UNASSIGNED: To investigate the expression levels and diagnostic value of glial cell line-derived neurotrophic factor (GDNF), carcinoembryonic antigen (CEA) and carbohydrate antigen199 (CA199) in patients with colorectal carcinoma (CRC).
UNASSIGNED: 50 CRC patients at our hospital from Feb. 2020 to Feb. 2021 were chosen as the malignant group, another 50 patients with benign colonic diseases were chosen as the benign group, and 50 healthy people who came to our hospital for physical examination during the same period were considered as the control group. Fasting peripheral venous blood was taken from all research subjects in the morning and tested by a fully-automated electrochemiluminometer to determine the GDNF, CEA and CA199 levels. The sensitivity and specificity of the combined detection of the three indexes for CRC were analyzed, and the receiver operating characteristic (ROC) curve was plotted to record the area under the curve (AUC).
UNASSIGNED: The malignant group had remarkably higher CEA and CA199 levels (P<0.001) and a lower GDNF level (P<0.001) when compared with the benign and control groups. The sensitivity, specificity, positive predictive value and negative predictive value of the combined detection were 96.0%, 94.0%, 88.9% and 97.9%, respectively. Under combined detection, AUC (95% CI) = 0.950 (0.909-0.991), standard error = 0.021, and P<0.001.
UNASSIGNED: The combined diagnosis of serum GDNF, CEA and CA199 is a reliable method to improve the diagnostic accuracy of CRC, and this strategy can effectively reduce the missed diagnosis rate and has high application value in clinic.
UNASSIGNED: Cilj je bio da se istraže nivoi ekspresije i dijagnostička vrednost neurotrofnog faktora (GDNF), karcinoembrionalnog antigena (CEA) i antigena ugljenih hidrata 199 (CA199) kod pacijenata sa kolorektalnim karcinomom (CRC).
UNASSIGNED: Za malignu grupu izabrano je 50 pacijenata sa CRC u našoj bolnici od februara 2020. do februara 2021. godine, za benignu grupu je izabrano još 50 pacijenata sa benignim oboljenjima debelog creva, a 50 zdravih ljudi koji su došli u našu bolnicu na fizički pregled tokom istog period su smatrani kontrolnom grupom. Periferna venska krv natašte je uzeta od svih ispitanika ujutru i testirana potpuno automatizovanim elektrohemiluminometrom da bi se odredili nivoi GDNF, CEA i CA199. Analizirana je osetljivost i specifičnost kombinovane detekcije tri indeksa za CRC, a kriva radne karakteristike prijemnika (ROC) je ucrtana da bi se zabeležila površina ispod krive (AUC).
UNASSIGNED: Maligna grupa je imala značajno više nivoe CEA i CA199 (P<0,001) i niži nivo GDNF (P<0,001) u poređenju sa benignom i kontrolnom grupom. Osetljivost, specifičnost, pozitivna prediktivna vrednost i negativna prediktivna vrednost kombinovane detekcije iznosile su 96,0%, 94,0%, 88,9% i 97,9%, respektivno. Pod kombinovanom detekcijom, AUC (95% CI) = 0,950 (0,909-0,991), standardna greška = 0,021 i P<0,001.
UNASSIGNED: Kombinovana dijagnoza serumskog GDNF, CEA i CA199 je pouzdana metoda za poboljšanje dijagnostičke tačnosti CRC, a ova strategija može efikasno smanjiti stopu promašene dijagnoze i ima visoku primenu u klinici.

Motor functional improvement represents a paramount treatment objective in the post-spinal cord injury (SCI) recovery process. However, neuronal cell death and axonal degeneration following SCI disrupt neural signaling, impeding the motor functional recovery. In this study, we developed a multifunctional decellularized spinal cord-derived extracellular matrix (dSECM), crosslinked with glial cell-derived neurotrophic factor (GDNF), to promote differentiation of stem cells into neural-like cells and facilitate axonogenesis and remyelination. After decellularization, the immunogenic cellular components were effectively removed in dSECM, while the crucial protein components were retained which supports stem cells proliferation and differentiation. Furthermore, sustained release of GDNF from the dSECM facilitated axonogenesis and remyelination by activating the PI3K/Akt and MEK/Erk pathways. Our findings demonstrate that the dSECM-GDNF platform promotes neurogenesis, axonogenesis, and remyelination to enhance neural signaling, thereby yielding promising therapeutic effects for motor functional improvement after SCI. STATEMENT OF SIGNIFICANCE: The dSECM promotes the proliferation and differentiation of MSCs or NSCs by retaining proteins associated with positive regulation of neurogenesis and neuronal differentiation, while eliminating proteins related to negative regulation of neurogenesis. After crosslinking, GDNF can be gradually released from the platform, thereby promoting neural differentiation, axonogenesis, and remyelination to enhance neural signaling through activation of the PI3K/Akt and MEK/Erk pathways. In vivo experiments demonstrated that dSECM-GDNF/MSC@GelMA hydrogel exhibited the ability to facilitate neuronal regeneration at 4 weeks post-surgery, while promoting axonogenesis and remyelination at 8 weeks post-surgery, ultimately leading to enhanced motor functional recovery. This study elucidates the ability of neural regeneration strategy to promote motor functional recovery and provides a promising approach for designing multifunctional tissue for SCI treatment.

