Clinical application of the dissection of the preperitoneal space without electrocoagulation in laparoscopic transperitoneal inguinal hernia repair throughout of the whole process.

Introduction: The dissection of the preperitoneal space is performed using a monopolar instrument to prevent bleeding in laparoscopic transabdominal preperitoneal hernia repair (TAPP). It may also cause energy injuries and nerve damage. Aim: To assess the effectiveness and safety of dissection of the preperitoneal space without electrocoagulation (DPSWE) in TAPP throughout the process. Material and methods: A retrospective analysis of data of 134 patients was made. The electrocoagulation group (EG) relied on monopolar instruments. In the non-electrocoagulation group (NEG) mainly scissors were used without electrocoagulation. The patients were followed for up for 3 months. Intraoperative and postoperative conditions and other complications were observed. Results: The VAS scores in the NEG were lower than those in the EG (p < 0.05). The operation time in the NEG was shorter than that in the EG (p < 0.05). Hospitalization expenses, scrotal seroma formation, and rupture of hernia sac in the NEG were lower than those in the EG (p < 0.05). The intraoperative bleeding volume above 20 ml in the NEG was higher than that in the EG. There was no significant difference in the incidence of postoperative bleeding, vas deferens injury, intestinal injury, surgical site infection, length of hospital stay, urinary retention and hernia recurrence in the NEG and the EG (p > 0.05). There was no significant difference in the incidence of surgical site infections (SSIs) in the NEG and the EG. Conclusions: DPSWE is effective and safe. DPSWE may reduce postoperative pain and have no significant increase in postoperative bleeding.

Unveiling early stage autoimmune gastritis: novel endoscopic insights from two case reports.

The predominant characteristic of autoimmune gastritis (AIG) is corpus-dominant advanced atrophy, which is mostly observed in the middle to late stages. More reports are needed on the endoscopic features of the early stage. In this report, we present two cases of early-stage AIG in which endoscopic examinations showed no atrophy of the gastric mucosa but displayed a transition of collecting venules from a regular to an irregular arrangement. In addition, yellowish-white cobblestone-like elevations were observed in the fundic gland region. Histologically, the observed manifestations included pseudohypertrophy and protrusion of parietal cells into the lumen, possibly along with hyperplasia of G cells, lymphocytic infiltration and potentially pseudopyloric gland metaplasia. Serologically, the anti-parietal cell antibody returned positive results, whereas the anti-intrinsic factor antibody yielded negative results. In this study, we summarized some endoscopic features of two patients, aiming to provide clues for endoscopists to detect early-stage AIG.

The p75 neurotrophin receptor attenuates secondary thalamic damage after cortical infarction by promoting angiogenesis.

BACKGROUND: Angiogenesis is crucial in neuroprotection of secondary thalamic injury after cortical infarction. The p75 neurotrophin receptor (p75NTR) plays a key role in activating angiogenesis. However, the effects of p75NTR on angiogenesis in the thalamus after cortical infarction are largely unknown. Herein we investigate whether p75NTR facilitates angiogenesis to attenuate secondary thalamic damage via activating hypoxia-inducible factor 1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway mediated by Von Hippel-Lindau (VHL) after distal middle cerebral artery occlusion (dMCAO). METHODS: The male rat model of dMCAO was established. The effects of p75NTR on the angiogenesis was evaluated using RNA-sequencing, immunohistochemistry, western blot, quantitative real-time polymerase chain reaction, magnetic resonance imaging, behavior tests, viral and pharmacological interventions. RESULTS: We found that the p75NTR and vessel density were decreased in ipsilateral thalamus after dMCAO. The p75NTR-VHL interaction was reduced, which promoted the ubiquitination degradation of HIF-1α and reduced VEGF expression after dMCAO. Notably, p75NTR overexpression restrained the ubiquitination degradation of HIF-1α by inhibiting VHL-HIF-1α interaction, further promoted angiogenesis, increased cerebral blood flow of ipsilateral thalamus and improved neurological function after dMCAO. CONCLUSION: For the first time, we highlighted that the enhancement of p75NTR-VHL interaction promoted angiogenesis in attenuating secondary thalamic damage after dMCAO.

The impact of affiliation naming proximity on the retrieval efficiency of Chinese universities-affiliated retractions in the Retraction Watch Database.

