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The study aimed to elucidate the underlying pharmacological mechanism of the traditional Chinese medicine Pue in ameliorating myocardial ischemia-reperfusion injury (MIRI), a critical clinical challenge exacerbated by reperfusion therapy. In vivo MIRI and in vitro anoxia/reoxygenation (A/R) models were constructed. The results demonstrated that Pue pretreatment effectively alleviated MIRI, as manifested by diminishing the levels of serum CK-MB and LDH, mitigating the extent of myocardial infarction and enhancing cardiac functionality. Additionally, Pue significantly alleviated histopathological damage in MIRI-treated myocardium, as evidenced by HE staining and TUNEL assay. In vitro, Pue pretreatment significantly alleviated A/R-induced damage by decreasing LDH levels, increasing cellular activity, inhibiting autophagic lysosomal overactivation, inhibiting oxidative stress (ROS, LIP ROS, MDA), increasing antioxidant defense (SOD, GSH-Px), and increasing P62 protein expression while decreasing LC3II/I ratio. Furthermore, Pue inhibited apoptosis and maintained mitochondrial homeostasis by up-regulating the expression of Hairy and Enhancer of Split-1 (HES1) protein, which was crucial for its cardioprotective effects. Nevertheless, the cardioprotective efficacy of Pue pretreatment was negated via the knockdown of HES1 protein expression via pAD/HES1-shRNA transfection. In conclusion, Pue effectively ameliorated HES1-mediated MIRI-induced autophagy, apoptosis, and mitochondrial dysfunction.

Sirtuin 3 (SIRT3) deacetylase is a key regulator for chemoresistance in acute myeloid leukemia (AML) cells due to its capability of modulating mitochondrial metabolism and reactive oxygen species (ROS). SIRT3 is de-SUMOylated by SUMO-specific peptidase 1 (SENP1), which enhances its deacetylase activity. Therefore, dysregulation of SIRT3 SUMOylation may lead to fortified chemoresistance in AML. Indeed, SIRT3 de-SUMOylation was induced by chemotherapeutic agents, which in turn, exacerbated resistance against chemotherapies in AML by activating SIRT3 via preventing its proteasome degradation. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation including inhibition of transcription factor Hes Family BHLH Transcription Factor 1 (HES1), a downstream substrate of Notch1 signaling pathway, leading to increased fatty acids oxidation (FAO). Moreover, the SENP1 inhibitor momordin-Ic or HES1 overexpression synergized with cytarabine to eradicate AML cells in vitro and in xenograft mouse models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in the regulation of chemoresistance in AML via HES1-dependent FAO and provided a rationale for SIRT3 SUMOylation and FAO targeted interventions to improve chemotherapies in AML.

