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Split-hand/foot malformation is a serious congenital limb malformation characterized by syndactyly and underdevelopment of the phalanges and metatarsals. In this study, we reported a case of a fetus with hand-foot cleft deformity. Whole exome and Sanger sequencing were used to filter out candidate gene mutation sites and provide pre-implantation genetic testing(PGT) for family members. Genetic testing results showed that there was a homozygous mutation c.786G>A (p.Trp262*) in the fetal WNT10B, and both parents were carriers of heterozygous mutations. PGT results showed that out of the two blastocysts, one was a heterozygous mutant and the other was a homozygous mutant. All the embryos had diploid chromosomes. The heterozygous embryo was transferred, and a singleton pregnancy was successfully achieved. This study suggests that homozygous mutations in WNT10B are the likely cause of hand-foot clefts in this family. For families with monogenic diseases, preimplantation genetic testing can effectively prevent the birth of an affected child only after identifying the pathogenic mutation.

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WNT signaling regulates osteosarcoma proliferation. However, there is controversy in the field of osteosarcoma as to whether WNT signaling is pro- or anti-tumorigenic. WNT-targeting therapeutics, both activators and inhibitors, are compared. WNT5B, a ß-catenin-independent ligand, and WNT10B, a ß-catenin-dependent WNT ligand, are each expressed in osteosarcomas, but they are not expressed in the same tumors. Furthermore, WNT10B and WNT5B regulate different histological subtypes of osteosarcomas. Using WNT signaling modulators as therapeutics may depend on the WNT ligand and/or the activated signaling pathway.

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The study demonstrated that melatonin (MT) can induce the development of secondary hair follicles in Inner Mongolian cashmere goats through the Wnt10b gene, leading to secondary dehairing. However, the mechanisms underlying the expression and molecular function of Wnt10b in dermal papilla cells (DPC) remain unknown. This research aimed to investigate the impact of MT on DPC and the regulation of Wnt10b expression, function, and molecular mechanisms in DPC. The findings revealed that MT promotes DPC proliferation and enhances DPC activity. Co-culturing DPC with overexpressed Wnt10b and MT showed a significant growth promotion. Subsequent RNA sequencing (RNA-seq) of overexpressed Wnt10b and control groups unveiled the regulatory role of Wnt10b in DPC. Numerous genes and pathways, including developmental pathways such as Wnt and MAPK, as well as processes like hair follicle morphogenesis and hair cycle, were identified. These results suggest that Wnt10b promotes the growth of secondary hair follicles in Inner Mongolian cashmere goats by regulating crucial factors and pathways in DPC proliferation.

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BACKGROUND: Wnt10b is one of critical Wnt family members that being involved in networks controlling stemness, pluripotency and cell fate decisions. However, its role in adipose-resident T lymphocytes and further in fat metabolism yet remains largely unknown. METHODS AND RESULTS: In the present study, we demonstrated a distinctive effect for Wnt10b on the relative balance of T lymphocytes in adipose tissue by using a Wnt10b knockdown mouse model. Wnt10b knockdown led to a reduction of adipose-resident CD4+ T cells and an elevation of Foxp3+/CD4+ Treg cells. Wnt10b-knockdown mice fed with standard diet showed less white fat deposition owing to the suppressed adipogenic process. Moreover, under high fat diet conditions, Wnt10b knockdown resulted in an alleviated obesity symptoms, as well as an improvement of glucose homeostasis and hepatic steatosis. CONCLUSIONS: Collectively, we reveal an unexpected and novel function for Wnt10b in mediating the frequency of adipose-resident T cell subsets, that when knockdown skewing toward a Treg-dominated phenotype and further improving fat metabolism.