The Retraction Watch Database (RWDB) is widely used to retrieve retraction data. However, its lack of affiliation normalization hinders the retrieval efficiency of retraction data for specific research-performing organizations. A query for a university name in the RWDB may yield retraction data entries for other universities with similar names, giving rise to the issue of affiliation naming proximity. This study assessed the impact of this issue on the retrieval efficiency of retraction records for 2,692 Chinese university names in English. The analysis revealed that the retrieval efficiency of retraction records for 206 Chinese university names can be influenced by 408 university names. As of 2022, the retrieval efficiency of retraction records for 96 Chinese university names was compromised by the involvement of 402 university names, resulting in an overall retraction inflation rate of 37.9% and an average rate of 45.0%. The findings highlight the importance of curating retraction data through affiliation-specific queries in the RWDB, adhering to the official English names of Chinese universities for scholarly publishing, and adopting the Research Organization Registry system for affiliation disambiguation. Given the significance of this issue concerning the English names of universities in non-English-speaking countries, the identified causes of the problem and proposed solutions can offer valuable insights for improving the retrieval of retraction records for non-Chinese universities in the RWDB.

Enhanced brain distribution of Ginsenoside F1 via intranasal administration in combination with absorption enhancers.

Ginsenoside F1 (GF1) is a potential drug candidate for the treatment of Alzheimer's disease. Nevertheless, its low oral bioavailability and poor solubility limit clinical application. By utilizing either a direct or indirect approach, intranasal administration is a non-invasive drug delivery method that can deliver drugs to the brain rapidly. But large molecule drug delivered to the brain through intranasal administration may be insufficient to reach required concentration for therapeutic effect. In this study, using GF1 as a model drug, the feasibility of intranasal administration in combination with absorption enhancers to increase brain distribution of GF1 was explored. First of all, the appropriate absorption enhancers were screened by in situ nasal perfusion study. GF1-HP-ß-CD inclusion complex was prepared and characterized. Thereafter, in vivo absorption of GF1 after intranasal or intravenous administration of its inclusion complex with/without absorption enhancers was investigated, and safety of the formulations was evaluated. The results showed that 2% Solutol HS 15 was a superior absorption enhancer. HP-ß-CD inclusion complex improved GF1 solubility by 150 fold. Following intranasal delivery, the absolute bioavailability of inclusion complex was 46%, with drug brain targeting index (DTI) 247% and nose-to-brain direct transport percentage (DTP) 58%. Upon further addition of 2% Solutol HS 15, the absolute bioavailability was increased to 75%, with DTI 315% and DTP 66%. Both nasal cilia movement and biochemical substances (total protein and lactate dehydrogenase) leaching studies demonstrated 2% Solutol HS 15 was safe to the nasal mucosa. In conclusion, intranasal administration combining with safe absorption enhancers is an effective strategy to enhance drug distribution in the brain, showing promise for treating disorders related to the central nervous system.

Hypoxic Preconditioning Attenuates Neuroinflammation via Inhibiting NF-κB/NLRP3 Axis Mediated by p-MLKL after Transient Global Cerebral Ischemia.

Hypoxic preconditioning (HPC) has been reported to alleviate neuronal damage and microglial activation in hippocampal CA1 after transient global cerebral ischemia (tGCI). However, the molecular mechanism is unclear. Recent studies identified that nuclear factor-kappa-B (NF-κB)/oligomerization domain-like receptors protein (NLRP) 3 inflammasome pathway is mainly involved in the activation of microglia and that phosphorylated (p)-mixed lineage kinase domain-like (MLKL) is related to the regulation of NF-κB/NLRP3 axis. Hence, in this study, we set out to investigate whether HPC attenuates neuronal damage and microglial activation through inhibiting NF-κB/NLRP3 axis mediated by p-MLKL after tGCI in CA1 of male rats. We found that HPC decreased NLRP3 inflammasome in microglia and inhibited M1 polarization of microglia in CA1 after tGCI. Mechanistically, HPC inhibited the activation of NF-κB signaling pathway and reduced the mRNA and protein levels of NLRP3 inflammasome after tGCI. Additionally, the knockdown of p-MLKL by short hairpin RNA (shRNA) administration inhibited the activation of the NF-κB signaling pathway and reduced the formation of NLRP3 inflammasome, thus attenuating M1 polarization of microglia and decreasing the release of interleukin 1 beta (IL-1ß) and necrosis factor alpha (TNF-α) in CA1 post ischemia. We consider that p-MLKL in microglia may be derived from necroptotic neurons after tGCI. In conclusion, the new finding in this study is that HPC-induced neuroprotection against tGCI through inhibiting NF-κB/NLRP3 pathway mediated by p-MLKL.