NOTCH1, NOTCH2, NOTCH3 and NOTCH4 are transmembrane receptors that transduce juxtacrine signals of the delta-like canonical Notch ligand (DLL)1, DLL3, DLL4, jagged canonical Notch ligand (JAG)1 and JAG2. Canonical Notch signaling activates the transcription of BMI1 proto-oncogene polycomb ring finger, cyclin D1, CD44, cyclin dependent kinase inhibitor 1A, hes family bHLH transcription factor 1, hes related family bHLH transcription factor with YRPW motif 1, MYC, NOTCH3, RE1 silencing transcription factor and transcription factor 7 in a cellular context-dependent manner, while non-canonical Notch signaling activates NF-κB and Rac family small GTPase 1. Notch signaling is aberrantly activated in breast cancer, non-small-cell lung cancer and hematological malignancies, such as T-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. However, Notch signaling is inactivated in small-cell lung cancer and squamous cell carcinomas. Loss-of-function NOTCH1 mutations are early events during esophageal tumorigenesis, whereas gain-of-function NOTCH1 mutations are late events during T-cell leukemogenesis and B-cell lymphomagenesis. Notch signaling cascades crosstalk with fibroblast growth factor and WNT signaling cascades in the tumor microenvironment to maintain cancer stem cells and remodel the tumor microenvironment. The Notch signaling network exerts oncogenic and tumor-suppressive effects in a cancer stage- or (sub)type-dependent manner. Small-molecule γ-secretase inhibitors (AL101, MRK-560, nirogacestat and others) and antibody-based biologics targeting Notch ligands or receptors [ABT-165, AMG 119, rovalpituzumab tesirine (Rova-T) and others] have been developed as investigational drugs. The DLL3-targeting antibody-drug conjugate (ADC) Rova-T, and DLL3-targeting chimeric antigen receptor-modified T cells (CAR-Ts), AMG 119, are promising anti-cancer therapeutics, as are other ADCs or CAR-Ts targeting tumor necrosis factor receptor superfamily member 17, CD19, CD22, CD30, CD79B, CD205, Claudin 18.2, fibroblast growth factor receptor (FGFR)2, FGFR3, receptor-type tyrosine-protein kinase FLT3, HER2, hepatocyte growth factor receptor, NECTIN4, inactive tyrosine-protein kinase 7, inactive tyrosine-protein kinase transmembrane receptor ROR1 and tumor-associated calcium signal transducer 2. ADCs and CAR-Ts could alter the therapeutic framework for refractory cancers, especially diffuse-type gastric cancer, ovarian cancer and pancreatic cancer with peritoneal dissemination. Phase III clinical trials of Rova-T for patients with small-cell lung cancer and a phase III clinical trial of nirogacestat for patients with desmoid tumors are ongoing. Integration of human intelligence, cognitive computing and explainable artificial intelligence is necessary to construct a Notch-related knowledge-base and optimize Notch-targeted therapy for patients with cancer.

The transcription factor receptor‐interacting protein 140 (RIP140) regulates intestinal homeostasis and tumorigenesis through Wnt signaling. In this study, we investigated its effect on the Notch/HES1 signaling pathway. In colorectal cancer (CRC) cell lines, RIP140 positively regulated HES1 gene expression at the transcriptional level via a recombining binding protein suppressor of hairless (RBPJ)/neurogenic locus notch homolog protein 1 (NICD)‐mediated mechanism. In support of these in vitro data, RIP140 and HES1 expression significantly correlated in mouse intestine and in a cohort of CRC samples, thus supporting the positive regulation of HES1 gene expression by RIP140. Interestingly, when the Notch pathway is fully activated, RIP140 exerted a strong inhibition of HES1 gene transcription controlled by the level of HES1 itself. Moreover, RIP140 directly interacts with HES1 and reversed its mitogenic activity in human CRC cells. In line with this observation, HES1 levels were associated with a better patient survival only when tumors expressed high levels of RIP140. Our data identify RIP140 as a key regulator of the Notch/HES1 signaling pathway, with a dual effect on HES1 gene expression at the transcriptional level and a strong impact on colon cancer cell proliferation. The authors show that the transcription factor RIP140 exerts a dual effect on HES1 gene transcription: an increase via an RBPJ/NICD‐mediated mechanism, and a strong inhibition controlled by the level of HES1 itself. Consequently, RIP140 participates in HES1 oscillatory expression, and controls its mitogenic activity and prognostic value in breast cancers.

Rotator cuff tendon injuries often lead to shoulder pain and dysfunction. Traditional treatments such as surgery and physical therapy can provide temporary relief, but it is difficult to achieve complete healing of the tendon, mainly because of the limited repair capacity of the tendon cells. Therefore, it is particularly urgent to explore new treatment methods. In vitro experiments were performed to explore the mechanism of differentiation of umbilical cord mesenchymal stem cells (UCMSCs) to tendon cells and to evaluate their potential in promoting rotator cuff injury repair. Growth factors such as CTGF, GDF-6, and GDF-7 were used to induce the differentiation of UCMSCs, and gene expression changes during the differentiation process were analyzed by single-cell sequencing. Hes1 overexpression and animal models were constructed to study its role in UCMSCs differentiation and rotator cuff injury repair. CTGF was the optimal factor for inducing the differentiation of UCMSCs into tendon cells. With increasing induction time, UCMSCs exhibited obvious tendon cell characteristics, such as changes in cell morphology and increased expression of tendon-specific proteins (MKX, SCX, and TNC). Single-cell sequencing analysis revealed key cellular subpopulations and signaling pathways during differentiation. Furthermore, overexpression of the Hes1 gene significantly promoted the differentiation of UCMSCs to tendon cells and showed its therapeutic effect in rotator cuff injury repair in an animal model. This study confirmed the potential of UCMSCs in tendon injury repair, especially the critical role of Hes1 in promoting UCMSCs differentiation and rotator cuff tendon-bone healing, which provides a theoretical basis and experimental rationale for the development of new cellular therapeutic strategies.

