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Oral cancer is among the most common cancers worldwide and has become a major global health problem because of its relatively high morbidity and mortality rates. The sex-determining region on the Y-chromosome-related high-mobility-group box (SOX) transcription factor 11 (SOX11) plays a key role in human development and differentiation and is frequently increased in various human cancers. However, the clinical significance of SOX11 polymorphisms in oral cancer and their association with oral cancer risk are unclear. In this study, we included 1196 patients with oral cancer and 1200 controls. Real-time polymerase chain reaction was applied to analyze three SOX11 single-nucleotide polymorphisms (rs77996007, rs66465560, and rs68114586). Our results shown that SOX11 polymorphisms carriers with betel quid chewing were found to have an 8.38- to 9.23-fold risk to have oral cancer compared to SOX11 wild-type carriers without betel quid chewing. Furthermore, oral cancer patients who carried SOX11 rs77996007 "TC + CC" variants were significantly associated with large tumor size (AOR, 1.324; 95% CI, 1.047-1.674; p = 0.019). Moreover, a database analysis using the Cancer Genome Atlas suggested that SOX11 mRNA expression was high during the tumor development process. In conclusion, our results suggest that SOX11 rs77996007 is involved in oral cancer progression and clinical characteristics.

Disorders of sexual development (DSDs) in dogs, similar to humans, arise from genetic mutations, gonadal differentiation, or phenotypic sex development. The French Bulldog, a breed that has seen a surge in popularity and demand, has also shown a marked increase in DSD incidence. This study aims to characterize the genetic underpinnings of DSDs in a French Bulldog named Brutus, exhibiting ambiguous genitalia and internal sexual anatomy, and to explore the impact of breeding practices on genetic diversity within the breed. We utilized a comprehensive approach combining conventional cytogenetics, molecular techniques, and deep sequencing to investigate the genetic profile of Brutus. The sequence data were compared to three other male French Bulldogs' genome sequences with typical reproductive anatomy, including Brutus's father and the canine reference genome (CanFam6). We found a Robertsonian fusion involving chromosome 23 previously reported in dogs as a causative mutation responsible for sex reversal syndrome. Our findings revealed a 22% mosaicism (78,XX/77,XX), the absence of the sex-determining region (SRY) gene, and the presence of 43 unique Single Nucleotide Variants (SNVs) not inherited from the father. Notably, the run of homozygosity (ROH) analysis showed Brutus has a higher number of homozygous segments compared to other Bulldogs, with a total length of these fragments 50% greater than the average, strongly suggesting this dog is the product of the mating between siblings. Although no direct causative genes for the DSD phenotype were identified, four candidate loci warrant further investigation. Our study highlighted the need for a better annotated and curated reference dog genome to define genes causative of any specific phenotype, suggests a potential genetic basis for the DSD phenotype in dogs, and underscores the consequences of uncontrolled breeding practices in French Bulldogs. These findings highlight the importance of implementing strategic genetic management to preserve genetic health and diversity in canine populations. [ABSTRACT FROM AUTHOR]

Mesenchymal stromal cells (MSCs) display heterogeneity in origin and functional role in tissue homeostasis. Subsets of MSCs derived from the neural crest express nestin and serve as niches in bone marrow, but the possibility of coaxing MSCs into nestin-expresing cells for enhanced supportive activity is unclear. In this study, as an approach to the chemical coaxing of MSC functions, we screened libraries of clinically approved chemicals to identify compounds capable of inducing nestin expression in MSCs. Out of 2000 clinical compounds, we chose vorinostat as a candidate to coax the MSCs into neural crest-like fates. When treated with vorinostat, MSCs exhibited a significant increase in the expression of genes involved in the pluripotency and epithelial–mesenchymal transition (EMT), as well as nestin and CD146, the markers for pericytes. In addition, these nestin-induced MSCs exhibited enhanced differentiation towards neuronal cells with the upregulation of neurogenic markers, including SRY-box transcription factor 2 (Sox2), SRY-box transcription factor 10 (Sox10) and microtubule associated protein 2 (Map2) in addition to nestin. Moreover, the coaxed MSCs exhibited enhanced supporting activity for hematopoietic progenitors without supporting leukemia cells. These results demonstrate the feasibility of the drug repositioning of MSCs to induce neural crest-like properties through the chemical coaxing of cell fates. [ABSTRACT FROM AUTHOR]

Sperm sexing is a technology that can generate great economic benefits in the animal production sector. Techniques such as sex-sorting promise over 90% accuracy in sperm sexing. However, for the correct standardization of the technique, some laboratory methodologies are required. The present manuscript describes in detail a standardized equine sperm sex-sorting protocol using an absolute qPCR-based methodology. Furthermore, the results of absolute qPCR were implemented and validated by generating equine/bovine heterologous embryos by intracytoplasmic sperm injection (ICSI) of presumably sexed equine spermatozoa into bovine oocytes using a piezoelectric system (Piezo-ICSI). Our results indicated that equine sex-sorting spermatozoa had a 97% and 94% certainty for X and Y sperm, respectively, while presumptive female and male equine/bovine hybrid embryos, generated by Piezo-ICSI, had an accuracy of 92% with respect to the desired sex. Therefore, it is concluded that the presented methodology is a reliable, cost-effective, and relatively simple option for standardizing sex-sorting of equine spermatozoa. This is supported by the results of the correct sexing of Piezo-ICSI heterologous embryos generated with the sexed spermatozoa, validating the correct sexing and viability of these gametes. [ABSTRACT FROM AUTHOR]

Osteoporosis is a bone disease that commonly results in a 30% incidence of fracture in hens used to produce eggs for human consumption. One of the causes of osteoporosis is the lack of mechanical strain placed on weight-bearing bones. In conventionally-caged hens, there is inadequate space for chickens to exercise and induce mechanical strain on their bones. One approach is to encourage mechanical stress on bones by the addition of perches to conventional cages. Our study focuses on the molecular mechanism of bone remodeling in end-of-lay hens (71 weeks) with access to perches. We examined bone-specific transcripts that are actively involved during development and remodeling. Using real-time quantitative PCR, we examined seven transcripts (COL2A1 (collagen, type II, alpha 1), RANKL (receptor activator of nuclear factor kappa-B ligand), OPG (osteoprotegerin), PTHLH (PTH-like hormone), PTH1R (PTH/PTHLH type-1 receptor), PTH3R (PTH/PTHLH type-3 receptor), and SOX9 (Sry-related high mobility group box)) in phalange, tibia and femur. Our results indicate that the only significant effect was a difference among bones for COL2A1 (femur > phalange). Therefore, we conclude that access to a perch did not alter transcript expression. Furthermore, because hens have been used as a model for human bone metabolism and osteoporosis, the results indicate that bone remodeling due to mechanical loading in chickens may be a product of different pathways than those involved in the mammalian model. [ABSTRACT FROM AUTHOR]

