Malignant proliferating liver cancer cells possess the ability to detect and respond to various body signals, thereby facilitating tumor growth, invasion, and metastasis. One crucial mechanism through which hepatocellular carcinoma (HCC) cells interpret these signals is crosstalk. Within liver cancer tissues, cancer cells engage in communication with hepatic stellate cells (HSCs), tumor-associated macrophages (TAMs), and immune cells. This interaction plays a pivotal role in regulating the proliferation, invasion, and metastasis of HCC cells. Crosstalk occurs in multiple ways, each characterized by distinct functions. Its molecular mechanisms primarily involve regulating immune cell functions through the expression of specific receptors, such as CD24 and CD47, modulating cell functions by secreting cytokines like transforming growth factor-β (TGF-β) and platelet-derived growth factor (PDGF), and mediating cell growth and proliferation by activating pathways such as Wnt/β-catenin and Hedgehog. A comprehensive understanding of the mechanisms and interactions within crosstalk is essential for unraveling the pathogenesis of HCC. It also opens up new avenues for the development of innovative therapeutic strategies. This article reviews the relationship between crosstalk and the progression of HCC, offering insights and inspiration for future research.
Humans ; Carcinoma, Hepatocellular/metabolism* ; Liver Neoplasms/metabolism* ; Hepatic Stellate Cells/physiology* ; Disease Progression ; Signal Transduction/physiology* ; Transforming Growth Factor beta/metabolism* ; Cell Proliferation ; Hedgehog Proteins/metabolism* ; Tumor-Associated Macrophages ; Platelet-Derived Growth Factor/metabolism* ; Cell Communication/physiology*

Human's robust cognitive abilities, including creativity and language, are made possible, at least in large part, by evolutionary changes made to the cerebral cortex. This paper reviews the biology and evolution of mammalian cortical radial glial cells (primary neural stem cells) and introduces the concept that a genetically step wise process, based on a core molecular pathway already in use, is the evolutionary process that has molded cortical neurogenesis. The core mechanism, which has been identified in our recent studies, is the extracellular signal-regulated kinase (ERK)-bone morphogenic protein 7 (BMP7)-GLI3 repressor form (GLI3R)-sonic hedgehog (SHH) positive feedback loop. Additionally, I propose that the molecular basis for cortical evolutionary dwarfism, exemplified by the lissencephalic mouse which originated from a larger gyrencephalic ancestor, is an increase in SHH signaling in radial glia, that antagonizes ERK-BMP7 signaling. Finally, I propose that: (1) SHH signaling is not a key regulator of primate cortical expansion and folding; (2) human cortical radial glial cells do not generate neocortical interneurons; (3) human-specific genes may not be essential for most cortical expansion. I hope this review assists colleagues in the field, guiding research to address gaps in our understanding of cortical development and evolution.
Humans ; Animals ; Biological Evolution ; Cerebral Cortex/metabolism* ; Neurogenesis/physiology* ; Signal Transduction/physiology* ; Hedgehog Proteins/metabolism* ; Ependymoglial Cells/physiology*

Global developmental delay (GDD) and intellectual disability (ID) refer to deficits in cognitive and adaptive functioning that arise during the developmental period. GDD/ID is often accompanied by complex developmental abnormalities, with congenital craniofacial malformations being among the most common, such as craniosynostosis, cleft lip and palate, and congenital tooth agenesis. However, the underlying mechanisms of GDD/ID associated with congenital craniofacial malformations remain unclear. With the increasing number of reported genetic syndromes, genetic factors are emerging as key contributors to the concurrent abnormalities in brain and craniofacial development. Studies have identified Wnt, SHH, FGF, and BMP as classical regulatory molecules in craniofacial development, and their roles have also been closely linked to various stages of brain development. This review focuses on the regulatory roles of Wnt, SHH, FGF, and BMP signaling pathways in brain and craniofacial development, as well as the pathogenic mechanisms underlying their association with GDD/ID and craniofacial malformations. The aim is to provide new insights into the etiology of GDD/ID combined with congenital craniofacial malformations.
Humans ; Craniofacial Abnormalities/complications* ; Signal Transduction ; Developmental Disabilities/metabolism* ; Intellectual Disability/complications* ; Animals ; Hedgehog Proteins/genetics* ; Fibroblast Growth Factors/genetics*

