CBX7 suppression prevents ischemia-reperfusion injury-induced endoplasmic reticulum stress through the Nrf-2/HO-1 pathway.

Renal ischemia-reperfusion injury (I/R) usually occurs in renal transplantation and partial nephrectomy, which could lead to acute kidney injury. However, the effective treatment for renal I/R still remains limited. In the present study, we investigated whether inhibition of chromobox 7 (CBX7) could attenuate renal I/R injury in vivo and in vitro as well as the potential mechanisms. Adult male mice were subjected to right renal ischemia and reperfusion for different periods, both with and without the CBX7 inhibitor UNC3866. In addition, human kidney cells (HK-2) were subjected to a hypoxia/reoxygenation (H/R) process for different periods, both with or without the CBX7 inhibitor or siRNA for CBX7. The results showed that expression of CBX7, glucose regulator protein-78 (GRP78), phosphorylated eukaryotic translation initiation factor-2α (p-eIF2α), and C/EBP homologous protein (CHOP) were increased after extension of I/R and H/R periods. Moreover, overexpression of CBX7 could elevate the expression of CBX7, GRP78, p-eIF2α, and CHOP. However, CBX7 inhibition with either UNC3866 or genetic knockdown led to reduced expression of GRP78, p-eIF2α, and CHOP through nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 activation in I/R and H/R injury. Furthermore, ML385, the Nrf2 inhibitor, could elevate endoplasmic reticulum stress levels, abrogating the protective effects of UNC3866 against renal I/R injury. In conclusion, our results demonstrated that CBX7 inhibition alleviated acute kidney injury by preventing endoplasmic reticulum stress via the Nrf2/HO-1 pathway, indicating that CBX7 inhibitor could be a potential therapeutic target for renal I/R injury.

Diabetes aggravates renal ischemia-reperfusion injury by repressing mitochondrial function and PINK1/Parkin-mediated mitophagy.

Diabetes could aggravate ischemia-reperfusion (I/R) injury, but the underlying mechanism is unclear. In the present study, we aimed to investigate whether diabetes exacerbates renal I/R injury and its possible mechanism. In vitro, HK-2 cells under normal or high glucose conditions were subjected to hypoxia (12 h) followed by reoxygenation (3 h) (H/R). Cell viability, intracellular ATP content, mitochondrial membrane potential, reactive oxygen species production, and apoptosis were measured. In vivo, streptozotocin-induced diabetic and nondiabetic rats were subjected to I/R. Renal pathology, function, and apoptosis were evaluated by hematoxylin and eosin staining, transmission electron microscopy, and Western blot analysis. Compared with the normal glucose + H/R group, mitochondrial function (ATP, mitochondrial membrane potential, and reactive oxygen species) and mitophagy were reduced in the high glucose + H/R group, as was expression of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) and Parkin. Also, cells in the high glucose + H/R group exhibited more apoptosis compared with the normal glucose + H/R group, as assessed by flow cytometry, TUNEL staining, and Western blot analysis. Compared with normal rats that underwent I/R, diabetic rats that underwent I/R exhibited more severe tubular damage and renal dysfunction as well as expression of the apoptotic protein caspase-3. Meanwhile, diabetes alleviated mitophagy-associated protein expression in rats subjected to I/R, including expression of PINK1 and Parkin. Transmission electron microscopy indicated that the mitophagosome could be hardly observed and that mitochondrial morphology and structure were obviously damaged in the diabetes + I/R group. In conclusion, our results, for the first time, indicate that diabetes could aggravate I/R injury by repressing mitochondrial function and PINK1/Parkin-mediated mitophagy in vivo and in vitro.

Diabetes aggravates renal ischemia and reperfusion injury in rats by exacerbating oxidative stress, inflammation, and apoptosis.