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Objective: Colorectal cancer remains a significant challenge with high mortality rates. The aim of this study was to investigate the effect of targeting the microRNA-148a/WNT10b axis with the long non-coding RNA LINC00261 on the proliferation and apoptosis of colorectal cancer cells. Methods: In vitro, small interfering RNA-LINC00261 and microRNA-148 inhibitor sequences were synthesized and transfected into SW480 cells. The study groups included a control group, small interfering RNA negative control group, small interfering RNA group, small interfering RNA negative control + microRNA -inhibitor group, small interfering RNA + microRNA -inhibitor group, and small interfering RNA + microRNA-negative control group. The transfection efficiency and expression levels of LINC00261 and miR-148a were evaluated by quantitative reverse transcription polymerase chain reaction. Cell proliferation, apoptosis, cell cycle distribution, and protein expression levels of WNT10b and ß-catenin were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, flow cytometry, and Western blot, respectively. Results: After small interfering RNA-LINC00261 transfection, a significant decrease in cell proliferation (p < 0.05) and an increase in apoptosis (p < 0.05) were observed, accompanied by cell cycle arrest in the G1 phase. Inhibition of LINC00261 by small interfering RNA resulted in increased microRNA-148a expression and decreased protein expression of WNT10b and ß-catenin. However, the small interfering RNA + microRNA inhibitor group showed significantly increased levels of WNT10b and ß-catenin protein expression. Conclusions: These results suggest that silencing of long non-coding RNA LINC00261 could potentially affect the proliferation of SW480 cells by regulating the micro RNA -148a/WNT10b axis.

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Introduction: Split hand and foot malformation (SHFM) or ectrodactyly is a rare limb deformity characterized by median cleft of the hand and foot with impaired or missing central rays. It can occur as an isolated anomaly or in association with abnormalities of other body parts. Methods: After delineating the clinical features of two families (A-B), with non-syndromic SHFM, exome and Sanger sequencing were employed to search for the disease-causing variants. Results: Analysis of exome and Sanger sequencing data revealed two causative variants in the WNT10B gene in affected members of the two families. This included a novel missense change [c.338G>C; p.(Gly113Ala)] in family A and a previously reported frameshift variant [c.884-896delTCCAGCCCCGTCT; p.(Phe295Cysfs*87)] in family B. Conclusion: Our findings add a novel variant in WNT10B gene as the underlying cause of SHFM. The finding adds to the growing body of knowledge about the genetic basis of developmental disorders and provides valuable insights into the molecular mechanisms that regulate limb development.

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OBJECTIVE: This study aimed to evaluate the Wnt/ß-catenin signaling pathway activity in gingival samples obtained from patients with periodontitis. MATERIALS AND METHODS: Fifteen patients with stage III grade B (SIIIGB) and eleven with stage III grade C (SIIIGC) periodontitis were included and compared to 15 control subjects. ß-Catenin, Wnt 3a, Wnt 5a, and Wnt 10b expressions were evaluated by Q-PCR. Topographic localization of tissue ß-catenin, Wnt 5a, and Wnt 10b was measured by immunohistochemical analysis. TNF-α was used to assess the inflammatory state of the tissues, while Runx2 was used as a mediator of active destruction. RESULTS: Wnt 3a, Wnt 5a, and Wnt 10b were significantly higher in gingival tissues in both grades of stage 3 periodontitis compared to the control group (p < 0.05). ß-Catenin showed intranuclear staining in connective tissue in periodontitis, while it was confined to intracytoplasmic staining in epithelial tissue and the cell walls in the control group. Wnt5a protein expression was elevated in periodontitis, with the most intense staining observed in the connective tissue of SIIIGC samples. Wnt10b showed the highest density in the connective tissue of patients with periodontitis. CONCLUSIONS: Our findings suggested that periodontal inflammation disrupts the Wnt/ß-catenin signaling pathway. CLINICAL RELEVANCE: Periodontitis disrupts Wnt signaling in periodontal tissues in parallel with tissue inflammation and changes in morphology. This change in Wnt-related signaling pathways that regulate tissue homeostasis in the immunoinflammatory response may shed light on host-induced tissue destruction in the pathogenesis of the periodontal disease.

