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BACKGROUND: As one of the most common intracranial tumors, pituitary adenomas, especially the Cushing’s disease subtype, have been studied for many years. However, at present, effective methods for the early diagnosis of pituitary adenomas are very limited, especially for subtypes such as Cushing’s disease. Therefore, it is of urgent importance to find effective molecular targets to develop new diagnostic and therapeutic methods for pituitary adenomas. METHODS: We showed the abnormally high expression of miR-30d in pituitary adenomas by analyzing data in the Gene Expression Omnibus (GEO) database and revealed a novel molecular mechanism of miR-30d in regulating the proliferation and invasion of a pituitary adenoma cell line (AtT-20). Cell culture and transfection, and RNA interference (RNAi) were used to treat AtT-20 cells to test the effects of miR-30d and TIMP3 on cells. Quantitative polymerase chain reaction (qPCR) was used to determine the messenger RNA (mRNA) expressions. We used 3-(4,5-diphenyltetrazolium bromide) (MTT) to determine cell viabilities. An invasion assay was performed using Transwell chambers. Luciferase activity was tested with a dual-luciferase assay. RESULTS: We found that the expression of miR-30d in pituitary adenoma was higher than that in normal pituitary tissues. It was revealed that miR-30d promoted the proliferation and invasion of AtT-20 cells by inhibiting the expression of TIMP3. In the above process, miR-30d could bind to the 3'-untranslated region (3'-UTR) of TIMP3 mRNA. CONCLUSIONS: The mir-30d/TIMP3 signaling pathway plays an important regulatory role in pituitary adenomas. These new discoveries may reveal more functions of miR-30d and lay the foundation for future clinical development of new drug targets.

Background Chronic subdural hematomas (CSDHs) are one of the most common neurosurgical conditions. The standard surgical technique includes burr-hole craniostomy, followed by intraoperative irrigation and placement of subdural closed-system drainage. The drainage is generally removed after 48 hours, which can be described as fixed-time drainage strategy. According to literature, the recurrence rate is 5–33% with this strategy. In our retrospective study, postoperative hematoma volume was found to significantly increase the risk of recurrence. Based on these results, an exhaustive drainage strategy is conducted to minimize postoperative hematoma volume and achieve a low recurrence rate and good outcomes. Methods This is a prospective, multicenter, randomized controlled trial designed to include 304 participants over the age of 18–90 years presenting with a symptomatic CSDH verified on cranial computed tomography or magnetic resonance imaging. Participants will be randomly allocated to perform exhaustive drainage (treatment group) or fixed-time drainage (control group) after one-burr hole craniostomy. The primary endpoint will be recurrence indicating a reoperation within 6 months. Discussion This study will validate the effect and safety of exhaustive drainage after one-burr hole craniostomy in reducing recurrence rates and provide critical information to improve CSDH surgical management. Trial registration Clinicaltrials.gov, NCT04573387. Registered on October 5, 2020. (https://www.clinicaltrials.gov/ct2/show/study/NCT04573387.)

Bone cancer pain (BCP) is a difficult-to-treat pathologic condition that impairs the patient's quality of life. The effective therapy options for BCP are restricted due to the unknown pathophysiology. Transcriptome data were obtained from the Gene Expression Omnibus (GEO) database and differentially expressed gene (DEGs) extraction was performed. Differentially expressed genes analysis (DEGs) integrated with pathological targets found 68 genes in the study. Butein was discovered as a possible medication for BCP after the 68 genes were submitted to the Connectivity Map (CMap) 2.0 database for drug prediction. To collect the butein targets, we used the CTD, SEA, TargetNet, and Super-PRED databases. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses revealed butein's pharmacological effects, indicating that butein may aid in treating BCP by altering the hypoxia-inducible factor, NF-kappa B, angiogenesis, and sphingolipid signaling pathways. Moreover, the pathological targets integrated with drug targets were obtained as the shared gene set A (GSA), which was analyzed by ClueGO and MCODE. Biological process analysis and MCODE algorithm further analyzed that BCP related targets were mainly involved in signal transduction process and ion channel-related pathways. Next, we integrated targets related to network topology parameters and targets of core pathways, identified PTGS2, EGFR, JUN, ESR1, TRPV1, AKT1 and VEGFA as butein regulated hub genes by molecular docking, which play a critical role in its analgesic effect. This study lays the scientific groundwork for elucidating the mechanism underlying butein's success in the treatment of BCP.