Diabetic patients are more susceptible to renal ischemia/reperfusion (I/R) injury (RI/RI) and have a poor prognosis, but the underlying mechanism remains unclear. The present study aimed to examine whether diabetes could worsen acute kidney injury induced by I/R in rats and clarify its mechanism. Control and streptozotocin-induced diabetic rats were subjected to 45 min renal pedicle occlusion followed by 24 h reperfusion. Tert-butylhydroquinone (TBHQ, 16.7 mg/kg) was administrated intraperitoneally 3 times at intervals of 8 h before ischemia. Serum and kidneys were harvested after reperfusion to evaluate renal function and histological injury. Enzyme-linked immunosorbent assays were used to test pro-inflammatory cytokines. Terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling assays were used to detect apoptotic cells, and western blotting was performed to determine the expression of B-cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax), and cleaved caspase-3, as well as oxidative stress and inflammation-related proteins, such as nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Toll-like receptor 4 (TLR4), and nuclear factor-κB (NF-κB). Compared with control animals, diabetic rats undergoing I/R exhibited more severe tubular damage and renal dysfunction. Diabetes exacerbated oxidative stress, the inflammatory response, and apoptosis after renal I/R by enhancing TLR4/NF-κB signaling and blocking the Nrf2/HO-1 pathway. RI/RI in diabetic rats was attenuated by pretreatment with TBHQ (a Nrf2 agonist), which exerted anti-inflammatory and anti-apoptotic properties by inhibiting NF-κB signaling. These findings indicate that hyperglycemia exacerbates RI/RI by intensifying oxidative stress, inflammation, and apoptosis. Antioxidant pretreatment may alleviate RI/RI in diabetic patients.

Treatment strategies for huge central neurocytomas.

Central neurocytomas (CNs), initially asymptomatic, sometimes become huge before detection. We described and analyzed the clinical, radiological, operational and outcome data of 13 cases of huge intraventricular CNs, and discussed the treatment strategies in this study. All huge CNs (n=13) in our study were located in bilateral lateral ventricle with diameter ≥5.0 cm and had a broad-based attachment to at least one side of the ventricle wall. All patients received craniotomy to remove the tumor through transcallosal or transcortical approach and CNs were of typical histologic and immunohistochemical features. Adjuvant therapies including conventional radiation therapy (RT) or gamma knife radiosurgery (GKRS) were also performed postoperatively. Transcallosal and transcortical approaches were used in 8 and 5 patients, respectively. Two patients died within one month after operation and 3 patients with gross total resection (GTR) were additionally given a decompressive craniectomy (DC) and/or ventriculoperitoneal shunt (VPS) as the salvage therapy. Six patients received GTR(+RT) and 7 patients received subtotal resection (STR)(+GKRS). Eight patients suffered serious complications such as hydrocephalus, paralysis and seizure after operation, and patients who underwent GTR showed worse functional outcome [less Karnofsky performance scale (KPS) scores] than those having STR(+GKRS) during the follow-up period. The clinical outcome of huge CNs seemed not to be favorable as that described in previous reports. Surgical resection for huge CNs should be meticulously considered to guarantee the maximum safety. Better results were achieved in STR(+GKRS) compared with GTR(+RT) for huge CNs, suggesting that STR(+GKRS) may be a better treatment choice. The recurrent or residual tumor can be treated with GKRS effectively.

Ni-catalyzed reductive homocoupling of unactivated alkyl bromides at room temperature and its synthetic application.

A room-temperature Ni-catalyzed reductive approach to homocoupling of unactivated primary, secondary, and tertiary alkyl bromides is described. The catalytic system can be easily generated from air-stable and cheap materials and demonstrates broad functional group tolerance, thus allowing facile access to useful dimeric triterpene and lignan-like molecules. Moreover, the dimerization of tertiary bromide 6 efficiently establishes sterically hindered vicinal quaternary carbons (C3a and C3a'), which is a key linkage of intriguing bispyrrolo[2,3-b]indoline alkaloids, thereby enabling us to complete the total syntheses of racemic chimonanthine (9) and folicanthine (10). In addition, this dimerization method can be expanded to the highly stereoselective synthesis of bisperhydrofuro[2,3-b]furan (5a) and the dimeric spiroketal 5b, signifying the involvement of possible radical species.

Collective synthesis of several 2,7'-cyclolignans and their correlation by chemical transformations.

Collective synthesis of anti-malarial 2,7'-cyclolignans has been stereoselectively achieved employing (±)-cyclogalgravin (2) as a linchpin through a series of functional group conversions, including redox reactions. Interestingly, 2 can be correlated with the neolignan (±)-kadangustin J (1) isolated from a different plant source, through a highly efficient dehydrative cyclization reaction with excellent diastereotopic differentiation of the veratryl group and concomitant construction of the C1­C7 bond. It is noteworthy that the first total synthesis of stereodivergent (±)-8,8'-epi-aristoligone (5), (±)-8'-epi-aristoligone (7), (±)-8'-epi-8-OH-aristoligone (8) and (±)-8'-epi-aristoligol (9) was demonstrated.

Total synthesis of (±)-sacidumlignans D and A through Ueno-Stork radical cyclization reaction.