Genetic factors play a significant role in the pathogenesis of mitral valve diseases, including mitral valve prolapse (MVP) and mitral valve regurgitation. Genes like Fibrillin-1 (FBN1), Filamin A (FLNA), matrix metalloproteinase 2 (MMP2), and SRY-box transcription factor 9 (SOX9) are known to influence mitral valve pathology but knowledge of the exact mechanism is far from clear. Data regarding serum parameters, transesophageal echocardiography, and genetic and histopathologic parameters were investigated in 54 patients who underwent cardiovascular surgery for mitral valve regurgitation. The possible association between Fibrillin-1, Filamin A, MMP2, and SOX9 gene expressions was checked in relationship with the parameters of systemic inflammatory response. The mRNA expression levels (RQ—relative quantification) were categorized into three distinct groups: low (RQ < 1), medium/normal (RQ = 1–2), and high (RQ > 2). Severe fibrosis of the mitral valve was reflected by high expression of FBN1 and low expression of MMP2 (p < 0.05). The myxoid degeneration level was associated with the mRNA expression level for FBN1 and a low lymphocyte-monocyte ratio was associated with an increased mRNA expression of FBN1 (p < 0.05). A high number of monocytes was associated with high values of FBN1 whereas the increase in the number of lymphocytes was associated with high levels of MMP2. In addition, we observed that the risk of severe hyalinization was enhanced by a low mRNA expression of FLNA and/or SOX9. In conclusion, a lower FLNA mRNA expression can reflect the aging process that is highlighted in mitral valve pathology as a higher risk for hyalinization, especially in males, that might be prevented by upregulation of the SOX9 gene. FBN1 and MMP2 influence the inflammation-related fibrotic degeneration of the mitral valve. Understanding the genetic base of mitral valve pathology can provide insights into disease mechanisms, risk stratification, and potential therapeutic targets. [ABSTRACT FROM AUTHOR]

In most mammals, the sex of the gonads is based on the fate of the supporting cell lineages, which arises from the proliferation of coelomic epithelium (CE) that surfaces on the bipotential genital ridge in both XY and XX embryos. Recent genetic studies and single-cell transcriptome analyses in mice have revealed the cellular and molecular events in the two-wave proliferation of the CE that produce the supporting cells. This proliferation contributes to the formation of the primary sex cords in the medullary region of both the testis and the ovary at the early phase of gonadal sex differentiation, as well as to that of the secondary sex cords in the cortical region of the ovary at the perinatal stage. To support gametogenesis, the testis forms seminiferous tubules in the medullary region, whereas the ovary forms follicles mainly in the cortical region. The medullary region in the ovary exhibits morphological and functional diversity among mammalian species that ranges from ovary-like to testis-like characteristics. This review focuses on the mechanism of gonadal sex differentiation along the cortical-medullary axis and compares the features of the cortical and medullary regions of the ovary in mammalian species. [ABSTRACT FROM AUTHOR]

The Chinese soft-shelled turtle Pelodiscus sinensis, an economically important species in China, exhibits significant sexual dimorphism. Males are more valuable than females owing to their wider calipash and faster growth. Estradiol (E2)-induced sex reversal is used to achieve all-male breeding of turtles; however, the mechanism of this sex reversal remains unclear. In this study, we characterized the Sox3 gene, whose expression level was high in the gonads and brain and exhibited significant sexual dimorphism in the ovary. During embryonic development, Sox3 was highly expressed at the initiation of ovarian differentiation. E2 and Sox3-RNAi treatment before sexual differentiation led to 1352, 908, 990, 1011, and 975 differentially expressed genes in five developmental stages, respectively, compared with only E2 treatment. The differentially expressed genes were clustered into 20 classes. The continuously downregulated and upregulated genes during gonadal differentiation were categorized into Class 0 (n = 271) and Class 19 (n = 606), respectively. KEGG enrichment analysis showed that Sox3 significantly affected sexual differentiation via the Wnt, TGF-β, and TNF signaling pathways and mRNA surveillance pathway. The expression of genes involved in these signaling pathways, such as Dkk4, Nog, Msi1, and Krt14, changed significantly during gonadal differentiation. In conclusion, the deletion of Sox3 may lead to significant upregulation of the mRNA surveillance pathway and TNF and Ras signaling pathways and downregulation of the Wnt and TGF-β signaling pathways, inhibiting E2-induced sex reversal. These findings suggest that Sox3 may play a certain promoting effect during E2-induced sex reversal in P. sinensis. [ABSTRACT FROM AUTHOR]

S-adenosylmethionine (SAM) is considered to be a useful therapeutic agent for degenerative cartilage diseases, although its mechanism is not clear. We previously found that polyamines stimulate the expression of differentiated phenotype of chondrocytes. We also found that the cellular communication network factor 2 (CCN2) played a huge role in the proliferation and differentiation of chondrocytes. Therefore, we hypothesized that polyamines and CCN2 could be involved in the chondroprotective action of SAM. In this study, we initially found that exogenous SAM enhanced proteoglycan production but not cell proliferation in human chondrocyte-like cell line-2/8 (HCS-2/8) cells. Moreover, SAM enhanced gene expression of cartilage-specific matrix (aggrecan and type II collagen), Sry-Box transcription factor 9 (SOX9), CCN2, and chondroitin sulfate biosynthetic enzymes. The blockade of the methionine adenosyltransferase 2A (MAT2A) enzyme catalyzing intracellular SAM biosynthesis restrained the effect of SAM on chondrocytes. The polyamine level in chondrocytes was higher in SAM-treated culture than control culture. Additionally, Alcian blue staining and RT-qPCR indicated that the effects of SAM on the production and gene expression of aggrecan were reduced by the inhibition of polyamine synthesis. These results suggest that the stimulation of polyamine synthesis and gene expression of chondrogenic differentiation factors, such as CCN2, account for the mechanism underlying the action of SAM on chondrocytes. [ABSTRACT FROM AUTHOR]

SRY-box transcription factor 18 (SOX18) is known to play a crucial role in the growth and development of hair follicles (HF) in both humans and mice. However, the specific effect of SOX18 on sheep hair follicles remains largely unknown. In our previous study, we observed that SOX18 was specifically expressed within dermal papilla cells (DPCs) in ovine hair follicles, leading us to investigate its potential role in the growth of hair follicles in sheep. In the present study, we aimed to examine the effect of SOX18 in DPCs and preliminarily study its regulatory mechanism through RNA-seq. We initially found that the overexpression of SOX18 promoted the proliferation of DPCs compared to the negative control group, while the interference of SOX18 had the opposite effect. To gain further insight into the regulatory mechanism of SOX18, we conducted RNA-seq analysis after knocking down SOX18 in Hu sheep DPCs. The result showed that the Wnt/β-Catenin signaling pathway was involved in the growth process of DPC after SOX18 knockdown. Subsequently, we investigated the effect of SOX18 on the Wnt/β-Catenin signaling pathway in DPCs using TOP/FOP-flash, qRT-PCR, and Western blot (WB) analysis. Our data demonstrated that SOX18 could activate the Wnt/β-Catenin signaling pathway in DPCs. Additionally, we observed that SOX18 could rescue the proliferation of DPCs after inhibiting the Wnt/β-Catenin signaling pathway. These findings underscore the essential role of SOX18 as a functional molecule governing the proliferation of DPCs. Additionally, these findings also greatly enhance our understanding of the role of SOX18 in the proliferation of DPCs and the growth of wool in Hu sheep. [ABSTRACT FROM AUTHOR]

