Visible Light-Accelerated Palladium-Catalyzed Thiocarbonylation Using Oxalic Acid Monothioester with Aryl/Alkenyl Sulfonium Salts.

Herein, we present a decarboxylative thiocarbonylation of aryl and alkenyl sulfonium salts with oxalic acid monothioethers (OAMs), which can be achieved by visible light-accelerated palladium catalysis. Sulfonium salts are widely available, and OAM is an easily accessible and stored reagent; this mild reaction method can also be used for the synthesis of different types of thioester compounds. The reaction represents a new application of visible light-accelerated palladium catalysis in catalytic decarboxylative cross-couplings.

Prevalence and Risk Factors of Anxiety Among Adult Patients with Chronic Pharyngitis in Wuhu, China.

Objective: Chronic pharyngitis (CP) is a common disease, which has a long duration and a wide range of onset. Anxiety is considered to be a common complication in patients with CP. The purpose of this study was to evaluate the anxiety level and potentially influencing factors in patients with CP, to provide insights for the management of anxiety in patients with CP. Methods: A total of 104 adult patients with CP meeting the inclusion/exclusion criteria were enrolled from a single center in Wuhu, China between October 2015 and December 2016. A Self-rating Anxiety Scale (SAS) was used to measure the status of anxiety. The relationship between SAS scores and illness period in patients with CP was analyzed by Pearson correlation test. Univariate analysis and binary logistic regression analysis were performed to analyze the risk factors of anxiety in patients with CP. Results: The average SAS score of 104 patients with CP was (44.17 ± 8.38), including 82 cases (78.85%) without anxiety and 22 cases (21.15%) with anxiety. Moreover, the illness period was found to be positively related to SAS scores in patients with CP (r = 0.378, P = 0.001). Furthermore, the results of univariate analysis showed that there were significant differences in anxiety state among CP patients with different age, illness period, source of treatment payment, and marital status (P < 0.05). Additionally, the results of binary logistic regression analysis showed that age, source of treatment payment, and marital status were the independent risk factors affecting the anxiety status of patients with CP (P < 0.05). Conclusion: These results suggested that CP patients with advanced age, self-pay, and unmarried status had higher risk for anxiety.

Atf7ip Inhibits Osteoblast Differentiation via Negative Regulation of the Sp7 Transcription Factor.

Epigenetic modifications are critical for cell differentiation and growth. As a regulator of H3K9 methylation, Setdb1 is implicated in osteoblast proliferation and differentiation. The activity and nucleus localization of Setdb1 are regulated by its binding partner, Atf7ip. However, whether Atf7ip is involved in the regulation of osteoblast differentiation remains largely unclear. In the present study, we found that Atf7ip expression was upregulated during the osteogenesis of primary bone marrow stromal cells and MC3T3-E1 cells, and was induced in PTH-treated cells. The overexpression of Atf7ip impaired osteoblast differentiation in MC3T3-E1 cells regardless of PTH treatment, as measured by the expression of osteoblast differentiation markers, Alp-positive cells, Alp activity, and calcium deposition. Conversely, the depletion of Atf7ip in MC3T3-E1 cells promoted osteoblast differentiation. Compared with the control mice, animals with Atf7ip deletion in the osteoblasts (Oc-Cre;Atf7ipf/f) showed more bone formation and a significant increase in the bone trabeculae microarchitecture, as reflected by µ-CT and bone histomorphometry. Mechanistically, Atf7ip contributed to the nucleus localization of Setdb1 in MC3T3-E1, but did not affect Setdb1 expression. Atf7ip negatively regulated Sp7 expression, and through specific siRNA, Sp7 knockdown attenuated the enhancing role of Atf7ip deletion in osteoblast differentiation. Through these data, we identified Atf7ip as a novel negative regulator of osteogenesis, possibly via its epigenetic regulation of Sp7 expression, and demonstrated that Atf7ip inhibition is a potential therapeutic measure for enhancing bone formation.

Quercetin alleviates kainic acid-induced seizure by inhibiting the Nrf2-mediated ferroptosis pathway.