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The effect of Wnt10b overexpression on adipose tissue development has been reported. However, the impact of Wnt10b knockdown on the function of brown adipose tissue (BAT) is yet largely unknown. Here, we used the CRISPR/Cas9 technique to generate Wnt10b-knockdown (Wnt10b+/- ) mice. We compared the development and thermogenic gene expression of interscapular BAT (iBAT) between Wnt10b+/- and Wnt10b+/+ mice under a chow diet, high-fat diet (HFD), and cold exposure conditions. Moreover, the effect of Wnt10b knockdown on brown adipocyte function was tested via in vitro experiments. Results indicated that Wnt10b knockdown decreased the iBAT mass and the brown adipocyte size and enhanced thermogenic gene expression, including UCP1, under chow diet conditions. In addition, Wnt10b+/- mice appeared to be able to maintain their body temperature better than the control in a cold environment, accompanied by higher UCP1 protein expression. Intriguingly, even under HFD conditions, Wnt10b+/- mice still showed higher UCP1 expression, which was associated with an alleviated obesity phenotype. In vitro studies further evidenced the Wnt10b knockdown stimulation of UCP1 expression and suppression of the adipogenic program. This study indicates that Wnt10b knockdown enhances UCP1 expression and inhibits the adipogenic differentiation of brown adipocytes, providing a novel option for therapeutic interventions in adiposity.

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In this study, Wingless-type MMTV (mouse mammary tumor virus) integration site family member (WNT10B) gene was sequence characterized in the Indian water buffalo. Sequence analysis revealed an open reading frame of 1176 nucleotides in buffalo, encoding 391 amino acids long protein. Nineteen nucleotide variations were observed between cattle and buffalo resulting in six amino acid changes. Phylogenetic analysis showed the clustering of ruminant species together. Real-time expression analysis of WNT10B in tissues collected from different organs of fetal and adult buffalo, revealed, the gene being abundantly expressed in the rumen and liver of the fetus. The fetal ovary, heart, kidney, lung, testis and mammary gland showed moderate expression, while in adult tissues, expression was high in the ovary, testis, brain, kidney, small intestine and liver, whereas lower expression was observed in the adult rumen. Significant differences in WNT10B expression levels were found for the brain, small intestine, testes, kidney, heart, rumen, and ovary when adult and fetal tissues were compared. A moderate level of genetic variation was found between cattle and buffalo WNT10B and expression patterns in a variety of tissues in adult buffalo implies that in addition to possible roles in adipogenesis and hematopoiesis, the WNT10B gene might be playing a significant role in other regulatory pathways as well.

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Introduction: Authors report a rare case report about split hand and foot malformation (SHFM) also sometimes referred to as ectrodactyly. Case Report: The patient with hand and foot malformations presented to casualty. A 60-year-old male was brought with alleged history of road traffic accident with tenderness and deformity in left thigh. On further physical examination, a malformation was present in bilateral feet and right hand. Plain radiographs were taken after emergency primary management which revealed a fracture of shaft of femur of the left side and absence of 2nd and 3rd phalanges in bilateral feet and lobster claw like malformation in the right hand. The patient was further investigated and operated with femur interlocking nail and later discharged under stable condition. Screening for other congenital defects was done. Conclusion: Patients with SHFM should undergo screening for other congenital anomalies. Electrocardiogram, 2D ECHO, chest radiograph, and ultrasonography abdomen should be done. Genetic analysis ideally should be done to identify mutations involved. Surgical intervention is only required when patient demands improved function of limb.