Sex determination is crucial for the transmission of genetic information through generations. In mammal, this process is primarily regulated by an antagonistic network of sex-related genes beginning in embryonic development and continuing throughout life. Nonetheless, abnormal expression of these sex-related genes will lead to reproductive organ and germline abnormalities, resulting in disorders of sex development (DSD) and infertility. On the other hand, it is possible to predetermine the sex of animal offspring by artificially regulating sex-related gene expression, a recent research hotspot. In this paper, we reviewed recent research that has improved our understanding of the mechanisms underlying the development of the gonad and primordial germ cells (PGCs), progenitors of the germline, to provide new directions for the treatment of DSD and infertility, both of which involve manipulating the sex ratio of livestock offspring. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate quantitative aberrations of novel fetal-specific epigenetic markers in maternal plasma of pregnancies with hypertensive disorders. We compared the concentrations of DSCR3, RASSF1A, and SRY as cell-free fetal DNA markers in 188 normal pregnancies, 16 pregnancies with early-onset preeclampsia (EO-PE), 47 pregnancies with late-onset preeclampsia (LO-PE), and 29 pregnancies with gestational hypertension (GH). The concentrations of all markers were significantly correlated with gestational age (p < 0.001 for all). Strong positive correlations were also observed between DSCR3 and SRY (r = 0.471, p < 0.001), as well as between RASSF1A and SRY (r = 0.326, p = 0.015) and between DSCR3 and RASSF1A (r = 0.673, p < 0.001). The concentrations of DSCR3 and RASSF1A in the EO-PE were significantly higher at 24-32 weeks and onwards (p < 0.05 for both). In the LO-PE, DSCR3 and RASSF1A concentrations were significantly higher only at 33-41 weeks compared with the controls. The concentrations of all markers in the GH group were not significantly different from those in the control group. This study is the first demonstration that DSCR3 is a novel epigenetic marker that can be an alternative to the RASSF1A for the prediction of EO-PE. [ABSTRACT FROM AUTHOR]

Background: Cancer metastasis is a deathly process, and a better understanding of the different steps is needed. The shedding of circulating tumor cells (CTCs) and CTC-cluster from the primary tumor, its survival in circulation, and homing are key events of the metastasis cascade. In vitro models of CTCs and in vivo models of metastasis represent an excellent opportunity to delve into the behavior of metastatic cells, to gain understanding on how secondary tumors appear., Methods: Using the zebrafish embryo, in combination with the mouse and in vitro assays, as an in vivo model of the spatiotemporal development of metastases, we study the metastatic competency of breast cancer CTCs and CTC-clusters and the molecular mechanisms., Results: CTC-clusters disseminated at a lower frequency than single CTCs in the zebrafish and showed a reduced capacity to invade. A temporal follow-up of the behavior of disseminated CTCs showed a higher survival and proliferation capacity of CTC-clusters, supported by their increased resistance to fluid shear stress. These data were corroborated in mouse studies. In addition, a differential gene signature was observed, with CTC-clusters upregulating cell cycle and stemness related genes., Conclusions: The zebrafish embryo is a valuable model system to understand the biology of breast cancer CTCs and CTC-clusters.

Pulmonary fibrosis (PF) associated with systemic sclerosis (SSc) results in significant morbidity and mortality. We previously reported that insulin-like growth factor-II (IGF-II) is overexpressed in lung tissues and fibroblasts from SSc patients, and IGF-II fosters fibrosis by upregulating collagen type I, fibronectin, and TGFβ. We now show that IGF-II augments mRNA levels of profibrotic signaling molecules TGFβ2 (p ≤ 0.01) and TGFβ3 (p ≤ 0.05), collagen type III (p ≤ 0.01), and the collagen posttranslational modification enzymes P4HA2 (p ≤ 0.05), P3H2 (p ≤ 0.05), LOX (p = 0.065), LOXL2 (p ≤ 0.05), LOXL4 (p ≤ 0.05) in primary human lung fibroblasts. IGF-II increases protein levels of TGFβ2 (p ≤ 0.01), as well as COL3A1, P4HA2, P4Hβ, and LOXL4 (p ≤ 0.05). In contrast, IGF-II decreases mRNA levels of the collagen degradation enzymes cathepsin (CTS) K, CTSB, and CTSL and protein levels of CTSK (p ≤ 0.05). The SRY-box transcription factor 9 (SOX9) is overexpressed in SSc lung tissues at the mRNA (p ≤ 0.05) and protein (p ≤ 0.01) levels compared to healthy controls. IGF-II induces SOX9 in lung fibroblasts (p ≤ 0.05) via the IGF1R/IR hybrid receptor, and SOX9 regulates TGFβ2 (p ≤ 0.05), TGFβ3 (p ≤ 0.05), COL3A1 (p ≤ 0.01), and P4HA2 (p ≤ 0.001) downstream of IGF-II. Our results identify a novel IGF-II signaling axis and downstream targets that are regulated in a SOX9-dependent and -independent manner. Our findings provide novel insights on the role of IGF-II in promoting pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Tendons help transmit forces from the skeletal muscles and bones. However, tendons have inferior regenerative ability compared to muscles. Despite studies on the regeneration of muscles and bone tissue, only a few have focused on tendinous tissue regeneration, especially tendon regeneration. Sex-determining region Y-box transcription factor 9 (Sox9) is an SRY-related transcription factor with a DNA-binding domain and is an important control factor for cartilage formation. Sox9 is critical to the early-to-middle stages of tendon development. However, how Sox9 participates in the healing process after tendon injury is unclear. We hypothesized that Sox9 is expressed in damaged tendons and is crucially involved in restoring tendon functions. We constructed a mouse model of an Achilles tendon injury by performing a 0.3 mm wide partial excision in the Achilles tendon of mice, and chronologically evaluated the function restoration and localization of the Sox9 expressed in the damaged sites. The results reveal that Sox9 was expressed simultaneously with the formation of the pre-structure of the epitenon, an essential part of the tendinous tissue, indicating that its expression is linked to the functional restoration of tendons. Lineage tracing for Sox9 expressed during tendon restoration revealed the tendon restoration involvement of cells that switched into Sox9-expressing cells after tendon injury. The stem cells involved in tendon regeneration may begin to express Sox9 after injury. [ABSTRACT FROM AUTHOR]