Cross-talk between gastric cancer and hepatic stellate cells promotes invadopodia formation during liver metastasis.

In gastric cancer (GC), the liver is a common organ for distant metastasis, and patients with gastric cancer with liver metastasis (GCLM) generally have poor prognosis. The mechanism of GCLM is unclear. Invadopodia are special membrane protrusions formed by tumor cells that can degrade the basement membrane and ECM. Herein, we investigated the role of invadopodia in GCLM. We found that the levels of invadopodia-associated proteins were significantly higher in liver metastasis than in the primary tumors of patients with GCLM. Furthermore, GC cells could activate hepatic stellate cells (HSCs) within the tumor microenvironment of liver metastases through the secretion of platelet-derived growth factor subunit B (PDGFB). Activated HSCs secreted hepatocyte growth factor (HGF), which activated the MET proto-oncogene, MET receptor of GC cells, thereby promoting invadopodia formation through the PI3K/AKT pathway and subsequently enhancing the invasion and metastasis of GC cells. Therefore, cross-talk between GC cells and HSCs by PDGFB/platelet derived growth factor receptor beta (PDGFRß) and the HGF/MET axis might represent potential therapeutic targets to treat GCLM.

A randomized controlled trial of cognitive behavioral therapy combined with attention training technique on auditory hallucinations of schizophrenia / 中国心理卫生杂志

Objective:To evaluate the effects of cognitive behavior therapy(CBT)combined with attention training technique(ATT)on auditory hallucinations of schizophrenia.Methods:Sixty schizophrenia patients with au-ditory hallucinations were recruited according to the criteria of International Classification of Diseases,tenth Edition(ICD-10).They were randomly divided into the CBT group(30 cases,26 cases completed)and the CBT+ATT group(30 cases,25 cases completed).The CBT group received only 4 weeks of cognitive behavioral intervention for auditory hallucinations,and the CBT+ATT group received 6 weeks of attention training technology intervention based on cognitive behavioral intervention.At baseline and after 12 weeks,the Psychotic Symptom Rating Scales-Auditory Hallucinations(PSYRATS-AH)and Scale of Social function in Psychosis Inpatients(SSPI)were used to evaluate the auditory hallucinations symptoms and social functioning of the two groups,and the Attentional Control Scale(ACS)was used to evaluate patients'attentional control ability of the CBT+ATT group.Results:After 12 weeks,the differences(post intervention score-baseline score)of PSYRATS-AH total scores[(-6.8±2.2)vs.(-4.2±1.5)],auditory hallucinations'frequency,duration,number of distresses,control of voices were lower in the CBT+ATT group than in the CBT group(Ps＜0.05),and the differences of the SSPI total scores[(13.9± 2.9)vs.(11.6±4.2)]and scores of Factor I and Factor Ⅲ were higher in the CBT+ATT group than in the CBT group(Ps＜0.05).Conclusion:This study shows cognitive behavioral therapy combined with attention training technique could improve auditory hallucinations and social function more effectively in patients with schizophrenia.

Identification of Key Novel lncRNAs RP11-400N13.3 and RP11-197K6.1 that Construct ceRNA Networks Associated with Recurrence and Metastasis in Colon Cancer.

BACKGROUND: Colon adenocarcinoma (COAD) is a major cause of cancer mortality worldwide. The occurrence and development of colon cancer is regulated by complex mechanisms that require further exploration. Recently, long non-coding RNAs (lncRNAs) were found to be related to the mortality of colon cancer patients through their participation in competing endogenous RNA (ceRNA) networks. Therefore, screening the lncRNAs involved in colon cancer may contribute to clarifying the complex mechanisms. METHODS: In this study, we explored the potential lncRNAs associated with colon cancer by establishing a ceRNA network using bioinformatics, followed by biological verification. RESULTS: RP11-197K6.1 and RP11-400N13.3 were screened out owing to their involvement in the expression of CDK2NA, a gene that potentially prevents colon cancer cells from high oxygen levels. CONCLUSIONS: Our work explored the mechanisms of recurrence and metastasis in colon cancer and provided potential targets for drug development.