Doxorubicin (DOX) is an effective chemotherapeutic drug; however, its cardiotoxicity and resistance compromise its therapeutic index. The Notch pathway was reported to contribute to DOX cancer resistance. The role of Notch pathway in DOX cardiotoxicity has not been identified yet. Notch receptors are characterized by their extracellular (NECD) and intracellular (NICD) domains (NICD). The γ-secretase enzyme helps in the release of NICD. Dibenzazepine (DBZ) is a γ-secretase inhibitor. The present study investigated the effect of Notch pathway inhibition on DOX cardiotoxicity. Twenty-four male Wistar rats were divided into four groups: control group, DOX group, acute cardiotoxicity was induced by a single dose of DOX (20 mg/kg) i.p., DOX (20 mg/kg) plus DBZ group, and DBZ group. The third and fourth groups received i.p. injection of DBZ daily for 14 days at 2 mg/kg dose. DOX cardiotoxicity increased the level of serum creatine kinase-MB and cardiac troponin I, and it was confirmed by the histopathological examination. Moreover, the antioxidants glutathione peroxidase and superoxide dismutase levels were markedly decreased, and the inflammatory markers, inducible nitric oxide synthase, nuclear factor-ķB, and tumor necrosis factor-α were markedly increased. Furthermore, DOX increased BAX protein and downregulated BCL-2. In addition, DOX upregulated Notch pathway-related parameters: Hes1 and Hey1 mRNA levels, and increased Hes1 protein levels. DBZ ameliorated DOX-induced cardiotoxicity, evidenced by reducing the cardiac injury biomarkers, improving cardiac histopathological changes, correcting antioxidant levels, and reducing inflammatory and apoptotic proteins. Our study indicates the protective effect of Notch inhibitor against DOX-induced cardiotoxicity.

Ageing‐related osteoporosis is becoming an emerging threat to human health along with the ageing of human population. The decreased rate of osteogenic differentiation and bone formation is the major cause of ageing‐related osteoporosis. Microtubule actin cross‐linking factor 1 (MACF1) is an important cytoskeletal factor that promotes osteogenic differentiation and bone formation. However, the relationship between MACF1 expression and ageing‐related osteoporosis remains unclear. This study has investigated the expression pattern of MACF1 in bone tissues of ageing‐related osteoporosis patients and ageing mice. The study has further elucidated the mechanism of MACF1 promoting bone formation by inhibiting HES1 expression and activity. Moreover, the therapeutic effect of MACF1 on ageing‐related osteoporosis and post‐menopausal osteoporosis was evaluated through in situ injection of the MACF1 overexpression plasmid. The study supplemented the molecular mechanisms between ageing and bone formation, and provided novel targets and potential therapeutic strategy for ageing‐related osteoporosis.