Considerable evidence now indicates that cognitive impairment is primarily a vascular disorder. The depletion of smooth muscle 22 alpha (SM22α) contributes to vascular smooth muscle cells (VSMCs) switching from contractile to synthetic and proinflammatory phenotypes in the context of inflammation. However, the role of VSMCs in the pathogenesis of cognitive impairment remains undetermined. Herein, we showed a possible link between VSMC phenotypic switching and neurodegenerative diseases via the integration of multi-omics data. SM22α knockout (Sm22α−/−) mice exhibited obvious cognitive impairment and cerebral pathological changes, which were visibly ameliorated by the administration of AAV-SM22α. Finally, we confirmed that SM22α disruption promotes the expression of SRY-related HMG-box gene 10 (Sox10) in VSMCs, thereby aggravating the systemic vascular inflammatory response and ultimately leading to cognitive impairment in the brain. Therefore, this study supports the idea of VSMCs and SM22α as promising therapeutic targets in cognitive impairment to improve memory and cognitive decline. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) continues to be the most devastating primary brain malignancy. Despite significant advancements in understanding basic GBM biology and enormous efforts in developing new therapeutic approaches, the prognosis for most GBM patients remains poor with a median survival time of 15 months. Recently, the interplay between the SOX (SRY-related HMG-box) genes and lncRNAs (long non-coding RNAs) has become the focus of GBM research. Both classes of molecules have an aberrant expression in GBM and play essential roles in tumor initiation, progression, therapy resistance, and recurrence. In GBM, SOX and lncRNAs crosstalk through numerous functional axes, some of which are part of the complex transcriptional and epigenetic regulatory mechanisms. This review provides a systematic summary of current literature data on the complex interplay between SOX genes and lncRNAs and represents an effort to underscore the effects of SOX/lncRNA crosstalk on the malignant properties of GBM cells. Furthermore, we highlight the significance of this crosstalk in searching for new biomarkers and therapeutic approaches in GBM treatment. [ABSTRACT FROM AUTHOR]

Sox proteins are known as crucial transcription factors for many developmental processes and for a wide range of common diseases. They were believed to specifically bind and bend DNA with other transcription factors and elicit transcriptional activation or repression activities in the early stage of transcription. However, their functions are not limited to transcription initiation. It has been showed that Sox proteins are involved in the regulation of alternative splicing regulatory networks and translational control. In this review, we discuss the current knowledge on how Sox transcription factors such as Sox2, Sry, Sox6, and Sox9 allow the coordination of co-transcriptional splicing and also the mechanism of SOX4-mediated translational control in the context of RNA polymerase III. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two common disorders that disrupt the quality of life of millions of people. These two chronic diseases cause damage to the joint cartilage and surrounding tissues of more than 220 million people worldwide. Sex-determining region Y-related (SRY) high-mobility group (HMG) box C, SOXC, is a superfamily of transcription factors that have been recently shown to be involved in various physiological and pathological processes. These include embryonic development, cell differentiation, fate determination, and autoimmune diseases, as well as carcinogenesis and tumor progression. The SOXC superfamily includes SOX4, SOX11, and SOX12, all have a similar DNA-binding domain, i.e., HMG. Herein, we summarize the current knowledge about the role of SOXC transcription factors during arthritis progression and their potential utilization as diagnostic biomarkers and therapeutic targets. The involved mechanistic processes and signaling molecules are discussed. SOX12 appears to have no role in arthritis, however SOX11 is dysregulated and promotes arthritic progression according to some studies but supports joint maintenance and protects cartilage and bone cells according to others. On the other hand, SOX4 upregulation during OA and RA was documented in almost all studies including preclinical and clinical models. Molecular details have indicated that SOX4 can autoregulate its own expression besides regulating the expression of SOX11, a characteristic associated with the transcription factors that protects their abundance and activity. From analyzing the currently available data, SOX4 seems to be a potential diagnostic biomarker and therapeutic target of arthritis. [ABSTRACT FROM AUTHOR]

The loss or dysfunction of human corneal endothelial cells (hCEnCs) is a leading cause of blindness due to corneal failure. Corneal transplantation with a healthy donor cornea has been the only available treatment for corneal endothelial disease. However, the need for way to regenerate the CEnCs has been increased due to the global shortage of donor corneas. The aim of the study is to investigate whether novel Rho-kinase (ROCK) inhibitors can induce the cultivation and regeneration of hCEnCs. Cultured hCEnCs were treated with Y-27632, sovesudil, or PHP-0961 for 24 h. Cellular responses, including cell viability, cytotoxicity, proliferation, and Ki67 expression with ROCK inhibitors were evaluated. We also evaluated wound healing and cell adhesion assays. Porcine corneas were used ex vivo to evaluate the effects of Y-27632, sovesudil, and PHP-0961 on wound healing and regeneration. We performed live/dead cell assays and immunofluorescence staining for SRY (sex determining region Y)-box 2 (SOX2), β-catenin, and ZO-1 on porcine corneas after ROCK inhibitor treatments. Cell viability, cell proliferation rate, and the number of Ki67-positive cells were higher in Y-27632, sovesudil and PHP-0961 treated cells compared to the control. There was no difference in LDH cytotoxicity test between any groups. Cells treated with Y-27632, sovesudil and PHP-0961 showed faster migration, wound healing, and cell adhesion. In the porcine ex vivo experiments, wound healing, the number of live cells, and SOX2-positive cells were higher in Y-27632, sovesudil and PHP-0961 treated corneas. In all experiments, sovesudil and PHP-0961, the novel ROCK inhibitors, were equal or superior to the results of the ROCK inhibitor positive control, Y-27632. In conclusion, sovesudil and PHP-0961, novel ROCK inhibitors have the capacity to regenerate hCEnCs by enhancing cell proliferation and adhesion between cells. [ABSTRACT FROM AUTHOR]

The lung originates from the ventral foregut and develops into an intricate branched structure of airways, alveoli, vessels and support tissue. As the lung develops, cells become specified and differentiate into the various cell lineages. This process is controlled by specific transcription factors, such as the SRY-related HMG-box genes SOX2 and SOX21, that are activated or repressed through intrinsic and extrinsic signals. Disturbances in any of these processes during the development of the lung may lead to various pediatric lung disorders, such as Congenital Diaphragmatic Hernia (CDH), Congenital Pulmonary Airway Malformation (CPAM) and Broncho-Pulmonary Dysplasia (BPD). Changes in the composition of the airways and the alveoli may result in reduced respiratory function and eventually lead to chronic lung disorders. In this concise review, we describe different intrinsic and extrinsic cellular processes required for proper differentiation of the epithelium during development and regeneration, and the influence of the microenvironment on this process with special focus on SOX2 and SOX21. [ABSTRACT FROM AUTHOR]

SOX2, a member of the SRY-related HMG-box (SOX) family, is abnormally expressed in many tumors and associated with cancer stem cell-like properties. Previous reports have shown that SOX2 is a biomarker for cancer stem cells in human bladder cancer (BC), and our most recent study has indicated that the inhibition of SOX2 by anticancer compound ChlA-F attenuates human BC cell invasion. We now investigated the mechanisms through which SOX2 promotes the invasive ability of BC cells. Our studies revealed that SOX2 promoted SKP2 transcription and increased SKP2-accelerated Sp1 protein degradation. As Sp1 is a transcriptionally regulated gene, HUR transcription was thereby attenuated, and, in the absence of HUR, FOXO1 mRNA was degraded fast, which promoted BC cell invasion. In addition, SOX2 promoted BC invasion through the upregulation of nucleolin transcription, which resulted in increased MMP2 mRNA stability and expression. Collectively, our findings show that SOX2 promotes BC invasion through both SKP2-Sp1-HUR-FOXO1 and nucleolin-MMP2 dual axes. [ABSTRACT FROM AUTHOR]