Background: CFTR, a chloride channel protein expressed on cell membrane, plays an important role in the transdermal transport of salt and the regulation of intracellular ion concentration, and may be closely related to the occurrence and development of cancer. Methods: In this study, the expression level of CFTR in hepatocellular carcinoma (HCC) and its correlation with metastasis and prognosis were predicted by TGCA, GEPIA and GTEx databases. By constructing MHCC97H with stable overexpression of CFTR and HepG2 with stable interference expression of CFTR cell lines, the expression level of CFTR and its correlation with proliferation and metastasis of HCC cells were preliminarily verified by Western Blot, MTT, Transwell and PI staining. In order to further clarify the potential related mechanism, it was predicted through String and Genecards databases, and the expression level of related proteins was verified by Western Blot. And it was further verified by orthotopic HCC transplanted tumor models combined with in vivo imaging system, western blot and immunohistochemical. Finally, CLUE Command database and autodock was used to predict the potential anti-HCC drugs targeting CFTR.Results: The results showed that the expression of CFTR was significantly lower in human HCC tissues (predicted by clinical data) and HCC cells (HepG2, MHCC97L, MHCC97H), and the expression level was negatively correlated with clinical stage, prognosis (predicted by clinical data) and metastatic potency of HCC cells. CFTR could regulate the metastasis and proliferation of HCC by regulating the expression of MMP2, MMP9, E-cadherin, N-cadherin, and CyclinB1 proteins in vitro and in vivo. CFTR could regulate the expression of HSP90, TERT, and DNAJC6, which meant that HSP90, TERT, and DNAJC6 might build a bridge for CFTR to regulate proliferation and metastasis proteins. Parecoxib might be one potential anti-HCC drug by targeting CFTR.Conclusions: The above studies further clarify a potential new mechanism of HCC occurrence and metastasis, and provide potential new targets and treatment schemes for the diagnosis and treatment of HCC.

Background This study aimed to explore the molecular mechanism of mild hypothermia in in the treatment of cerebral ischemia, microRNA (miRNA) microarrays and bioinformatics analysis were employed to examine the miRNA expression profiles of rats with mild therapeutic hypothermia after middle cerebral artery occlusion (MCAO). Methods MCAO was induced in Male Sprague-Dawley rats. Mild hypothermia treatment began from the onset of ischemia and maintained for 3 hours. miRNA expressions following focal cerebral ischemia and mild hypothermia treatment were profiled using microarray technology. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to analyze the functions of the target genes in mild therapeutic hypothermia after MCAO. 60 min before MCAO, mimics and inhibitor of miR-291b were injected into the right lateral ventricle respectively, then the infarct volume and neuronal apoptosis were analyzed. Results Six upregulated miRNAs and 6 downregulated miRNAs were detected 4 hours after mild therapeutic hypothermia, and after 24 hours, 41 and 10 miRNAs were upregulated and downregulated, respectively. The target genes of the differentially expressed genes were mainly related with multicellular organism development and the mucin type O-glycan biosynthesis pathway was the most enriched KEGG pathway. Among the differentially expressed miRNAs, miR-291b was selected to assess the effects of mild therapeutic hypothermia in MCAO rats. At 24 hours after mild therapeutic hypothermia, miR-291b overexpression was proved to exhibit neuroprotective effects. Conclusions The results showed that miRNAs might play a pivotal role in mild therapeutic hypothermia in cerebral ischemia/reperfusion injury. Further understanding of the mechanism and function of miRNAs would help to illuminate the mechanism of mild therapeutic hypothermia in cerebral ischemia/reperfusion injury.

BACKGROUND: The aim of the present study was to discuss the efficacy of delayed wider endoscopic optic decompression in traumatic optic neuropathy (TON). METHODS: A total of 479 patients were treated with corticosteroids and delayed wider endoscopic optic decompression, including the injury-to-surgery interval, within 2 weeks in patients with no light perception (NLP), and within 1 month in patients with residual eyesight. Based on the traditional decompression range, the superior wall of the optic canal was further decompressed. The preoperative and postoperative visual acuities (VAs) were reviewed, and the therapeutic efficacy was analyzed. RESULTS: The final VA was 0.1 or better in 29 cases, finger count in 79 cases, hand motion in 99 cases, light perception (LP) in 25 cases, and NLP in 247 cases. A total of 136 patients (136/383, 35.5%) recovered after NLP treatment, and 78 patients (69/96, 71.9%) had improved residual eyesight. The improvement rate in patients with residual eyesight was significantly higher than that of patients with NLP (P