Case report: A Chinese patient with spinocerebellar ataxia finally confirmed as Gerstmann-Sträussler-Scheinker syndrome with P102L mutation.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic prion disease caused by a mutation in the prion protein (PRNP) gene. It is typically characterized by progressive cerebellar ataxia and slowly progressive dementia. We present a case study of the GSS from China in which a 45-year-old male with a progressive gait and balance disorder developed cerebellar ataxia onset but was misdiagnosed as spinocerebellar ataxia (SCA) for 2 years. The patient's clinical, electrophysiological, and radiological data were retrospectively analyzed. Examination revealed ataxia, dysarthria, muscle weakness, areflexia in lower limbs, including a pyramidal sign, whereas cognitive decline was insignificant. His late mother had a similar unsteady gait. An electroencephalogram (EEG) showed normal findings, and 14-3-3 protein was negative. A brain MRI was performed for global brain atrophy and ventricular enlargement. Positron emission tomography-computed tomography (PET-CT) (18F-fluoro-2-deoxy-d-glucose, FDG) images showed mild to moderate decreased glucose metabolism in the left superior parietal lobe and left middle temporal lobe. According to genetic testing, his younger brother also had the P102L variant in the PRNP gene. This single case adds to the clinical and genetic phenotypes of GSS.

Transplantation of hESCs-Derived Neural Progenitor Cells Alleviates Secondary Damage of Thalamus After Focal Cerebral Infarction in Rats.

Human embryonic stem cells-derived neural progenitor cells (hESCs-NPCs) transplantation holds great potential to treat stroke. We previously reported that delayed secondary degeneration occurs in the ventroposterior nucleus (VPN) of ipsilateral thalamus after distal branch of middle cerebral artery occlusion (dMCAO) in adult male Sprague-Dawley (SD) rats. In this study, we investigate whether hESCs-NPCs would benefit the neural recovery of the secondary damage in the VPN after focal cerebral infarction. Permanent dMCAO was performed with electrocoagulation. Rats were randomized into Sham, dMCAO groups with or without hESCs-NPCs treatment. HESCs-NPCs were engrafted into the peri-infarct regions of rats at 48 h after dMCAO. The transplanted hESCs-NPCs survive and partially differentiate into mature neurons after dMCAO. Notably, hESCs-NPCs transplantation attenuated secondary damage of ipsilateral VPN and improved neurological functions of rats after dMCAO. Moreover, hESCs-NPCs transplantation significantly enhanced the expression of BDNF and TrkB and their interaction in ipsilateral VPN after dMCAO, which was reversed by the knockdown of TrkB. Transplantated hESCs-NPCs reconstituted thalamocortical connection and promoted the formation of synapses in ipsilateral VPN post-dMCAO. These results suggest that hESCs-NPCs transplantation attenuates secondary damage of ipsilateral thalamus after cortical infarction, possibly through activating BDNF/TrkB pathway, enhancing thalamocortical projection, and promoting synaptic formation. It provides a promising therapeutic strategy for secondary degeneration in the ipsilateral thalamus post-dMCAO.

Efficacy of image-enhanced endoscopy for colorectal adenoma detection: A multicenter, randomized trial.