Background: The biological role of EGFRvIII (epidermal growth factor receptor variant three) remains unclear. Methods: Three glioblastoma DK-MG sublines were tested with EGF (epidermal growth factor) and TGFβ (transforming growth factor β). Sublines were characterized by an increased percentage of EGFRvIII-positive cells and doubling time (DK-MGlow to DK-MGextra-high), number of amplicons, and EGFRvIII mRNA expression. The influence of the growth factors on primary EGFRvIII positive glioblastomas was assessed. Results: The overexpression of exoEGFRvIII in DK-MGhigh did not convert them into DK-MGextra-high, and this overexpression did not change DK-MGlow to DK-MGhigh; however, the overexpression of RASG12V increased the proliferation of DK-MGlow. Moreover, the highest EGFRvIII phosphorylation in DK-MGextra-high did not cause relevant AKT (known as protein kinase B) and ERK (extracellular signal-regulated kinase) activation. Further analyses indicate that TGFβ is able to induce apoptosis of DK-MGhigh cells. This subline was able to convert to DK-MGextra-high, which appeared resistant to this proapoptotic effect. EGF acted as a pro-survival factor and stimulated proliferation; however, simultaneous senescence induction in DK-MGextra-high cells was ambiguous. Primary EGFRvIII positive (and SOX2 (SRY-Box Transcription Factor 2) positive or SOX2 negative) glioblastoma cells differentially responded to EGF and TGFβ. Conclusions: The roles of TGFβ and EGF in the EGFRvIII context remain unclear. EGFRvIII appears as a weak oncogene and not a marker of GSC (glioma stem cells). Hence, it may not be a proper target for CAR-T (chimeric antigen receptor T cells). [ABSTRACT FROM AUTHOR]

Androgens and anti-Müllerian hormone (AMH), secreted by the foetal testis, are responsible for the development of male reproductive organs and the regression of female anlagen. Virilization of the reproductive tract in association with the absence of Müllerian derivatives in the XX foetus implies the existence of testicular tissue, which can occur in the presence or absence of SRY. Recent advancement in the knowledge of the opposing gene cascades driving to the differentiation of the gonadal ridge into testes or ovaries during early foetal development has provided insight into the molecular explanation of XX maleness. [ABSTRACT FROM AUTHOR]

The Sox transcription factor family is characterized with the presence of a Sry-related high-mobility group (HMG) box and plays important roles in various biological processes in animals, including sex determination and differentiation, and the development of multiple organs. In this study, 27 Sox genes were identified in the genome of the Nile tilapia (Oreochromis niloticus), and were classified into seven groups. The members of each group of the tilapia Sox genes exhibited a relatively conserved exon-intron structure. Comparative analysis showed that the Sox gene family has undergone an expansion in tilapia and other teleost fishes following their whole genome duplication, and group K only exists in teleosts. Transcriptome-based analysis demonstrated that most of the tilapia Sox genes presented stage-specific and/or sex-dimorphic expressions during gonadal development, and six of the group B Sox genes were specifically expressed in the adult brain. Our results provide a better understanding of gene structure and spatio-temporal expression of the Sox gene family in tilapia, and will be useful for further deciphering the roles of the Sox genes during sex determination and gonadal development in teleosts. [ABSTRACT FROM AUTHOR]

The swimming crab (Portunus trituberculatus) is an economically important species in China, and its growth traits show obvious sexual dimorphism. Thus, it is important to study the mechanism of sex determination and differentiation in this species. Herein, we identified 2138 differentially expressed genes and 132 differentially expressed long non-coding RNAs (lncRNAs) using Oxford Nanopore Technology full-length transcriptome sequencing. We predicted 561 target genes of the differentially expressed lncRNAs according to their location and base pair complimentary principles. Furthermore, pathways related to sex determination, differentiation, and reproduction were enriched for lncRNAs according to gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses. This indicated that lncRNAs might play regulatory roles in these pathways. Our results could form the basis for future studies of sex determination and differentiation in P. trituberculatus. [ABSTRACT FROM AUTHOR]

Congenital Adrenal Hyperplasia (CAH) is a group of autosomal recessive endocrine disorders characterized by alteration in adrenal hormonal secretions. The most common form is caused by CYP21A2 mutations that result in 21-hydroxylase deficiency. Clinical features can vary, from salt-wasting forms, characterized by a lack of mineralocorticoid activity with a risk of perinatal-onset adrenal crises, to "simple-virilizing" forms with sufficient aldosterone secretion, up to milder "non-classical" forms, with a variable grade of hyperandrogenism but no severe hormonal deficiencies. During pregnancy, CAH 46,XX fetuses are exposed to elevated androgen levels, leading to a variable grade of virilization and potential central nervous system effects if untreated. These patients are usually (but not always) assigned female at birth, but some cases may be misdiagnosed and assigned male, potentially inducing fertility, gender identity, and sexual behavior issues in adulthood. In these patients, the benefits and risks of a late gender transition should be carefully evaluated. In this paper, we reviewed the literature concerning the most interesting peculiarities of these conditions. [ABSTRACT FROM AUTHOR]

Fibrosis is characterized by scarring and hardening of tissues and organs. It can affect every organ system, and so could result in organ failure due to the accumulation of extracellular matrix proteins. Previous studies suggest that mechanical forces (such as shockwave therapy, SWT) initiate a process of mechanotransduction and thus could regulate fibrosis. Nevertheless, it is largely unexamined which pathways are exactly involved in the application of SWT and can regulate fibrosis. The present article seeks to elucidate the underlying effect of SWT on fibrosis. Evidence shows that SWT activates macrophage activity, fibroblast activity, collagen amount and orientation and apoptosis, which ultimately lead to an adaptation of inflammation, proliferation, angiogenesis and apoptosis. The included articles reveal that other proteins and pathways can be activated depending on the energy levels and frequency of SWT. These findings demonstrate that SWT has beneficial effects on fibrosis by influencing the proteins and pathways. Based on these data, which highlights the underlying mechanisms, we can make preliminary conclusions about the treatment modalities of SWT in scar formation, such as the energy levels and frequencies that are necessary to prevent or treat fibrotic tissue. [ABSTRACT FROM AUTHOR]

