review focuses on the involvement of Wnt signaling and its related molecular pathways in drug resistance, highlighting their associations with cancer hallmarks, stemness, and tumorigenesis linked to chemoresistance. Additionally, the overexpression of Wnt proteins has been shown to accelerate cancer drug resistance, with regulation mediated by non-coding RNAs. Elevated Wnt activity reduces cell death in cancers, particularly by affecting mechanisms like apoptosis, autophagy, and ferroptosis. Furthermore, pharmacological compounds and small molecules have demonstrated the potential to modulate Wnt signaling in cancer therapy. Given its impact, Wnt expression can also serve as a prognostic marker and a factor influencing survival outcomes in human cancers.