BACKGROUND: Improved adenoma detection at colonoscopy has decreased the risk of developing colorectal cancer. However, whether image-enhanced endoscopy (IEE) further improves the adenoma detection rate (ADR) is controversial. AIM: To compare IEE with white-light imaging (WLI) endoscopy for the detection and identification of colorectal adenoma. METHODS: This was a multicenter, randomized, controlled trial. Participants were enrolled between September 2019 to April 2021 from 4 hospital in China. Patients were randomly assigned to an IEE group with WLI on entry and IEE on withdrawal (n = 2113) or a WLI group with WLI on both entry and withdrawal (n = 2098). The primary outcome was the ADR. The secondary endpoints were the polyp detection rate (PDR), adenomas per colonoscopy, adenomas per positive colonoscopy, and factors related to adenoma detection. RESULTS: A total of 4211 patients (966 adenomas) were included in the analysis (mean age, 56.7 years, 47.1% male). There were 2113 patients (508 adenomas) in the IEE group and 2098 patients (458 adenomas) in the WLI group. The ADR in two group were not significantly different [24.0% vs 21.8%, 1.10, 95% confidence interval (CI): 0.99-1.23, P = 0.09]. The PDR was higher with IEE group (41.7%) than with WLI group (36.1%, 1.16, 95%CI: 1.07-1.25, P = 0.01). Differences in mean withdrawal time (7.90 ± 3.42 min vs 7.85 ± 3.47 min, P = 0.30) and adenomas per colonoscopy (0.33 ± 0.68 vs 0.28 ± 0.62, P = 0.06) were not significant. Subgroup analysis found that with narrow-band imaging (NBI), between-group differences in the ADR, were not significant (23.7% vs 21.8%, 1.09, 95%CI: 0.97-1.22, P = 0.15), but were greater with linked color imaging (30.9% vs 21.8%, 1.42, 95%CI: 1.04-1.93, P = 0.04). the second-generation NBI (2G-NBI) had an advantage of ADR than both WLI and the first-generation NBI (27.0% vs 21.8%, P = 0.01; 27.0% vs 21.2.0%, P = 0.01). CONCLUSION: This prospective study confirmed that, among Chinese, IEE didn't increase the ADR compared with WLI, but 2G-NBI increase the ADR.

Dual functional pullulan-based spray-dried microparticles for controlled pulmonary drug delivery.

Two main challenges are associated with current spray-dried microparticles for inhalation, including the enhancement of aerosolization performance of microparticles and the creation of sustained drug release for continuous treatment on-site. For achieving these purposes, pullulan was explored as a novel excipient to prepare spray-dried inhalable microparticles (with salbutamol sulphate, SS, as a model drug), which were further modified by additives of leucine (Leu), ammonium bicarbonate (AB), ethanol and acetone. It was demonstrated that all pullulan-based spray-dried microparticles had improved flowability and enhanced aerosolization behavior, with the fine particle (<4.46 µm) fraction of 42.0-68.7% w/w, much higher than 11.4% w/w of lactose-SS. Moreover, all modified microparticles showed augmented emitted fractions of 88.0-96.9% w/w, over 86.5% w/w of pullulan-SS. The pullulan-Leu-SS and pullulan-(AB)-SS microparticles demonstrated further increased fine particle (<1.66 µm) doses of 54.7 µg and 53.3 µg respectively, surpassing that (49.6 µg) of pullulan-SS, suggesting an additionally increased drug deposition in the deep lungs. Furthermore, pullulan-based microparticles revealed sustained drug release profiles with elongated time (60mins) over the control (2mins). Clearly, pullulan has a great potential to construct dual functional microparticles for inhalation with improved pulmonary delivery efficiency and sustained drug release on-site.

Surgical robot-assisted tripod percutaneous reconstruction technique combined with bone cement filling technique for the treatment of acetabular metastasis.

Background: Acetabular metastasis is a type of metastatic bone cancer, and it mainly metastasizes from cancers such as lung cancer, breast cancer, and renal carcinoma. Acetabular metastasis often causes severe pain, pathological fractures, and hypercalcemia which may seriously affect the quality of life of acetabular metastasis patients. Due to the characteristics of acetabular metastasis, there is no most suitable treatment to address it. Therefore, our study aimed to investigate a novel treatment technique to relieve these symptoms. Methods: Our study explored a novel technique to reconstruct the stability of the acetabular structure. A surgical robot was used for accurate positioning and larger-bore cannulated screws were accurately inserted under the robot's guidance. Then, the lesion was curetted and bone cement was injected through a screw channel to further strengthen the structure and kill tumor cells. Results: A total of five acetabular metastasis patients received this novel treatment technique. The data relating to surgery were collected and analyzed. The results found that this novel technique can significantly reduce operation time, intraoperative bleeding, visual analogue score scores, Eastern Cooperative Oncology Group scores, and postoperative complications (e.g., infection, implant loosening, hip dislocation) after treatment. Follow-up time ranged from 3 months to 6 months, and the most recent follow-up results showed that all patients survived and no acetabular metastasis progressed in any of the patients after surgery. Conclusion: Surgical robot-assisted tripod percutaneous reconstruction combined with the bone cement filling technique may be a novel and suitable treatment in acetabular metastasis patients. Our study may provide new insights into the treatment of acetabular metastasis.