The corneal homeostasis is maintained by limbal epithelial stem cells (LESCs), which reside in the limbal niche. This microenvironment comprises the cells, the extracellular matrix (ECM), and their interactions that balance the quiescent and proliferative states of LESCs. The stress caused by removing the cells from their niche triggers the quiescent stem cells to enter the proliferative state, which is beneficial for expansion, but reduces their self-renewal capability, making them less suitable for transplantation. Fibronectin (FN), a key ECM component, widely used in tissue engineering and scaffold structure, has been shown to preserve the self-renewal ability of LESCs . In parallel, paracrine growth factors are crucial for maintaining limbal niche homeostasis and promoting corneal epithelial regeneration. Limbal-niche-cells-conditioned media is a potential reservoir of limbal niche paracrine growth factors. However, whether utilizing fibronectin and limbal-niche-cells-conditioned media can sustain or enhance the stemness and proliferation ability of LESCs has not yet been investigated. Primary cultures of limbal niche cells, including LESCs, limbal mesenchymal stromal cells (LMSCs), and limbal melanocytes (LM), were established from remnant human corneal transplant specimens, and human epidermal melanocytes (HEMn) were included as a negative control. The proliferation ability (doubling time) and self-renewal potential (as assessed by and gene expressions) of LESCs were evaluated after culture in LM-, LMSC-, and HEMn-conditioned media, as well as coating with 3, 5, and 8 µg/cm concentrations of FN. Compared to the control group, the LMSC- and LM-conditioned media showed a clear trend towards upregulated and gene expressions. FN coating generally upregulated the expression of and genes, with this effect being most prominent at 3 µg/cm . These findings illustrate the potential of utilizing niche-cell-conditioned media and direct contact with FN on the self-renewal of LESCs . Further research is required to provide a more comprehensive understanding of these effects and to elucidate the underlying mechanisms of action.

Tle1 (transducin-like enhancer of split 1) is a corepressor that interacts with a variety of DNA-binding transcription factors and has been implicated in many cellular functions; however, physiological studies are limited. Tle1-deficient (Tle1Δ/Δ ) mice, although grossly normal at birth, exhibit skin defects, lung hypoplasia, severe runting, poor body condition, and early mortality. Tle1Δ/Δ mice display a chronic inflammatory phenotype with increased expression of inflammatory cytokines and chemokines in the skin, lung, and intestine and increased circulatory IL-6 and G-CSF, along with a hematopoietic shift toward granulocyte macrophage progenitor and myeloid cells. Tle1Δ/Δ macrophages produce increased inflammatory cytokines in response to Toll-like receptor (TLR) agonists and lipopolysaccharides (LPS), and Tle1Δ/Δ mice display an enhanced inflammatory response to ear skin 12-O-tetradecanoylphorbol-13-acetate treatment. Loss of Tle1 not only results in increased phosphorylation and activation of proinflammatory NF-κB but also results in decreased Hes1 (hairy and enhancer of split-1), a negative regulator of inflammation in macrophages. Furthermore, Tle1Δ/Δ mice exhibit accelerated growth of B6-F10 melanoma xenografts. Our work provides the first in vivo evidence, to our knowledge, that TLE1 is a major counterregulator of inflammation with potential roles in a variety of inflammatory diseases and in cancer progression.

Here, we study the dynamical expression of endogenously labeled Hes1, a transcriptional repressor implicated in controlling cell proliferation, to understand how cell-cycle length heterogeneity is generated in estrogen receptor (ER)⁺ breast cancer cells. We find that Hes1 shows oscillatory expression with ∼25 h periodicity and during each cell cycle has a variable peak in G1, a trough around G1–S transition, and a less variable second peak in G2/M. Compared to other subpopulations, the cell cycle in CD44HighCD24Low cancer stem cells is longest and most variable. Most cells divide around the peak of the Hes1 expression wave, but preceding mitoses in slow dividing CD44HighCD24Low cells appear phase-shifted, resulting in a late-onset Hes1 peak in G1. The position, duration, and shape of this peak, rather than the Hes1 expression levels, are good predictors of cell-cycle length. Diminishing Hes1 oscillations by enforcing sustained expression slows down the cell cycle, impairs proliferation, abolishes the dynamic expression of p21, and increases the percentage of CD44HighCD24Low cells. Reciprocally, blocking the cell cycle causes an elongation of Hes1 periodicity, suggesting a bidirectional interaction of the Hes1 oscillator and the cell cycle. We propose that Hes1 oscillations are functionally important for the efficient progression of the cell cycle and that the position of mitosis in relation to the Hes1 wave underlies cell-cycle length heterogeneity in cancer cell subpopulations.