Background and Purpose— Interleukin-4 (IL-4) is a unique cytokine that may contribute to brain repair by regulating microglia/macrophage functions. Thus, we examined the effect of IL-4 on long-term recovery and microglia/macrophage polarization in 2 well-established stroke models. Methods— Transient middle cerebral artery occlusion or permanent distal middle cerebral artery occlusion was induced in wild-type and IL-4 knockout C57/BL6 mice. In a separate cohort of wild-type animals, IL-4 (60 ng/d for 7 days) or vehicle was infused into the cerebroventricle after transient middle cerebral artery occlusion. Behavioral outcomes were assessed by the Rotarod, corner, foot fault, and Morris water maze tests. Neuronal tissue loss was verified by 2 independent neuron markers. Markers of classically activated (M1) and alternatively activated (M2) microglia were assessed by real-time polymerase chain reaction, immunofluorescence, and flow cytometry. Results— Loss of IL-4 exacerbated sensorimotor deficits and impaired cognitive functions ≤21 days post injury. In contrast to the delayed deterioration of neurological functions, IL-4 deficiency increased neuronal tissue loss only in the acute phase (5 days) after stroke and had no impact on neuronal tissue loss 14 or 21 days post injury. Loss of IL-4 promoted expression of M1 microglia/macrophage markers and impaired expression of M2 markers at 5 and 14 days post injury. Administration of IL-4 into the ischemic brain also enhanced long-term functional recovery. Conclusions— The cytokine IL-4 improves long-term neurological outcomes after stroke, perhaps through M2 phenotype induction in microglia/macrophages. These results are the first to suggest that immunomodulation with IL-4 is a promising approach to promote long-term functional recovery after stroke.

MicroRNAs (miRNAs) regulate biogenesis and disease development by targeting numerous mRNAs. miRNA (miR)‑124 and its direct target, inhibitor of apoptosis‑stimulating protein of p53 (iASPP), may be involved in tumor development and progression. The aim of the present study was to explore the role of miR‑124‑targeted iASPP in glioma. The results demonstrated that miR‑124 was aberrantly expressed in astrocytic glioma tissue and in the human glioblastoma cell lines U87 and U251. The expression of miR‑124 was lower in astrocytic gliomas compared with normal brain (NB) tissues, with a more reduced expression in higher‑grade tumors. In addition, several miR‑124 loci (including miR‑124‑1, miR‑124‑2 and miR‑124‑3) were revealed to be more highly methylated in U87 cells compared with methylation levels in U251 cells and NB cells. Furthermore, the expression of iASPP was higher in high‑grade astrocytic gliomas compared with low‑grade astrocytic gliomas. miR‑124 overexpression effectively inhibited U87 and U251 cell migration. In addition, miR‑124 regulated cell viability and arrested the cell cycle at the G0/G1 phase in these two cell lines. miR‑124 also reduced the expression levels of the cell cycle related genes iASPP, cyclin‑dependent kinase (CDK)4, CDK6 and cyclin D1. Results from the present study indicated that expression of the miR‑124 target gene iASPP may contribute to glioma development and progression.

Background and Purpose— p53-mediated neuronal death is a central pathway of stroke pathophysiology, but its mechanistic details remain unclear. Here, we identified a novel microRNA mechanism that downregulation of inhibitory member of the apoptosis-stimulating proteins of p53 family (iASPP) by the brain-specific microRNA-124 (miR-124) promotes neuronal death after cerebral ischemia. Methods— In a mouse model of focal permanent cerebral ischemia, the expression of iASPP and miR-124 was quantified by reverse transcription quantitative real-time polymerase chain reaction, immunofluorescence staining, and Western blot. Luciferase reporter assay was used to validate whether miR-124 can directly bind to the 3′-untranslated region of iASPP mRNA. To evaluate the role of miR-124, miR-124 mimic and its inhibitor were transfected into Neuro-2a cells and C57 mice. Results— There was no change in the iASPP mRNA level in cerebral ischemia. However, iASPP protein was remarkably decreased, with a concurrent elevation in miR-124 level. Furthermore, miR-124 can bind to the 3′-untranslated region of iASPP in 293T cells and downregulate its protein levels in Neuro-2a cells. In vivo, infusion of miR-124 decreased brain levels of iASPP, whereas inhibition of miR-124 enhanced iASPP levels and significantly reduced infarction in mouse focal cerebral ischemia. Conclusions— These data demonstrate that p53-mediated neuronal cell death after stroke can be nontranscriptionally regulated by a novel mechanism involving suppression of endogenous cell death inhibitors by miR-124. Further dissection of microRNA regulatory mechanisms may lead to new therapeutic opportunities for preventing neuronal death after stroke.