Efficient synthesis of (±)-sacidumlignan D (4) has been successfully achieved employing Ueno-Stork radical cyclization of α-bromo acetal 21 as a key step. Two synthetic approaches for the symmetrical diaryl ketone 19 have been discussed in detail. Notably, sacidumlignan A (1) can be also efficiently synthesized in only 7 steps with 25% overall yield, where acid triggered tandem reaction starting from analogous Ueno-Stork cyclization product 27 played an important role. Moreover, potentially biomimetic conversion from (±)-sacidumlignan D (4) to sacidumlignan A (1) could be realized.

[Targeted therapy of malignant glioma by a chimeric fusion toxin composed of IL-13 and Pseudomonas exotoxin in vitro].

OBJECTIVE: To examine the antitumor activity of IL-13PE38 on solid malignant glioma cells in vitro and to investigate its relationship between the antitumor activity of IL-13PE38 and the expression level of IL-13Rα2 in malignant glioma. METHODS: Ten fresh tissues of anaplastic glioma and 11 fresh tissues of glioblastoma multiforme were obtained during craniotomy at First Affiliated Hospital, Wenzhou Medical College between June 2009 and December 2010. All fresh glioma cells were cultured in vitro with IL-13PE38. Then the cytotoxicity of IL-13PE38 was determined by colorimetric MTS proliferation assay and the SR (survival rate) calculated. The expression level of IL-13Rα2 was studied by immunohistochemical SABC method in 21 cases of malignant glioma. And the value of integrated optical density (IOD) was examined by computer assisted pathological image analysis system. The correlation between the IOD of IL-13Rα2 and the SR of malignant glioma cells was also studied. RESULTS: (1) There were strongly positive expression of IL-13Rα2 in most cases (19/21, 90%). And the expression level of IL-13Rα2 in glioblastoma multiforme was higher than the expression level of IL-13Rα2 in anaplastic glioma (P < 0.05). (2) As the fresh malignant glioma cells were cultured with IL-13PE38 of same concentration, the number of surviving cells decreased in different degrees. The survival rate of 14 cases were < 70% and 9 cases < 50%. And the survival rate of anaplastic glioma cells was higher than that of glioblastoma multiforme cells (P < 0.05). (3) The IOD of IL-13Rα2 and the SR of malignant glioma cells were strongly negatively correlated (r = -0.093, P < 0.01). CONCLUSION: A low concentration of IL-13PE38 shows a high level of cytotoxicity for solid malignant glioma cells. And its cytotoxic efficiency depends on the expression level of IL-13Rα2.

Combined Endovascular and Surgical Treatment for Brain Arteriovenous Malformations in Biplanar Hybrid Operating Room.

OBJECTIVE: Combined surgical and endovascular treatment for vascular disorders has become prevalent in recent years. However, reports on one-session hybrid surgery for arteriovenous malformations (AVMs) are relatively rare. The safety and efficiency of combined treatment for brain AVMs were analyzed in biplanar hybrid operating room (OR) at one stage. METHODS: We retrospectively analyzed 20 patients with AVMs undergoing combined surgical and endovascular treatment from October 2015 to June 2018. The data for resection rate, microcatheter adhesion, surgical position and postoperative outcomes were analyzed. Total resection or near-total resection was achieved in all cases. RESULTS: A total of 13 patients were under combined endovascular and surgical procedures, and 7 experienced surgery with intraoperative digital subtraction angiography. Sitting position was applied in 3 of them; 2 niduses in cerebellum, and 1 in parietal lobe. Compared with admission modified Rankin Scale (mRS) in all patients, postoperative 12-month mRS showed a significant decline. Besides, 3 patients experienced microcatheter adhesion after endovascular embolization, thereafter underwent surgical adhesion removal while nidus resection was done. CONCLUSION: Combined endovascular and surgical modality in a hybrid OR at one stage provides a safe strategy for the treatment of AVMs. The biplanar hybrid neurointerventional suite is endowed with unconstrained operating angle which enables combined endovascular and surgical treatment in sitting position. It also reduces the risk of microcatheter adhesion, which enables interventional radiologists to perform aggressively.

Current observer-based online open-switch fault diagnosis for voltage-source inverter.

In order to guarantee the system reliability and enhance post-fault maintenance efficiency of inverters, this paper presents an current observer-based online open-switch fault diagnosis method for the voltage-source inverters (VSI). Analyzing the state space model of VSI when fault occurs, a state observer of the system is built to estimate phase currents. Once the open-switch fault occurs, the current residual vector between the estimated currents on observer and the measured currents, and fault diagnosis is realized by exploiting the featured amplitude and phase of the current residual vector. In order to realize on-line diagnosis with high reliability and speed, the average value of current residuals in a fundamental period is obtained and Clark transformation is performed so as to acquire vector angle. In addition, the sum of absolute values of measured currents is normalized to serve as the sign of fault occurrence. The simulation and experimental results show the effectiveness of proposed method.