The seat of human intelligence is the human cerebral cortex, which is responsible for our exceptional cognitive abilities. Identifying principles that lead to the development of the large-sized human cerebral cortex will shed light on what makes the human brain and species so special. The remarkable increase in the number of human cortical pyramidal neurons and the size of the human cerebral cortex is mainly because human cortical radial glial cells, primary neural stem cells in the cortex, generate cortical pyramidal neurons for more than 130 days, whereas the same process takes only about 7 days in mice. The molecular mechanisms underlying this difference are largely unknown. Here, we found that bone morphogenic protein 7 (BMP7) is expressed by increasing the number of cortical radial glial cells during mammalian evolution (mouse, ferret, monkey, and human). BMP7 expression in cortical radial glial cells promotes neurogenesis, inhibits gliogenesis, and thereby increases the length of the neurogenic period, whereas Sonic Hedgehog (SHH) signaling promotes cortical gliogenesis. We demonstrate that BMP7 signaling and SHH signaling mutually inhibit each other through regulation of GLI3 repressor formation. We propose that BMP7 drives the evolutionary expansion of the mammalian cortex by increasing the length of the neurogenic period.
Animals ; Mice ; Humans ; Ependymoglial Cells/metabolism* ; Hedgehog Proteins/metabolism* ; Ferrets/metabolism* ; Cerebral Cortex ; Neurogenesis ; Mammals/metabolism* ; Neuroglia/metabolism* ; Bone Morphogenetic Protein 7/metabolism*

The Hedgehog(Hh) signaling pathway has the functions of improving embryogenesis and maintaining tissue homeostasis. By influencing the tumor microenvironment, intervening in cell apoptosis, and regulating angiogenesis, it is pivotal in the occurrence, progression, and recovery of various tumors. Therefore, targeting and inhibiting the abnormal activation of the Hh pathway has become a potential research strategy for alleviating and treating cancer. Currently, traditional Chinese medicine(TCM) is highly favored for treating cancer and other challenging and severe diseases due to its advantages, such as minimal side effects, high efficacy, lack of dependency, and the ability to address both symptoms and underlying causes. This review aimed to provide a scientific foundation and research ideas for the prevention and treatment of cancer with TCM by summarizing and reviewing the correlation between the Hh pathway and tumors, as well as the feasibility of using TCM to modulate the Hh pathway for anti-tumor effects.
Hedgehog Proteins/genetics* ; Humans ; Signal Transduction/drug effects* ; Neoplasms/metabolism* ; Animals ; Drugs, Chinese Herbal/pharmacology* ; Medicine, Chinese Traditional