Cutaneous melanoma accounts for the majority of skin cancer-related deaths, and its incidence increases each year. The growing number of melanoma cases, especially in advanced stages, poses a significant socio-medical challenge throughout the world. Extensive research on melanoma pathogenesis identifies UV radiation as the most important factor in melanocytic transformation. Oxidative effects of UV irradiation exert their influence on melanoma pathogenesis primarily through modification of nucleic acids, proteins, and lipids, further disrupting cellular signaling and cell cycle regulation. Its effects extend beyond melanocytes, leading to immunosuppression in the exposed skin tissue, which consequently creates conditions for immune surveillance evasion and further progression. In this review, we focus on the specific molecular changes observed in the UV-dependent oxidative stress environment and their biological consequences in the course of the disease, which have not been considered in previous reviews on melanoma. Nonetheless, data show that the exact role of oxidative stress in melanoma initiation and progression remains unclear, as it affects cancerous cells differently depending on the specific context. A better understanding of the pathophysiological basis of melanoma development holds promise for identifying potential targets, which could lead to effective melanoma prevention strategies. [ABSTRACT FROM AUTHOR]

Fetal exposures to many drugs of abuse, e.g., opioids and alcohol (EtOH), are associated with adverse neurodevelopmental problems in early childhood, including abnormalities in activity of the serotonin (5HT) transporter (SERT), which transports 5HT across the placenta. Little is known about the effects of these drugs on SERT expression. Pregnant women who used EtOH or opioids were compared to gestational age-matched controls using a structured questionnaire to determine prenatal substance exposure. Following elective pregnancy termination, placental membranous vesicles and exosomes were prepared from first and second trimester human placentas. Changes in EtOH- or opioid-exposed placental SERT expression and modifications were assessed by quantitative western blot. Novel SERT isoforms were sequenced and analyzed. Opioid-exposed but not EtOH-exposed maternal placentas showed SERT cleavage and formation of new SERT fragments (isoforms). Alcohol-exposed cases showed reduced SERT levels. Antibodies to the N-terminal SERT region did not recognize either of the two cleavage products, while antibodies to the central and C-terminal regions recognized both bands. The secondary band seen in the opioid group may represent a hypophosphorylated SERT fragment. These changes in SERT modifications and expression may result in altered fetal brain serotonergic neurotransmission, which could have neurodevelopmental implications. [ABSTRACT FROM AUTHOR]

CD133 protein expression is observable in differentiated cells, stem cells, and progenitor cells within normal tissues, as well as in tumor tissues, including colorectal cancer cells. The CD133 protein is the predominant cell surface marker utilized to detect cancer cells exhibiting stem cell-like characteristics. CD133 alters common abnormal processes in colorectal cancer, such as the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and Wnt/β-catenin pathways. Autophagy is a cellular self-digestion mechanism that preserves the intracellular milieu and plays a dual regulatory role in cancer. In cancer cells, apoptosis is a critical cell death mechanism that can impede cancer progression. CD133 can modulate autophagy and apoptosis in colorectal cancer cells via several signaling pathways; hence, it is involved in the regulation of these intricate processes. This can be an explanation for why CD133 expression is associated with enhanced cellular self-renewal, migration, invasion, and survival under stress conditions in colorectal cancer. The purpose of this review article is to explain the complex relationship between the CD133 protein, apoptosis, and autophagy. We also want to highlight the possible ways that CD133-mediated autophagy may affect the apoptosis of colorectal cancer cells. Targeting the aforementioned mechanisms may have a significant therapeutic role in eliminating CD133-positive stem cell-phenotype colorectal cancer cells, which can be responsible for tumor recurrence. [ABSTRACT FROM AUTHOR]

Bladder cancer is among the most prevalent tumors in the urinary system and is known for its high malignancy. Although traditional diagnostic and treatment methods are established, recent research has focused on understanding the molecular mechanisms underlying bladder cancer. The primary objective of this study is to identify novel diagnostic markers and discover more effective targeted therapies for bladder cancer. This study identified differentially expressed genes (DEGs) between bladder cancer tissues and adjacent normal tissues using data from The Cancer Genome Atlas (TCGA). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were conducted to explore the functional roles of these genes. A protein–protein interaction (PPI) network was also constructed to identify and analyze hub genes within this network. Gene set variation analysis (GSVA) was conducted to investigate the involvement of these genes in various biological processes and pathways. Ten key genes were found to be significantly associated with bladder cancer: IL6, CCNA2, CCNB1, CDK1, PLK1, TOP2A, AURKA, AURKB, FOXM1, and CALML5. GSVA analyses revealed that these genes are involved in a variety of biological processes and signaling pathways, including coagulation, UV-response-down, apoptosis, Notch signaling, and Wnt/beta-catenin signaling. The diagnostic relevance of these genes was validated through ROC curve analysis. Additionally, potential therapeutic drug interactions with these key genes were identified. This study provides valuable insights into key genes and their roles in bladder cancer. The identified genes and their interactions with therapeutic drugs could serve as potential biomarkers, presenting new opportunities for enhancing the diagnosis and prognosis of bladder cancer. [ABSTRACT FROM AUTHOR]

The Northern snakehead (Channa argus) is a significant economic aquaculture species in China. Exhibiting sexual dimorphism in the growth rate between females and males, mono-sex breeding holds substantial value for aquaculture. This study employed GWAS and transcriptome analysis were applied to identify sex determination genomic regions and develop sex-specific markers. A total of 270 single-nucleotide polymorphisms (SNPs) and 31 insertion-deletions (InDels) were identified as being sexually dimorphic through GWAS and fixation index (Fst) scanning. Based on GWAS results, two sex-specific InDel markers were developed, effectively distinguishing genetic sex for XX females, XY males, and YY super-males via (polymerase chain reaction) PCR amplification. A major genomic segment of approximately 115 kb on chromosome 3 (Chr 03) was identified as the sex-determination region. A comparative transcriptome analysis of gonads for three sexes identified 158 overlapping differentially expressed genes (DEGs). Additionally, three sex-related candidate genes were identified near the sex determination region, including id2, sox11, and rnf144a. Further studies are required to elucidate the functions of these genes. Overall, two sex-specific InDel markers support a male heterogametic XX/XY sex-determination system in Northern snakeheads and three candidate genes offer new insights into sex determination and the evolution of sex chromosomes in teleost fish. [ABSTRACT FROM AUTHOR]

Milk production is an essential economic trait in cattle, and understanding the genetic regulation of this trait can enhance breeding strategies. The discoidin domain receptor 1 (DDR1) gene has been identified as a key candidate gene that influences milk production, and ETS homologous factor (EHF) is recognized as a critical transcription factor that regulates DDR1 expression. Codon usage bias, which affects gene expression and protein function, has not been fully explored in cattle. This study aims to examine the codon usage bias of DDR1 and EHF transcription factors to understand their roles in dairy production traits. Data from 24 species revealed that both DDR1 and EHF predominantly used G/C-ending codons, with the GC3 content averaging 75.49% for DDR1 and 61.72% for EHF. Synonymous codon usage analysis identified high-frequency codons for both DDR1 and EHF, with 17 codons common to both genes. Correlation analysis indicated a negative relationship between the effective number of codons and codon adaptation index for both DDR1 and EHF. Phylogenetic and clustering analyses revealed similar codon usage patterns among closely related species. These findings suggest that EHF plays a crucial role in regulating DDR1 expression, offering new insights into genetically regulating milk production in cattle. [ABSTRACT FROM AUTHOR]