Giant Serpentine Aneurysm of the Middle Cerebral Artery.

BACKGROUND: Giant serpentine aneurysms (GSAs) are a subgroup of giant intracranial aneurysms, distinct from saccular and fusiform varieties, that are defined as partially thrombosed giant aneurysms with tortuous internal vascular channel. Clinicopathologic characteristics of middle cerebral artery GSAs have been rarely reported in the literature, with discussion of radiologic characteristics only. We clarify patient clinical and neuroradiologic features and discuss the mechanism of formation and progression. CASE DESCRIPTION: A 43-year-old woman presented with a GSA arising from the middle cerebral artery. There was a separate inflow and outflow channel of the aneurysm, with the outflow channel feeding the distal branches of the parent artery and supplying normal brain parenchyma. The GSA was treated successfully by aneurysmectomy and superficial temporal artery-middle cerebral artery bypass followed by proximal occlusion and vascular reconstruction. An aneurysm specimen was examined to correlate pathologic findings and morphologic characteristics. RESULT: Pathologic results showed that thickness of the aneurysmal wall was typically increased and varied, and no internal elastic lamina or endothelial lining could be identified. The sac contained thrombi of various ages with recanalizing vessel formation and chronic inflammation infiltration. Intimal hyperplasia and neoangiogenesis in the wall and hyaline degeneration of the media were observed. Vessels coursing in their adventitia showed mucoid changes, which are responsible for the contrast enhancement of the aneurysmal rim on computed tomography scan. CONCLUSIONS: GSAs are a specific pathologic entity with unique morphologic and pathologic characteristics that can affect intracranial blood vessels. The pathogenic mechanisms are unclear; this report suggests that GSAs may be associated with degeneration of the vascular wall.

Histopathological features of middle cerebral artery and superficial temporal artery from patients with moyamoya disease and enlightenments on clinical treatment.

The histopathological features of the middle cerebral artery (MCA) and superficial temporal artery (STA) from moyamoya disease (MMD) and their relationships with gender, age, angiography stage were explored. The causes and the clinical significance of vasculopathy of STA were also discussed. The clinical data and specimens of MCA and STA from 30 MMD patients were collected. Twelve samples of MCA and STA from non-MMD patients served as control group. Histopathological examination was then performed by measuring the thickness of intima and media, and statistical analysis was conducted. The MCA and STA specimens from MMD group had apparently thicker intima and thinner media than those from the control group. There was no significant pathological difference between the hemorrhage group and non-hemorrhage group, and between the males and females in MMD patients. Neither the age nor the digital subtraction angiography (DSA) stage was correlated with the thickness of intima in MCA and STA. MMD is a systemic vascular disease involving both intracranial and extracranial vessels. Preoperative external carotid arteriography, especially super-selective arteriography of the STA, benefits the selection of donor vessel.

Glycine Potentiates AMPA Receptor Function through Metabotropic Activation of GluN2A-Containing NMDA Receptors.

NMDA receptors are Ca2+-permeable ion channels. The activation of NMDA receptors requires agonist glutamate and co-agonist glycine. Recent evidence indicates that NMDA receptor also has metabotropic function. Here we report that in cultured mouse hippocampal neurons, glycine increases AMPA receptor-mediated currents independent of the channel activity of NMDA receptors and the activation of glycine receptors. The potentiation of AMPA receptor function by glycine is antagonized by the inhibition of ERK1/2. In the hippocampal neurons and in the HEK293 cells transfected with different combinations of NMDA receptors, glycine preferentially acts on GluN2A-containing NMDA receptors (GluN2ARs), but not GluN2B-containing NMDA receptors (GluN2BRs), to enhance ERK1/2 phosphorylation independent of the channel activity of GluN2ARs. Without requiring the channel activity of GluN2ARs, glycine increases AMPA receptor-mediated currents through GluN2ARs. Thus, these results reveal a metabotropic function of GluN2ARs in mediating glycine-induced potentiation of AMPA receptor function via ERK1/2 activation.

Significance of cyclooxygenase-2 elevation in middle cerebral artery for patients with hemorrhagic moyamoya disease.