BACKGROUND: Perturbations in bone marrow mesenchymal stem cell (BMSC) differentiation play an important role in steroid-induced osteonecrosis of the femoral head (SONFH). At present, studies on SONFH concentrate upon the balance within BMSC osteogenic and adipogenic differentiation. However, BMSC apoptosis as well as proliferation are important prerequisites in their differentiation. The hedgehog (HH) signaling pathway regulates bone cell apoptosis. Baicalin (BA), a well-known compound in traditional Chinese medicine, can affect the proliferation and apoptosis of numerous cell types via HH signaling. However, the potential role and mechanisms of BA on BMSCs are unclear. Thus, we aimed to explore the role of BA in dexamethasone (Dex)-induced BMSC apoptosis in this study. METHODS: Primary BMSCs were treated with 10 -6 mol/L Dex alone or with 5.0 μmol/L, 10.0 μmol/L, or 50.0 μmol/L BA for 24 hours followed by co-treatment with 5.0 μmol/L, 10.0 μmol/L, or 50.0 μmol/L BA and 10 -6 mol/L Dex. Cell viability was assayed through the Cell Counting Kit-8 (CCK-8). Cell apoptosis was evaluated using Annexin V-fluorescein isothiocyanate/propidium iodide (PI) staining followed by flow cytometry. The imaging and counting, respectively, of Hochest 33342/PI-stained cells were used to assess the morphological characteristics and proportion of apoptotic cells. To quantify the apoptosis-related proteins (e.g., apoptosis regulator BAX [Bax], B-cell lymphoma 2 [Bcl-2], caspase-3, and cleaved caspase-3) and HH signaling pathway proteins, western blotting was used. A HH-signaling pathway inhibitor was used to demonstrate that BA exerts its anti-apoptotic effects via the HH signaling pathway. RESULTS: The results of CCK-8, Hoechst 33342/PI-staining, and flow cytometry showed that BA did not significantly promote cell proliferation (CCK-8: 0 μmol/L, 100%; 2.5 μmol/L, 98.58%; 5.0 μmol/L, 95.18%; 10.0 μmol/L, 98.11%; 50.0 μmol/L, 99.38%, F   =  2.33, P   >  0.05), but it did attenuate the effect of Dex on apoptosis (Hoechst 33342/PI-staining: Dex+ 50.0 μmol/L BA, 12.27% vs. Dex, 39.27%, t  = 20.62; flow cytometry: Dex + 50.0 μmol/L BA, 12.68% vs. Dex, 37.43%, t  = 11.56; Both P  < 0.05). The results of western blotting analysis showed that BA reversed Dex-induced apoptosis by activating the HH signaling pathway, which down-regulated the expression of Bax, cleaved-caspase 3, and suppressor of fused (SUFU) while up-regulating Bcl-2, sonic hedgehog (SHH), and zinc finger protein GLI-1 (GLI-1) expression (Bax/Bcl-2: Dex+ 50.0 μmol/L BA, 1.09 vs. Dex, 2.76, t  = 35.12; cleaved caspase-3/caspase-3: Dex + 50.0 μmol/L BA, 0.38 vs . Dex, 0.73, t  = 10.62; SHH: Dex + 50.0 μmol/L BA, 0.50 vs . Dex, 0.12, t  = 34.01; SUFU: Dex+ 50.0 μmol/L BA, 0.75 vs . Dex, 1.19, t  = 10.78; GLI-1: Dex+ 50.0 μmol/L BA, 0.40 vs . Dex, 0.11, t  = 30.68. All P  < 0.05). CONCLUSIONS BA antagonizes Dex-induced apoptosis of human BMSCs by activating the HH signaling pathway. It is a potential candidate for preventing SONFH.
Humans ; Hedgehog Proteins/metabolism* ; bcl-2-Associated X Protein ; Caspase 3/metabolism* ; Signal Transduction/physiology* ; Apoptosis ; Apoptosis Regulatory Proteins/pharmacology* ; Dexamethasone/pharmacology* ; Mesenchymal Stem Cells/metabolism* ; Bone Marrow Cells

In growing children, growth plate cartilage has limited self-repair ability upon fracture injury always leading to limb growth arrest. Interestingly, one type of fracture injuries within the growth plate achieve amazing self-healing, however, the mechanism is unclear. Using this type of fracture mouse model, we discovered the activation of Hedgehog (Hh) signaling in the injured growth plate, which could activate chondrocytes in growth plate and promote cartilage repair. Primary cilia are the central transduction mediator of Hh signaling. Notably, ciliary Hh-Smo-Gli signaling pathways were enriched in the growth plate during development. Moreover, chondrocytes in resting and proliferating zone were dynamically ciliated during growth plate repair. Furthermore, conditional deletion of the ciliary core gene Ift140 in cartilage disrupted cilia-mediated Hh signaling in growth plate. More importantly, activating ciliary Hh signaling by Smoothened agonist (SAG) significantly accelerated growth plate repair after injury. In sum, primary cilia mediate Hh signaling induced the activation of stem/progenitor chondrocytes and growth plate repair after fracture injury.
Mice ; Animals ; Hedgehog Proteins/genetics* ; Receptors, G-Protein-Coupled/metabolism* ; Cilia/metabolism* ; Cartilage/metabolism* ; Regeneration