Radioresistance poses a significant challenge in the effective treatment of cervical cancer, often leading to poor patient outcomes. MicroRNA-21 (miR-21) and MicroRNA-145 (miR-145) are oncogenic micro-RNAs associated with various cancers, including cervical cancer, but their potential as predictive biomarkers for radioresistance remains underexplored. This study aimed to investigate the association between miR-21 and miR-145 expressions and the response to radiation therapy in cervical cancer patients. An analytical cross-sectional study was conducted on 140 subjects with cervical cancer stages IIIB and IVA who received definitive radiotherapy. miR-21 and miR-145 expressions were measured using real-time reverse transcriptase–polymerase chain reaction (RT-qPCR). A total of 102 subjects (72.9%) were classified as having stage III cervical cancer, and 38 subjects (27.1%) were classified as having stage IV cervical cancer. Disease progression occurred in 60.7% of subjects. The cut-off value for miR-21 expression was 0.00088 nmol/(mg/mL) (AUC 0.676, sensitivity 70.8%, specificity 50.8%), and a higher expression was significantly associated with radioresistance (p = 0.010). miR-145, with a cut-off of 0.0239 nmol/(mg/mL) (AUC 0.612, sensitivity 67.5%, specificity 45.5%), showed no significant association with treatment response (p = 0.132). Combining miR-21 and miR-145 (AUC 0.639, sensitivity 68.6%, specificity 46.9%, p = 0.063) did not significantly improve the predictive accuracy. This study suggests that an elevated miR-21 expression is significantly associated with radioresistance in cervical cancer patients, while miR-145 expression shows no significant correlation with treatment response. Additionally, combining miR-21 and miR-145 does not enhance the predictive power. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD), which severely affects the quality of patients' lives. However, the current therapeutic approaches can only postpone its progression to ESRD. It is therefore imperative to develop a novel therapeutic strategy for renal injury in DKD, with the objective of restoring renal function and reversing the process of ESRD. In recent years, the potential of mesenchymal stem cell (MSC) therapy for DKD has garnered increasing attention within the scientific community. Preclinical research on MSC therapy has yielded promising results, and the safety of MSC treatment in vivo has been substantiated in clinical studies. An increasing body of evidence suggests that MSC therapy has significant potential for the treatment of DKD. This article reviews the existing research on MSCs and their derived exosomes in treating DKD and analyzes the underlying mechanism of MSC-based therapy for DKD. Additionally, we discuss the potential of combining MSC therapy with conventional pharmacological treatments, along with the constraints and prospects of MSC therapy for DKD. We hope this review can provide a precise and comprehensive understanding of MSCs for the treatment of DKD. [ABSTRACT FROM AUTHOR]

Organ and tissue damage can result from injury and disease. How to facilitate regeneration from damage has been a topic for centuries, and still, we are trying to find agents to use for treatments. Two groups of biological substances are known to facilitate wound healing. Phytochemicals with bioactive properties form one group. Many phytochemicals have anti-inflammatory effects and enhance wound healing. Recent studies have described their effects at the gene and protein expression levels, highlighting the receptors and signaling pathways involved. The extremely large number of phytochemicals and the multiple types of receptors they activate suggest a broad range of applicability for their clinical use. The hydrophobic nature of many phytochemicals and the difficulty with chemical stabilization have been a problem. Recent developments in biotechnology and nanotechnology methods are enabling researchers to overcome these problems. The other group of biological substances is extracellular vesicles (EVs), which are now known to have important biological functions, including the improvement of wound healing. The proteins and nanoparticles contained in mammalian EVs as well as the specificity of the targets of microRNAs included in the EVs are becoming clear. Plant-derived EVs have been found to contain phytochemicals. The overlap in the wound-healing capabilities of both phytochemicals and EVs and the differences in their nature suggest the possibility of a combinatorial use of the two groups, which may enhance their effects. [ABSTRACT FROM AUTHOR]

Endometrial carcinoma is a heterogeneous group of malignancies characterized by distinct histopathological features and genetic underpinnings. The 2020 WHO classification has provided a comprehensive framework for the categorization of endometrial carcinoma. However, it has not fully addressed the spectrum of uncommon entities that are currently not recognized by the 2020 WHO and have only been described in the form of small case series and case reports. These neoplasms represent a real diagnostic challenge for pathologists; furthermore, their therapeutic management still remains controversial and information regarding tumor prognosis is very limited. This review aims to elucidate these lesser-known variants of endometrial carcinoma. We discuss the challenges of identifying these rare subtypes and the molecular alterations associated with them. Furthermore, we propose the need for expanded classification systems that include these variants to enhance clinical outcomes and research efforts. We believe that a better histological typing characterization of these entities may lead to more reproducible and accurate diagnoses and more personalized treatments. By raising awareness of these rare entities, we also hope to encourage further investigation and integration into clinical practice to improve patient care in endometrial carcinoma. [ABSTRACT FROM AUTHOR]

Atherosclerosis, a term derived from the Greek "athero" (atheroma) and "sclerosis" (hardening), is a long-standing process that leads to the formation of atheromatous plaques in the arterial wall, contributing to the development of atherosclerotic cardiovascular disease. The proliferation and migration of vascular smooth muscle cells (VSMCs) and the switching of their phenotype play a crucial role in the whole process. Retinoic acid (RA), a natural derivative of vitamin A, has been used in the treatment of various inflammatory diseases and cell proliferation disorders. Numerous studies have demonstrated that RA has an important inhibitory effect on the proliferation, migration, and dedifferentiation of vascular smooth muscle cells, leading to a significant reduction in atherosclerotic lesions. In this review article, we explore the effects of RA on the pathogenesis of atherosclerosis, focusing on its regulatory action in VSMCs and its role in the phenotypic switching, proliferation, and migration of VSMCs. Despite the potential impact that RA may have on the process of atherosclerosis, further studies are required to examine its safety and efficacy in clinical practice. [ABSTRACT FROM AUTHOR]

Chronic pain is a debilitating condition that affects up to 1.5 billion people worldwide and bears a tremendous socioeconomic burden. The success of pain medicine relies on our understanding of the type of pain experienced by patients and the mechanisms that give rise to it. Ion channels are among the key targets for pharmacological intervention in chronic pain conditions. Therefore, it is important to understand how changes in channel properties, trafficking, and molecular interactions contribute to pain sensation. In this review, we discuss studies that have demonstrated the involvement of transient receptor potential M2, M3, and M8 channels in pain generation and transduction, as well as the controversies surrounding these findings. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) are a novel class of noncoding RNAs that have emerged as pivotal players in gene regulation. Our understanding of circRNAs has greatly expanded over the last decade, with studies elucidating their biology and exploring their therapeutic applications. In this review, we provide an overview of the current understanding of circRNA biogenesis, outline their mechanisms of action in cancer, and assess their clinical potential as biomarkers. Furthermore, we discuss circRNAs as a potential therapeutic strategy, including recent advances in circRNA production and translation, along with proof-of-concept preclinical studies of cancer vaccines. [ABSTRACT FROM AUTHOR]