Manifestation of the malignant progression of glioma following initial intracerebral hemorrhage: A case report.

BACKGROUND: Intracranial hemorrhage is extremely rare during the initial stages of glioma. Here, we report a case of glioma with unclassified pathology and intracranial bleeding. CASE SUMMARY: After the second surgery for intracerebral hemorrhage, the patient experienced weakness in the left arm and leg, but could walk unassisted. One month after discharge, the weakness in the left limbs had exacerbated and the patient also suffered from headaches and dizziness. A third surgery was ineffective against the rapidly growing tumor. Intracerebral hemorrhage may be the initial symptom of glioma in some rare cases, and atypical perihematomal edema can be used for diagnosis during an emergency. Certain histological and molecular features seen in our case were similar to that of glioblastoma with a primitive neuronal component, which is termed diffuse glioneuronal tumor with features similar to oligodendroglioma and nuclear clusters (DGONC). The patient underwent three surgeries to remove the tumor. The first tumor resection had been performed when the patient was 14-years-old. Resection of the hemorrhage and bone disc decompression were performed when the patient was 39-years-old. One month after the last discharge, the patient underwent neuronavigation-assisted resection of the right frontotemporal parietal lesion plus extended flap decompression. On the 50th d after the third operation, computed tomography imaging showed rapid tumor growth accompanied by brain hernia. The patient was discharged and died 3 d later. CONCLUSION: Glioma can present as bleeding in the initial stage and should be considered in such a setting. We have reported a case of DGONC, which is a rare molecular subtype of glioma with a unique methylation profile.

Hypoxic postconditioning restores mitophagy against transient global cerebral ischemia via Parkin-induced posttranslational modification of TBK1.

Hypoxic postconditioning (HPC) has been reported to enhance Parkin-catalyzed mitochondrial ubiquitination to restore mitophagy in hippocampal CA1 against transient global cerebral ischemia (tGCI). However, the molecular mechanism leading ubiquitinated mitochondria to final clearance during HPC-mediated mitophagy after tGCI is unclear. This study aims to investigate whether HPC restores mitophagy after tGCI through Parkin-induced K63-linked poly-ubiquitination (K63-Ub) to activate tumor necrosis factor associated factor family member associated nuclear factor κB activator -binding kinase 1 (TBK1) in CA1 of male rats. We found that HPC maintained TBK1 expression, promoted p62 and TBK1 phosphorylation in mitochondria, and enhanced their recruitments to mitochondria in CA1 after tGCI. However, these effects were partially abolished by TBK1 inhibitor BX795. K63-Ub of mitochondrial TBK1 was disturbed at 26 h of reperfusion after tGCI, which was reversed by HPC. The maintenance of K63-Ub of mitochondrial TBK1 induced by HPC was counteracted under Parkin knockdown with AAV-mediated Prkn small-interfering RNA, accompanied by the suppression on TBK1 activation and the reduction of mitochondrial p62 phosphorylation. This innovative study indicated that HPC maintained K63-Ub of TBK1 in a Parkin-dependent manner to promote TBK1 phosphorylation, and then phosphorylated TBK1 activated p62 to restore mitophagy, thereby alleviating neuronal damage in CA1 after tGCI.

Stabilization of nuclear ß-catenin by inhibiting KDM2A mediates cerebral ischemic tolerance.