Adipose tissue-derived stem cells (ADSCs) are a kind of stem cells with multi-directional differentiation potential, which mainly restore tissue repair function and promote cell regeneration. It can be directionally differentiated into Schwann-like cells to promote the repair of peripheral nerve injury. Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the repair of nerve injury, but the underlying mechanism remains unclear, which seriously limits its further application.The study aimed to identify the molecular mechanism by which overexpression of glial cell line-derived neurotrophic factor (GDNF) facilitates the differentiation of ADSCs into Schwann cells, enhancing nerve regeneration after injury. In vitro, ADSCs overexpressing GDNF for 48 h exhibited changes in their morphology, with 80% of the cells having two or more prominences. Compared with that of ADSCs, GDNF-ADSCs exhibited increased expression of the Schwann cell marker S100, nerve damage repair-related factors.ADSC cells in normal culture and ADSC cells were overexpressing GDNF(GDNF-ADSCs) were analysed using TMT-Based Proteomic Analysis and revealed a significantly higher expression of MTA1 in GDNF-ADSCs than in control ADSCs. Hes1 expression was significantly higher in GDNF-ADSCs than in ADSCs and decreased by MTA1 silencing, along with a simultaneous decrease in the expression of S100 and nerve damage repair factors. These findings indicate that GDNF promotes the differentiation of ADSCs into Schwann cells and induces factors that accelerate peripheral nerve damage repair.

Cattleyak is a typically male sterile species. The meiosis process is blocked and the scarcity of spermatogenic stems cells are both contributing factors to the inability of male cattleyak to produce sperm. While Glial cell line-derived neurotrophic factor (GDNF) is the first discovered growth factor known to promote the proliferation and self-renewal of spermatogenic stem cells, its relationship to the spermatogenesis arrest of cattleyak remains unclear. In this report, we studied the differential expression of GDNF in the testis of yak and cattleyak, and discussed the optimal concentration of GDNF in the culture medium of undifferentiated spermatogonia (UDSPG) of cattleyak in vitro and the effect of GDNF on the proliferation of cattleyak UDSPG. The results indicated that GDNF expression in the testicular tissue of cattleyak was inferior to that of yak. Moreover, the optimum value for the UDSPG in vitro culture was determined to be 20-30 ng/mL for cattleyak. In vitro, the proliferation activity of UDSPG was observed to increase with additional GDNF due to the up-regulation of proliferation-related genes and the down-regulation of differentiation-related genes. We hereby report that the scarcity of cattleyak UDSPG is due to insufficient expression of GDNF, and that the addition of GDNF in vitro can promote the proliferation of cattleyak UDSPG by regulating the expression of genes related to proliferation and differentiation. This work provides a new insight to solve the issue of spermatogenic arrest in cattleyak.

Germ cell transplantation (GCT) is a promising biotechnology that enables the production of donor-derived gametes in surrogate recipients. It plays a crucial role in the protection of endangered species, the propagation of elite species with desired traits, and long-term preservation of genetic resources. This significance is particularly pronounced when GCT is synergistically employed with cryopreservation techniques. However, GCT often encounters challenges due to low colonization rates and, in some cases, complete loss of donor cells in recipients. Glial cell line-derived neurotrophic factor (GDNF) plays a pivotal role in sustaining the self-renewal of spermatogonial stem cells (SSCs) in mammals. Additionally, it has been shown to promote the proliferation of spermatogonia in vitro cultures in certain animal species. In turbot (Scophthalmus maximus), we found that the expressions of gdnf and gfrα1a were predominantly observed in spermatogonia rather than somatic cells, which differed from their expression patterns in mammals. The efficiency of exogenous spermatogonia transplantation in Japanese flounder (Paralichthys olivaceus) larvae could be substantially enhanced by incubating donor cells from turbot with 100 ng/ml GDNF prior to transplantation. This led to a noteworthy increase in the colonization rate, rising from 33%-50%-61.5%. Additionally, the addition of 20 ng/ml GDNF in cell medium could also promote the proliferation of turbot germ cells in vitro. These results demonstrated the gdnf in turbot testis expression characteristics and suggested that addition of GNDF could be an effective way to improve the GCT efficiency and promote the germ cells expansion during in vitro culture.