Steroidogenic factor 1 (SF-1) is a nuclear receptor that regulates steroidogenesis and reproductive development. NR5A1/SF-1 variants are associated with a broad spectrum of phenotypes across individuals with disorders of sex development (DSDs). Oligogenic inheritance has been suggested as an explanation. SF-1 interacts with numerous partners. Here, we investigated a constellation of gene variants identified in a 46,XY severely undervirilized individual carrying an ACMG-categorized 'pathogenic' NR5A1/SF-1 variant in comparison to the healthy carrier father. Candidate genes were revealed by whole exome sequencing, and pathogenicity was predicted by different in silico tools. We found variants in NR1H2 and INHA associated with steroidogenesis, sex development, and reproduction. The identified variants were tested in cell models. Novel SF-1 and NR1H2 binding sites in the AR and INHA gene promoters were found. Transactivation studies showed that wild-type NR5A1/SF-1 regulates INHA and AR gene expression, while the NR5A1/SF-1 variant had decreased transcriptional activity. NR1H2 was found to regulate AR gene transcription; however, the NR1H2 variant showed normal activity. This study expands the NR5A1/SF-1 network of interacting partners, while not solving the exact interplay of different variants that might be involved in revealing the observed DSD phenotype. It also illustrates that understanding complex genetics in DSDs is challenging. [ABSTRACT FROM AUTHOR]

Among the most deadly malignancies that strike women worldwide, ovarian cancer is still one of the most common. The primary factor affecting a patient's survival is early lesion discovery. Unfortunately, because ovarian cancer is a sneaky illness that usually manifests as nonspecific symptoms only in advanced stages, its early detection and screening are challenging. A lot of research is being conducted on effective methods of diagnosing and treating ovarian cancer. Recently, non-coding RNAs (ncRNAs) have gained great popularity, which are considered to be the main regulators of many cellular processes, especially those occurring in cancer. LncRNAs are also being studied for their therapeutic use in the treatment of ovarian cancer and their use in diagnostics and as indicators of poor prognosis. In this article, we reviewed lncRNAs described in the literature that may play an important role in ovarian cancer. [ABSTRACT FROM AUTHOR]

O-linked β-N-acetylglucosamine (O-GlcNAc, O-GlcNAcylation) is a post-translational modification of serine/threonine residues of proteins. Alterations in O-GlcNAcylation have been implicated in several types of cancer, regulation of tumor progression, inflammation, and thrombosis through its interaction with signaling pathways. We aim to explore the relationship between O-GlcNAcylation and hemostasis, inflammation, and cancer, which could serve as potential prognostic tools or clinical predictions for cancer patients' healthcare and as an approach to combat cancer. We found that cancer is characterized by high glucose demand and consumption, a chronic inflammatory state, a state of hypercoagulability, and platelet hyperaggregability that favors thrombosis; the latter is a major cause of death in these patients. Furthermore, we review transcription factors and pathways associated with O-GlcNAcylation, thrombosis, inflammation, and cancer, such as the PI3K/Akt/c-Myc pathway, the nuclear factor kappa B pathway, and the PI3K/AKT/mTOR pathway. We also review infectious agents associated with cancer and chronic inflammation and potential inhibitors of cancer cell development. We conclude that it is necessary to approach both the diagnosis and treatment of cancer as a network in which multiple signaling pathways are integrated, and to search for a combination of potential drugs that regulate this signaling network. [ABSTRACT FROM AUTHOR]

Particulate matter (PM) is a harmful air pollutant composed of chemicals and metals which affects human health by penetrating both the respiratory system and skin, causing oxidative stress and inflammation. This review investigates the association between PM and skin disease, focusing on the underlying molecular mechanisms and specific disease pathways involved. Studies have shown that PM exposure is positively associated with skin diseases such as atopic dermatitis, psoriasis, acne, and skin aging. PM-induced oxidative stress damages lipids, proteins, and DNA, impairing cellular functions and triggering inflammatory responses through pathways like aryl hydrocarbon receptor (AhR), NF-κB, and MAPK. This leads to increased production of inflammatory cytokines and exacerbates skin conditions. PM exposure exacerbates AD by triggering inflammation and barrier disruption. It disrupts keratinocyte differentiation and increases pro-inflammatory cytokines in psoriasis. In acne, it increases sebum production and inflammatory biomarkers. It accelerates skin aging by degrading ECM proteins and increasing MMP-1 and COX2. In conclusion, PM compromises skin health by penetrating skin barriers, inducing oxidative stress and inflammation through mechanisms like ROS generation and activation of key pathways, leading to cellular damage, apoptosis, and autophagy. This highlights the need for protective measures and targeted treatments to mitigate PM-induced skin damage. [ABSTRACT FROM AUTHOR]

The basal cell maintains the airway's respiratory epithelium as the putative resident stem cell. Basal cells are known to self-renew and differentiate into airway ciliated and secretory cells. However, it is not clear if every basal cell functions as a stem cell. To address functional heterogeneity amongst the basal cell population, we developed a novel monoclonal antibody, HLO1-6H5, that identifies a subset of KRT5+ (cytokeratin 5) basal cells. We used HLO1-6H5 and other known basal cell-reactive reagents to isolate viable airway subsets from primary human airway epithelium by Fluorescence Activated Cell Sorting. Isolated primary cell subsets were assessed for the stem cell capabilities of self-renewal and differentiation in the bronchosphere assay, which revealed that bipotent stem cells were, at minimum 3-fold enriched in the HLO1-6H5+ cell subset. Crosslinking-mass spectrometry identified the HLO1-6H5 target as a glycosylated TFRC/CD71 (transferrin receptor) proteoform. The HLO1-6H5 antibody provides a valuable new tool for identifying and isolating a subset of primary human airway basal cells that are substantially enriched for bipotent stem/progenitor cells and reveals TFRC as a defining surface marker for this novel cell subset. [ABSTRACT FROM AUTHOR]

Prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein, was shown to be expressed 100–1000 fold higher in prostate adenocarcinoma as compared to normal prostate epithelium. Given the enzymatic function of PSMA with the presence of an internalization triggering motif, various Glu-urea-Lys-based inhibitors have been developed and, amongst others, radiolabeled with positron emitters for targeted positron emission tomography imaging such as 68Ga-PSMA-HBED-CC Glu-urea-Lys(Ahx) as well as with beta and alpha-emitting radioisotopes for targeted therapy, e.g., 177Lu-PSMA-617. In this paper, we review and discuss the potential implications for targeted imaging and therapy of altered PSMA-glycosylation, of PSMA-driven activation of the P13K/Akt/mTOR, of the evolution over time and the relationship with androgen signaling and changes in DNA methylation of PSMA, and of androgen deprivation therapy (ADT) in prostate carcinoma. [ABSTRACT FROM AUTHOR]