Hypoxic postconditioning (HPC) with 8% oxygen increases nuclear accumulation of ß-catenin through activating the classical Wnt pathway, thereby alleviating transient global cerebral ischemia (tGCI)-induced neuronal damage in the hippocampal CA1 subregion of adult rats. However, little is understood about the regulatory mechanism of nuclear ß-catenin in HPC-mediated cerebral ischemic tolerance. Although lysine(K)-specific demethylase 2A (KDM2A) has been known as a crucial regulator of nuclear ß-catenin destabilization, whether it plays an important role through modulating nuclear ß-catenin in cerebral ischemic tolerance induced by HPC remains unknown. In this study, we explored the molecular mechanism of stabilizing nuclear ß-catenin by inhibiting KDM2A-mediated demethylation in the HPC-offered neuroprotection against tGCI. In addition, we confirmed that nuclear methylated-ß-catenin in CA1 decreased and nuclear ß-catenin turnover increased after tGCI, which were reversed by HPC. The administration with methyltransferase inhibitor AdOx abrogated HPC-induced methylation and stabilization of nuclear ß-catenin in CA1, as well as the neuroprotection against tGCI. Notably, HPC downregulated the expression of KDM2A in CA1 and reduced the interaction between KDM2A and ß-catenin in the nucleus after tGCI. The knockdown of KDM2A with small-interfering RNA could upregulate nuclear methylated-ß-catenin and stabilize ß-catenin, thereby increasing survivin in CA1 and improving the cognitive function of rats after tGCI. Opposite results were observed by the administration of KDM2A-carried adenovirus vector. Furthermore, we demonstrated that KDM2A mediates the demethylation of nuclear ß-catenin through jumonji C (JmjC) domain of KDM2A in HEK-293T and SH-SY5Y cells. Our data support that the inhibition of KDM2A-mediated demethylation of nuclear ß-catenin contributes to HPC-induced neuroprotection against tGCI.

Design, synthesis and structure-activity relationship of N-phenyl aromatic amide derivatives as novel xanthine oxidase inhibitors.

Our previous studies suggested that N-phenyl aromatic amides are a class of promising xanthine oxidase (XO) inhibitor chemotypes. In this effort, several series of N-phenyl aromatic amide derivatives (4a-h, 5-9, 12i-w, 13n, 13o, 13r, 13s, 13t and 13u) were designed and synthesized to carry out an extensive structure-activity relationship (SAR). The investigation provided some valuable SAR information and identified N-(3-(1H-imidazol-1-yl)-4-((2-methylbenzyl)oxy)phenyl)-1H-imidazole-4-carboxamide (12r, IC50 = 0.028 µM) as the most potent XO inhibitor with close in vitro potency to that of topiroxostat (IC50 = 0.017 µM). Molecular docking and molecular dynamics simulation rationalized the binding affinity through a series of strong interactions with the residues Glu1261, Asn768, Thr1010, Arg880, Glu802, etc. In vivo hypouricemic studies also suggested that the uric acid lowering effect of compound 12r was improved compared with the lead g25 (30.61 % vs 22.4 % reduction in uric acid levels at 1 h; 25.91 % vs 21.7 % reduction in AUC of uric acid) . Pharmacokinetic studies revealed that compound 12r presented a short t1/2 of 0.25 h after oral administration. In addition, 12r has non-cytotoxicity against normal cell HK-2. This work may provide some insights for further development of novel amide-based XO inhibitors.

Attenuation of Piwil2 induced by hypoxic postconditioning prevents cerebral ischemic injury by inhibiting CREB2 promoter methylation.

Epigenetic modification contributes to the pathogenesis of cerebral ischemia. Piwil2 belongs to the PIWI proteins subfamily and has a key role in the regulation of gene transcription through epigenetics. However, the roles of Piwil2 in cerebral ischemia have not been investigated. In this study, we aim to elucidate the roles and the underlying molecular mechanisms of Piwil2 in ischemic tolerance induced by hypoxic postconditioning (HPC) against transient global cerebral ischemia (tGCI). We found that the expression of Piwil2 in CA1 was downregulated by HPC after tGCI. Silencing Piwil2 with antisense oligodeoxynucleotide (AS-ODN) in CA1 after tGCI decreased the expression of apoptosis-related proteins and exerted neuroprotective effects. Opposite results were observed after overexpression of Piwil2 induced by administration of Piwil2-carried lentivirus. Furthermore, we revealed differentially expressed Piwil2-interacting piRNAs in CA1 between HPC and tGCI groups by RNA binding protein immunoprecipitation (RIP) assay. Moreover, downregulating Piwil2 induced by HPC or AS-ODN after tGCI caused a marked reduction of DNA methyltransferase 3A (DNMT3A), which in turn abolished the tGCI-induced increase in the DNA methylation of cyclic AMP response element-binding 2 (CREB2), thus increasing mRNA and protein of CREB2. Finally, downregulating Piwil2 restored dendritic complexity and length, prevented the loss of dentritic spines, thereby improving cognitive function after tGCI. These data firstly reveal that Piwil2 plays an important part in HPC-mediated neuroprotection against cerebral ischemia through epigenetic regulation of CREB2.