BACKGROUND: Testosterone contributes to male organism development, such as bone density, muscle development, and fat repartition. Estrogen (derived from testosterone) also contributes to female reproductive system development. Here, we investigated the effect of testosterone on glioma cells and brain neuron inflammation essential for cancer development and progression.
METHODS: The human astrocyte and glioma cell lines were treated with 6 ng/ml exogenous testosterone in vitro. We performed cell counting kit-8, transwell, and wound healing assays to determine the effect of testosterone on glioma cell proliferation, migration, and invasion. The glioma cells were injected into the xenograft and treated with 5 µl concentrated testosterone. Transcriptional suppression of glial cell line-derived neurotrophic factor (GDNF) was performed to evaluate brain neuron inflammation and survival. The tumor tissues were assessed by hematoxylin-eosin staining and immunohistochemistry.
RESULTS: Testosterone upregulates GDNF to stimulate proliferation, migration, and invasion of glioma cells. Pathologically, the augmentation of GDNF and cyclophilin A contributed to neuroprotection when treated with testosterone. Our investigation showed that testosterone contributes to brain neuron and astrocyte inflammation through the upregulation of nuclear factor erythroid 2-related factor 2 (NRF2), glial fibrillary acid protein (GFAP), and sirtuin 5 (SIRT5), resulting in pro-inflammatory macrophages recruitments into the neural microenvironment. Mechanically, testosterone treatment regulates GDNF translocation from the glioma cells and astrocyte nuclei to the cytoplasm.
CONCLUSIONS: Testosterone upregulates GDNF in glioma cells and astrocytes essential for microglial proliferation, migration, and invasion. Testosterone contributes to brain tumor growth via GDNF and inflammation. The contribution of testosterone, macrophages, and astrocytes, in old neuron rescue, survival, and proliferation. During brain neuron inflammation, the organism activates and stimulates the neuron rescue through the enrichment of the old neuron microenvironment with growth factors such as GDNF, BDNF, SOX1/2, and MAPK secreted by the surrounding neurons and glial cells to maintain the damaged neuron by inflammation alive even if the axon is dead. The immune response also contributes to brain cell survival through the secretion of proinflammatory cytokines, resulting in inflammation maintenance. The rescued old neuron interaction with infiltrated macrophages contributes to angiogenesis to supplement the old neuron with more nutrients leading to metabolism activation and surrounding cell uncontrollable cell growth.

Aberrations in brain connections are implicated in the pathogenesis of Parkinson\'s disease (PD). We previously demonstrated that Glial cell-derived neurotrophic factor (GDNF) reduction is associated with cognition decline. Nonetheless, it is elusive if the pattern of brain topological connectivity differed across PD with divergent serum GDNF levels, and the accompanying profile of cognitive deficits has yet to be determined.
We collected data on the participants\' cognition, demographics, and serum GDNF levels. Participants underwent 3.0T magnetic resonance imaging, and we assessed the degree centrality, brain network topology, and cortical thickness of the healthy control (HC) (n = 25), PD-high-GDNF (n = 19), and PD-low-GDNF (n = 19) groups using graph-theoretic measures of resting-state functional MRI to reveal how much brain connectivity varies and its clinical correlates, as well as to determine factors predicting the cognitive status in PD.
The results show different network properties between groups. Degree centrality abnormalities were found in the right inferior frontal gyrus and right parietal lobe postcentral gyrus, linked with cognition scores. The two aberrant clusters serve as a potentially powerful signal for determining whether a patient has PD and the patient\'s cognition level after integrating with GDNF, duration, and dopamine dosage. Moreover, we found a significant positive relationship between the thickness of the left caudal middle frontal lobe and a plethora of cognitive domains. Further discriminant analysis revealed that the cortical thickness of this region could distinguish PD patients from healthy controls. The mental state evaluation will also be more precise when paired with GDNF and duration.
Our findings reveal that the topological features of brain networks and cortical thickness are altered in PD patients with cognitive deficits. The above change, accompanied by the serum GDNF, may have merit as a diagnosis marker for PD and, arguably, cognition status.