Traditional Chinese medicine has unique advantages in the treatment of degenerative bone and joint diseases, and its widely used in clinical practice. In recent years, many scholars have conducted a large number of basic studies on the delay of intervertebral disc degeneration by herbal compound and monomeric components from different perspectives. In order to further elucidate its mechanism of action, this paper summarizes the in vivo and in vitro experimental studies conducted at the level of both herbal compound and single components, respectively, in order to provide references for the basic research on the treatment of lumbar intervertebral disc degeneration by Chinese medicine. A summary shows that commonly used herbal compound prescriptions include both classical prescriptions such as Duhuo Jisheng Decoction, as well as clinical experience prescriptions such as Yiqi Huoxue Recipe. Angelicae Sinensis Radix, Chuanxiong Rhizoma, Rehmanniae Radix Praeparata, Achyranthis Bidentatae Radix, and Eucommiae Cortex were used most frequently. Tonic for deficiency and blood stasis activators were used most frequently. The most utilized monomeric components include icariin, ginsenoside Re, salvianolic acid B and aucubin. The main molecular mechanisms by which herbal compound and monomeric components delay of lumbar intervertebral disc degeneration include improving the intervertebral disc microenvironment, promoting the synthesis of aggregated proteoglycans and type Ⅱ collagen in the intervertebral disc, reducing the degradation of the extracellular matrix, and inhibiting apoptosis in the nucleus pulposus cells, etc. The main signaling pathways involved include Wnt/β-catenin signaling pathway, MAPK-related signaling pathway, mTOR signaling pathway, Fas/FasL signaling pathway, PI3 K/Akt signaling pathway, NF-κB signaling pathway, JAK/STAT signaling pathway, and hedgehog signaling pathway, etc.
China ; Drugs, Chinese Herbal/therapeutic use* ; Hedgehog Proteins/metabolism* ; Humans ; Intervertebral Disc Degeneration/metabolism* ; Nucleus Pulposus/metabolism* ; Wnt Signaling Pathway

In recent years, liver fibrosis has become a hotspot in the field of liver diseases. MicroRNA(miRNA)-mediated Nod-like receptor pyrin domain containing 3(NLRP3) inflammasome activation is pivotal in the pathogenesis of liver fibrosis. The present study mainly discussed the role of miRNA-mediated NLRP3 inflammasome activation in the pathogenesis of liver fibrosis. Different miRNA molecules regulated liver fibrosis by mediating NLRP3 inflammasome activation, including miRNA-350-3 p(miR-350-3 p)/interleukin-6(IL-6)-mediated signal transducer and activator of transcription 3(STAT3)/c-myc signaling pathway, miR-148 a-induced autophagy and apoptosis of hepatic stellate cells via hedgehog signaling pathway, miR-155-mediated NLRP3 inflammasome by the negative feedback of the suppressor of cytokine signaling-1(SOCS-1), miR-181 a-mediated downstream NLRP3 inflammatory pathway activation through mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)/nuclear transcription factor κB(NF-κB) inflammatory pathway, miR-21-promoted expression of NF-κB and NLRP3 of RAW264.7 cells in mice by inhibiting tumor necrosis factor-α inducible protein 3(A20), and miR-20 b-promoted expression of IL-1β and IL-18 by activating NLRP3 signaling pathway. Additionally, the anti-liver fibrosis mechanism of different active components in Chinese medicines(such as Curcumae Rhizoma, Glycyrrhizae Radix et Rhizoma, Aurantii Fructus, Polygoni Cuspidati Rhizoma et Radix, Moutan Cortex, Paeoniae Radix Alba, Epimedii Folium, and Cinnamomi Cortex) was also explored based on the anti-liver fibrosis effect of miRNA-mediated NLRP3 inflammasome activation.
Animals ; Hedgehog Proteins ; Inflammasomes/metabolism* ; Interleukin-6 ; Liver Cirrhosis/metabolism* ; Medicine, Chinese Traditional ; Mice ; MicroRNAs/genetics* ; NF-kappa B/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Proto-Oncogene Proteins c-myc/metabolism* ; Signal Transduction

The damage of sweat glands in patients with extensive deep burns results in the loss of thermoregulation, which seriously affects the quality of life of patients. At present, there are many researches on the repair of sweat gland function, but the mechanism of human sweat gland development has not been fully clarified. More and more studies have shown that the cascaded pathways of Wnt/β-catenin, ecto- dysplasin A/ectodysplasin A receptor/nuclear factor-κB, sonic hedgehog, and forkhead box transcription factor jointly affect the development of sweat glands, and it has been reported that the cascaded signaling pathways can be used to achieve the reconstruction of sweat adenoid cells in vitro. This article reviews the signaling pathways that affect the development of sweat glands and their involvement in the reconstruction of sweat adenoid cells in vitro.
Adenoids/metabolism* ; Hedgehog Proteins/metabolism* ; Humans ; Quality of Life ; Signal Transduction ; Sweat/metabolism* ; Sweat Glands/physiology*