The etiology and pathogenesis of moyamoya disease (MMD) remain elusive. Some inflammatory proteins, such as cyclooxygenase (COX)-2, are believed to be implicated in the development of MMD. So far, the relationship between COX-2 and MMD is poorly understood and reports on the intracranial vessels of MMD patients are scanty. In this study, tiny pieces of middle cerebral artery (MCA) and superficial temporal artery (STA) from 13 MMD patients were surgically harvested. The MCA and STA samples from 5 control patients were also collected by using the same technique. The expression of COX-2 was immunohistochemically detected and the average absorbance (A) of positively-stained areas was measured. High-level COX-2 expression was found in all layers of the MCA samples from all 5 hemorrhagic MMD patients, while positive but weak expression of COX-2 was observed only in the endothelial layer of the MCA samples from most ischemic MMD patients (6/8, 75%). The average A values of COX-2 in the hemorrhagic MMD patients were substantially higher than those in their ischemic counterparts (t=4.632, P=0.001). There was no significant difference in the COX-2 expression among the "gender" groups, or "radiographic grade" groups, or "lesion location" groups (P>0.05 for all). The COX-2 expression was detected neither in the MCA samples from the controls nor in all STA specimens. Our results suggested that COX-2 was up-regulated in the MCA of MMD patients, especially in hemorrhagic MMD patients. We are led to speculate that COX-2 may be involved in the pathogenesis of MMD and even contribute to the hemorrhagic stroke of MMD patients.

Risk factors for new onset diabetes mellitus after liver transplantation: A meta-analysis.

AIM: To determine the risk factors for new-onset diabetes mellitus (NODM) after liver transplantation by conducting a systematic review and meta-analysis. METHODS: We electronically searched the databases of MEDLINE, EMBASE and the Cochrane Library from January 1980 to December 2013 to identify relevant studies reporting risk factors for NODM after liver transplantation. Two authors independently assessed the trials for inclusion and extracted the data. Discrepancies were resolved in consultation with a third reviewer. All statistical analyses were performed with the RevMan5.0 software (The Cochrane Collaboration, Oxford, United Kingdom). Pooled odds ratios (OR) or weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated using either a fixed effects or a random effects model, based on the presence (I (2) < 50%) or absence (I (2) > 50%) of significant heterogeneity. RESULTS: Twenty studies with 4580 patients were included in the meta-analysis, all of which were retrospective. The meta-analysis identified the following significant risk factors: hepatitis C virus (HCV) infection (OR = 2.68; 95%CI: 1.92-3.72); a family history of diabetes (OR = 1.69, 95%CI: 1.09-2.63, P < 0.00001); male gender (OR = 1.53; 95%CI: 1.24-1.90; P < 0.0001); impaired fasting glucose (IFG; OR = 3.27; 95%CI: 1.84-5.81; P < 0.0001); a family history of diabetes (OR = 1.69; 95%CI: 1.09-2.63; P = 0.02); use of tacrolimus (OR = 1.34; 95%CI: 1.03-1.76; P = 0.03) and body mass index (BMI)(WMD = 1.19, 95%CI: 0.69-1.68, P < 0.00001). Other factors, such as hepatitis B virus infection and alcoholism, were not found to be associated with the incidence of NODM. CONCLUSION: The study showed that HCV infection, IFG, a family history of diabetes, male gender, tacrolimus and BMI are risk factors for NODM after liver transplantation.

Diagnosis and treatment of carcinosarcoma of the renal pelvis: A case report.

Carcinosarcoma is a rare type of renal pelvis malignancy, the diagnosis of which requires the presence of malignant epithelial and mesenchymal components. The prognosis of this disease is extremely poor due to its rapid progression and widespread metastases. The present study describes a case of carcinosarcoma involving the right renal pelvis in a 73-year-old female who presented with intermittent hematuria and right-flank pain that had persisted for one month. Computed tomography revealed a 2.4×2.5 cm mass in the right renal pelvis, which was diagnosed as a right renal pelvic tumor. Laparoscopic radical resection of the right kidney and ureter was performed. Following surgery, immunohistochemical analysis showed positive reactions for epithelial and mesenchymal markers. Based on these findings, the patient was diagnosed with carcinosarcoma. Thus, immunohistochemical analysis is a critical method for the accurate diagnosis of carcinosarcoma.

Nickel-mediated inter- and intramolecular C-S coupling of thiols and thioacetates with aryl iodides at room temperature.

A Ni(0)-catalyzed intermolecular cross-coupling of various functionalized thiols and aryl iodides has been developed and successfully extended to less explored intramolecular versions, where thioacetates could also be utilized as the strategic surrogate. Air-stable precatalysts, very mild conditions, and an easy protocol allow rapid access to medicinally useful aryl thioethers, as demonstrated in the facile synthesis of (±)-chuangxinmycin as a key step.