The teratomas formation has severely hindered the application of embryonic stem cells (ESCs) in clinical trials. Apurinic/apyrimidinic endonuclease 1 (APE1) is strongly involved in the development of tumors and differentiation process of stem cells. However, the role of APE1 in teratomas remains unknown. The expression of APE1 was examined in mouse ESCs (mESCs) by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. The role and mechanism of APE1 in the proliferation, pluripotency and differentiation of E14 cells were determined by cell counting, flow cytometry and western blot assays. Besides, the role of APE1 in teratomas was also probed in xenografted mice. The expression of APE1 was upregulated in mESCs with differentiation. Knockdown of APE1 reduced the cell numbers, induced the arrest of the G2/M phase, and decreased the expression of cell cycle-related proteins in E14 cells. Besides, loss- and gain-of-function assays revealed that APE1 enhanced the levels of proteins involved in pluripotency, reduced the protein expression of ectoderm markers, and increased the protein levels of endoderm markers in E14 cells. Mechanically, inhibition of APE1 downregulated the expression of GDNF and GFRα1 in E14 cells. GDNF reversed the role of APE1 in the proliferation, pluripotency and embryogenesis of E14 cells. Moreover, suppression of APE1 reduced the teratoma volume and the relative protein expression of endoderm markers, but increased the relative protein expression of ectoderm markers in xenografted mice. Collectively, knockdown of APE1 attenuated proliferation, pluripotency and embryogenesis of mESCs via GDNF/GFRα1 axis.

How to efficiently regenerate jawbone defects caused by trauma, jaw osteomyelitis, tumors, or intrinsic genetic diseases is still challenging. Ectoderm-derived jawbone defect has been reported to be regenerated by selectively recruiting cells from its embryonic origin. Therefore, it is important to explore the strategy for promoting ectoderm-derived jaw bone marrow mesenchymal stem cells (JBMMSCs) on the repair of homoblastic jaw bone. Glial cell-derived neurotrophic factor (GDNF) is an important growth factor and is essential in the process of proliferation, migration and differentiation of nerve cells. However, whether GDNF promoting the function of JBMMSCs and the relative mechanism are not clear. Our results showed that activated astrocytes and GDNF were induced in the hippocampus after mandibular jaw defect. In addition, the expression of GDNF in the bone tissue around the injured area was also significantly increased after injury. Data from in vitro experiments demonstrated that GDNF could effectively promote the proliferation and osteogenic differentiation of JBMMSCs. Furthermore, when implanted in the defected jaw bone, JBMMSCs pretreated with GDNF exhibited enhanced repair effect compared with JBMMSCs without treatment. Mechanical studies found that GDNF induced the expression of Nr4a1 in JBMMSCs, activated PI3K/Akt signaling pathway and then enhanced the proliferation and osteogenic differentiation capacities of JBMMSCs. Our studies reveal that JBMMSCs are good candidates for repairing jawbone injury and pretreated with GDNF is an efficient strategy for enhancing bone regeneration.

RET, a single-pass receptor tyrosine kinase encoded on human chromosome 10, is well known to the field of developmental biology for its role in the ontogenesis of the central and enteric nervous systems and the kidney. In adults, RET alterations have been characterized as drivers of non-small cell lung cancer and multiple neuroendocrine neoplasms. In breast cancer, RET signaling networks have been shown to influence diverse functions including tumor development, metastasis, and therapeutic resistance. While RET is known to drive the development and progression of multiple solid tumors, therapeutic agents selectively targeting RET are relatively new, though multiple multi-kinase inhibitors have shown promise as RET inhibitors in the past; further, RET has been historically neglected as a potential therapeutic co-target in endocrine-refractory breast cancers despite mounting evidence for a key pathologic role and repeated description of a bi-directional relationship with the estrogen receptor, the principal driver of most breast tumors. Additionally, the recent discovery of RET enrichment in breast cancer brain metastases suggests a role for RET inhibition specific to advanced disease. This review assesses the status of research on RET in breast cancer and evaluates the therapeutic potential of RET-selective kinase inhibitors across major breast cancer subtypes.