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BACKGROUND: The fat storage capacity of the adipose tissue prevents ectopic lipid deposition, which is one of the risk factors for metabolic abnormalities in obesity. This capacity depends upon the adipogenic gene expression and blood supply provision for tissue expansion through angiogenesis. Here, we studied hyperplasia/hypertrophy of subcutaneous white adipose tissue (scWAT) concerning adipogenic gene expression, angiogenic status, and metabolic parameters in non-obese and different classes of obese individuals. METHODS: The scWAT samples were collected from 80 individuals. The anthropometric parameters, adipose tissue cell size, serum biochemistry, ER stress-induced XBP1 splicing, PPARγ2, SFRP1, WNT10B, and VEGFA gene expression levels were studied. In addition, the CD31 level was investigated by Western blotting. RESULTS: The obese individuals had greater waist circumferences and higher serum TG, TC, insulin, and HOMA-IR than the non-obese group. However, the largest adipocyte size, increased TNFα, insulin, and HOMA-IR, and the highest expression level of sXBP1, WNT10B, and VEGFA were observed in Class I obese individuals. It means that inflammation, insulin resistance, and ER stress accompany hypertrophic scWAT adipocytes with limited adipose tissue expansion ability. Furthermore, the Class II + III obese individuals showed high PPARγ2 expression and CD31 levels. There is adipogenesis through hyperplasia in this group. The SFRP1 expression was not significantly different in the studied groups. CONCLUSION: The results suggest that the capability of adipogenesis with inadequate angiogenesis is related to the metabolic status, inflammation, and ER function. Therefore, therapeutic strategies that support both angiogenesis and adipogenesis can effectively prevent the complications of obesity.

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WNT10B, a member of the WNT family of secreted glycoproteins, activates the WNT/ß-catenin signaling cascade to control proliferation, stemness, pluripotency, and cell fate decisions. WNT10B plays roles in many tissues, including bone, adipocytes, skin, hair, muscle, placenta, and the immune system. Aberrant WNT10B signaling leads to several diseases, such as osteoporosis, obesity, split-hand/foot malformation (SHFM), fibrosis, dental anomalies, and cancer. We reviewed WNT10B a decade ago, and here we provide a comprehensive update to the field. Novel research on WNT10B has expanded to many more tissues and diseases. WNT10B polymorphisms and mutations correlate with many phenotypes, including bone mineral density, obesity, pig litter size, dog elbow dysplasia, and cow body size. In addition, the field has focused on the regulation of WNT10B using upstream mediators, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). We also discussed the therapeutic implications of WNT10B regulation. In summary, research conducted during 2012-2022 revealed several new, diverse functions in the role of WNT10B in physiology and disease.

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WNT molecules are the regulators of various biological functions, including body axis formation, organ development, and cell proliferation and differentiation. WNTs have been extensively studied as causative genes for an array of diseases. WNT10A and WNT10B, which are considered to be genes of the same origin, have been identified as causative genes for tooth deficiency in humans. However, the disrupted mutant of each gene does not show a decrease in teeth number. A negative feedback loop, interacting with several ligands based on a reaction-diffusion mechanism, was proposed to be important for the spatial patterning of tooth formation, and WNT ligands have been considered to play a pivotal role in controlling tooth patterning from mutant phenotypes of LDL receptor-related proteins (LRPs) and WNT co-receptors. The Wnt10a and Wnt10b double-mutants demonstrated severe root or enamel hypoplasia. In Wnt10a-/- and Wnt10a+/-;Wnt10b-/- mice, changes in the feedback loop may collapse the modulation of fusion or split a sequence of tooth formation. However, in the double-knockout mutant, a decrease in the number of teeth was observed, including the upper incisor or third molar in both jaws. These findings suggest that there may be a functional redundancy between Wnt10a and Wnt10b and that the interaction between the two genes functions in conjunction with other ligands to control the spatial patterning and development of teeth.