To investigate the relevant factors affecting the prognosis of traumatic optic neuropathy (TON).A total of 685 cases (719 eyes) of TON from June 2007 to June 2012 were analyzed retrospectively. A total of 9 independent variables (X) including sex, side of TON, duration of coma, vision after trauma, fracture of optic nerve canal, fracture of big ridge of sphenoid bone, hematoma in sphenoid sinus and surgical treatment, and the dependent variable (Y) of visual prognosis were analyzed using the unconditioned Logistic regression analysis to find the risk factors for the visual prognosis of TON.A total of 325 eyes (45.2%) recovered out of 719 eyes. Four variables showed a significant relation with the visual recovery: duration of coma0.5 h (X3, P0.01), remnant vision after trauma (X4, P0.01) and sphenoid ridge fractures (X7, P0.01), and surgical treatment (X9, P0.01). These factors above were also proved to be significant in Logistic regression.The duration of coma0.5 h, no light perception after trauma, sphenoid ridge fractures are risk factors of visual recovery, while surgical treatment is the protective factor for the visual recovery after TON.

Mild therapeutic hypothermia, a robust neuroprotectant, reduces neuronal apoptosis, but the precise mechanism is not well understood. Our previous study showed that a novel inhibitor of an apoptosis-stimulating protein of p53 (iASPP) might be involved in neuronal death after stroke. The aim of this study was to confirm the role of iASPP after stroke treated with mild therapeutic hypothermia. To address this, we mimicked ischemia/reperfusion injury in vitro by using oxygen-glucose deprivation/reperfusion (OGD/R) in primary rat neurons. In our in vivo approach, we induced middle cerebral artery occlusion (MCAO) for 60 min in C57/B6 mice. From the beginning of ischemia, focal mild hypothermia was applied for two hours. To evaluate the role of iASPP, small interfering RNA (siRNA) was injected intracerebroventricularly. Our results showed that mild therapeutic hypothermia increased the expression of iASPP and decreased the expression of its targets, Puma and Bax, and an apoptosis marker, cleaved caspase-3, in primary neurons under OGD/R. Increased iASPP expression and decreased ASPP1/2 expression were observed under hypothermia treatment in MCAO mice. iASPP siRNA (iASPPi) or hypothermia plus iASPPi application increased infarct volume, apoptosis and aggravated the neurological deficits in MCAO mice. Furthermore, iASPPi downregulated iASPP expression, and upregulated the expression of proapoptotic effectors, Puma, Bax and cleaved caspase-3, in mice after stroke treated with mild therapeutic hypothermia. In conclusion, mild therapeutic hypothermia protects against ischemia/reperfusion brain injury in mice by upregulating iASPP and thus attenuating apoptosis. iASPP may be a potential target in the therapy of stroke.

As recombinant tissue plasminogen activator is the only drug approved for the clinical treatment of acute ischemic stroke, there is an urgent unmet need for novel stroke treatments. Endogenous defense mechanisms against stroke may hold the key to new therapies for stroke. A large number of studies suggest that nicotinamide phosphoribosyl-transferase (NAMPT is an attractive candidate to improve post-stroke recovery. NAMPT is a multifunctional protein and plays important roles in immunity, metabolism, aging, inflammation, and stress responses. NAMPT exists in both the intracellular and extracellular space. As a rate-limiting enzyme, the intracellular form (iNAMPT catalyzes the first step in the biosynthesis of nicotinamide adenine dinucleotide (NAD from nicotinamide. iNAMPT closely regulates energy metabolism, enhancing the proliferation of endothelial cells, inhibiting apoptosis, regulating vascular tone, and stimulating autophagy in disease conditions such as stroke. Extracellular NAMPT (eNAMPT is also known as visfatin (visceral fat-derived adipokine and has pleotropic effects. It is widely believed that the diverse biological functions of eNAMPT are attributed to its NAMPT enzymatic activity. However, the effects of eNAMPT on ischemic injury are still controversial. Some authors have argued that eNAMPT exacerbates ischemic neuronal injury non-enzymatically by triggering the release of TNF-α from glial cells. In addition, NAMPT also participates in several pathophysiological processes such as hypertension, atherosclerosis, and ischemic heart disease. Thus, it remains unclear under what conditions NAMPT is beneficial or destructive. Recent work using in vitro and in vivo genetic/ pharmacologic manipulations, including our own studies, has greatly improved our understanding of NAMPT. This review focuses on the multifaceted and complex roles of NAMPT under both normal and ischemic conditions.