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Following the publication of this article, a concerned reader drew to the Editor's attention that various of the data panels showing the results from Transwell cell migration and invasion assay experiments in Figs. 2D and 4D contained groupings of cells that were markedly similar, even though the cells appeared in separate panels that were intended to show the results from different experiments. In addition, the cell images shown in Fig. 2B were strikingly similar to data that had appeared in different form in another article published by different authors at a different research institution. After having conducted an internal investigation of this matter, the Editor of Oncology Reports has judged that the groupings of cells, appearing as they did among various different panels in Figs. 2 and 4, were too extensive that their apperance could have been attributed to pure coincidence. Also in view of the fact that some of the data were derived from a previously published source, the Editor has decided that this article should be retracted from the publication. After having been in contact with the authors of this study, they agreed with the Editor's decision to retract this article. The Editor sincerely apologizes to the readership for any incovenience caused, and we thank the reader for bringing this matter to our attention. [Oncology Reports 38: 301­308, 2017; DOI: 10.3892/or.2017.5705].

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Adverse events of diabetes mellitus (DM) include bone damages, such as the increased incidence of osteoporosis and bone fractures, which are known as diabetic osteopathy. The pathogenic mechanism of diabetic osteopathy is complex, and hyperglycemia is a vital cause involved in it. Bone marrow mesenchymal stem cells (BMSCs) exert a significant effect on bone formation. Therefore, in this paper, transcriptomic changes of BMSCs cultured in high glucose (35 mM) for 30 days are mainly investigated. In addition, 794 up-regulated genes and 1,162 down-regulated genes were identified. Then, biological functions of the differentially expressed genes in the high glucose microenvironment were investigated by two kinds of functional analyses. Gene Set Enrichment Analysis was also applied to focus on the significant gene sets and it is found that Wnt10b expression witnessed a remarkable decrease in BMSCs under the high glucose microenvironment. At last, in vitro experiments revealed that oleuropein effectively reversed high glucose-induced osteogenic inhibition via activating Wnt10b in BMSCs.

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When fish are under oxidative stress, levels of reactive oxygen species (ROS) are chronically elevated, which play a crucial role in fish innate immunity. In the present study, the mechanism by which betaine regulates ROS production via Wnt10b/ß-catenin signaling was investigated in zebrafish liver. Our results showed that betaine enrichment of diet at 0.1, 0.2 and 0.4 g/kg induced Wnt10b and ß-catenin gene expression, but suppressed GSK-3ß expression in zebrafish liver. In addition, the content of superoxide anion (O2 ·-), hydrogen peroxide (H2O2) and hydroxyl radical (·OH) was decreased by all of the experimental betaine treatments. However, betaine enrichment of diet at 0.1, 0.2 and 0.4 g/kg enhanced gene expression and activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-PX) and catalase (CAT) in zebrafish liver. In addition, Wnt10b RNA was further interfered in zebrafish, and the results of Wnt10b RNAi indicated that Wnt10b plays a key role in regulating ROS production and antioxidant enzyme activity. In conclusion, betaine can inhibit ROS production in zebrafish liver through the Wnt10b/ß-catenin signaling pathway.

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The self-renewal of spermatogonial stem cells (SSCs) requires a special microenvironment and is strictly controlled. Previously, we identified BMI1 as a key regulator of spermatogenesis in a knock-out mouse model. However, the mechanisms by which BMI1 regulates SSC maintenance remain largely unknown. Herein, we show that BMI1 is essential for SSC maintenance. BMI1 directs the transcriptional repression of target genes by increasing H2AK119ub and reducing H3K4me3 in SSCs. Furthermore, BMI1 inhibition resulted in the transcriptional activation of Wnt10b and thereby promoted the nuclear translocation of ß-catenin in SSCs. Importantly, the suppression of Wnt/ß-catenin signaling restored both the cytoplasmic expression of ß-catenin and SSC maintenance in BMI1-deficient SSCs. Finally, we demonstrated that Wnt/ß-catenin signaling was also involved in BMI1-mediated SSC maintenance in vivo. Altogether, our study not only reveals a novel mechanism for BMI1 in the process of SSC maintenance, but also provides a potential new strategy for treating male infertility.

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SCOPE: Clostridium butyricum (CB) exerts beneficial actions in several disorders. However, the impact and molecular cues of CB in fat metabolism remain elusive. This study demonstrates the CB inhibition of fat deposition by increasing the relative number of adipose tissue-resident Treg cells (aTregs). METHODS AND RESULTS: CB is administered orally to wild type (WT) mice fed with chow diet, which decrease fat deposition and adipogenic gene expression, associating with elevated serum levels of butyrate. Sodium butyrate (SB) feeding mimics the CB suppression of fat accumulation. Of note, the frequency of aTregs in both the CB and SB treatments, analyzed by flow cytometry, is markedly increased, accompanied by activated Wnt10b expression in white adipose tissues. However, CB and SB fail to inhibit fat deposition in Wnt10b-KO mice. Intriguingly, CB and SB are able to alleviate the obesity, fatty liver, and glucose abnormalities in high fat diet (HFD)-fed WT mice. CONCLUSIONS: These findings suggest that CB, through its metabolite butyrate, inhibits fat deposition via potentiating aTreg cell generation, and support the option of CB and SB for therapeutic interventions in obesity and related disorders.

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Sinomenine hydrochloride (SH) has anti-breast cancer effect, but whether it can act on breast cancer stem cells (BCSCs) is unclear. Here, we explored the effect of SH on BCSCs and its mechanism. We observed that SH decreased the ratio of CD44+/CD24- BCSCs and the expression of BCSCs-related genes in MCF-7 and MDA-MB-231 cells. SH significantly inhibited the stemness of CD44+/CD24- BCSCs, including the capacity of self-renewal, oncosphere formation, migration and invasion, and the expression of stemness-related genes. Furthermore, SH obviously inhibited the expression of Wnt signaling pathway genes in CD44+/CD24- BCSCs, especially the expression of WNT10B and its downstream target genes. While WNT10B was overexpressed, the inhibitory effect of SH on the stemness of BCSCs was blocked, indicating that SH inhibited the stemness of BCSCs by down-regulating WNT10B. When WNT10B was knocked down, the stemness of BCSCs was significantly inhibited, indicating that WNT10B was involved in the stemness maintenance of BCSCs. SH also significantly inhibited the growth of MDA-MB-231 BCSCs xenografts, decreased the expression of BCSCs related genes and suppressed Wnt signaling pathway in vivo. In conclusion, SH negatively regulates the stemness of CD44+/CD24- BCSCs by inhibiting Wnt signaling pathway through down-regulation of WNT10B expression.

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Long non-coding RNAs (lncRNAs) have gained extensive attentions due to their significant roles in diverse biological process. However, the potential functions of lncRNAs participation in adipocyte differentiation have not been fully explored. In the present study, we globally profiled lncRNA expression using lncRNA microarray and identified 1745 lncRNA probes with differential expression on day 0 and day 4 post-induction in both C3H10T1/2 mesenchymal stem cells and 3T3-L1 preadipocytes. Furthermore, we showed that stable shRNA knockdown (KD) of NR_015556, a novel lncRNA that was significantly down-regulated in adipocyte differentiation, promoted adipocyte differentiation by increasing the number of lipid droplets and adipocyte markers such as Fabp4, Adipsin and Fasn. Mechanistically, NR_015556 KD attenuated the expression of Wnt signaling components Wnt10b and non-phospho (active) ß-catenin, and elevated adipocyte master factors Ppar-γ and C/EBPα levels. Conversely, pharmacological activation of Wnt10b-ß-catenin signaling by LiCl suppressed NR_015556 KD-induced enhancement of adipocyte differentiation and Ppar-γ and C/EBPα expression levels. Taken together, these results indicate that down-regulation of NR_015556 promotes adipocyte differentiation through inhibiting Wnt10b-ß-catenin signaling pathway and then elevating Ppar-γ and C/EBPα triggered transcriptional cascades.

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