BACKGROUND: Epilepsy is one of the most common neurological disorders in childhood. However, classical antiepileptic drugs are linked with drug toxicity and cognitive function impairment in children. Hence, it is essential to develop a novel therapy to solve this problem. Currently, studies indicate regulating the nuclear factor-erythroid 2-related factor 2 (Nrf2)-mediated ferroptosis pathway represents a potential advanced therapy for seizures. Hence, the present study aimed to explore whether quercetin, a natural polyphenol, could alleviate seizure-induced neuron death and preserve cognitive function by inhibiting Nrf2-mediated ferroptosis. METHODS: Kainic acid-induced epileptic mice model, morris water maze (MWM) test, cell counting kit-8 (CCK-8) assays, western blotting analysis, enzyme-linked immunosorbent assay, flow cytometry, quantitative real-time reverse transcription PCR (qRT-PCR), immunofluorescence staining, and RNA sequencing analysis were employed to explore the potential mechanisms by which quercetin exerts protective effects on seizure-induced neuron death in kainic acid-induced epileptic mice model and glutamate-induced HT22 neuronal cell death. RESULTS: Our findings suggested the association between the Nrf2-mediated ferroptosis pathway and seizures in a clinical setting. Quercetin pretreatment alleviates seizure-like behaviors and cognitive impairment in KA-induced epileptic mice. Additionally, in vitro, co-treatment with quercetin effectively exerts neuroprotective effects in glutamate-induced HT22 neuronal cell death. These protective effects were also closely linked to regulating the Nrf2-mediated ferroptosis pathway. Furthermore, bioinformatic profiling revealed that the SIRT1/Nrf2/SLC7A11/GPX4 pathway plays a crucial role in the Glu-induced HT22 cell death pretreated with quercetin. CONCLUSIONS: These findings indicated that quercetin effectively protects against seizure-induced neuron death in vivo and in vitro and alleviates cognitive function impairment via the SIRT1/Nrf2/SLC7A11/GPX4 pathway.

Salubrinal-mediated activation of eIF2α signaling improves oxidative stress-induced BMSCs senescence and senile osteoporosis.

Bone cells of various lineages become senescent in bone microenvironment. Senotherapies that clear the senescent bone cells improve bone microarchitecture of aged bones. However, the mechanisms underlie for the formation and maintenance of senescent bone cells are largely unknown. Here, we focus on the relationship between endoplasmic reticulum stress (ER stress)-activated unfolded protein response (UPR) signaling and cellular senescence of bone marrow mesenchymal stem cells (BMSCs). The PKR-like endoplasmic reticulum kinase (PERK)-eukaryotic initiation factor 2 α(eIF2α) signaling branch was specifically activated and tightly regulated in senescent BMSCs induced by hydrogen peroxide (H2O2). However, blocking PERK-eIF2α signaling with AMG'44 could not reverse the cellular senescence phenotype of senescent BMSCs. Treated the senescent cells with salubrinal, an inhibitor for dephosphorylation of eIF2α, decreased SA-ß-Gal positive cells and the expression of markers for cellular senescence. Moreover, salubrinal enhanced the apoptosis of senescent BMSCs and upregulated expression of Chop and BIM. Furthermore, salubrinal treatment significantly improved the osteogenesis capacity of senescent BMSCs as reflected by the increase of Alp, Runx2 and Osteocalcin, the formation of Alp-positive staining cells and matrix mineralization. Salubrinal administration results in significant recovery in the bone microarchitecture of senile SAMP6 mice. Taken together, our data reveal an undefined role of PERK-eIF2α signaling in the maintenance of cellular senescent phenotype in BMSCs. The activation of eIF2α signaling with salubrinal is helpful for the clearance of senescent BMSCs and the improvement of bone integrity of aged mice.

The Protective Role of E-64d in Hippocampal Excitotoxic Neuronal Injury Induced by Glutamate in HT22 Hippocampal Neuronal Cells.

Epilepsy is the most common childhood neurologic disorder. Status epilepticus (SE), which refers to continuous epileptic seizures, occurs more frequently in children than in adults, and approximately 40-50% of all cases occur in children under 2 years of age. Conventional antiepileptic drugs currently used in clinical practice have a number of adverse side effects. Drug-resistant epilepsy (DRE) can progressively develop in children with persistent SE, necessitating the development of novel therapeutic drugs. During SE, the persistent activation of neurons leads to decreased glutamate clearance with corresponding glutamate accumulation in the synaptic extracellular space, increasing the chance of neuronal excitotoxicity. Our previous study demonstrated that after developmental seizures in rats, E-64d exerts a neuroprotective effect on the seizure-induced brain damage by modulating lipid metabolism enzymes, especially ApoE and ApoJ/clusterin. In this study, we investigated the impact and mechanisms of E-64d administration on neuronal excitotoxicity. To test our hypothesis that E-64d confers neuroprotective effects by regulating autophagy and mitochondrial pathway activity, we simulated neuronal excitotoxicity in vitro using an immortalized hippocampal neuron cell line (HT22). We found that E-64d improved cell viability while reducing oxidative stress and neuronal apoptosis. In addition, E-64d treatment regulated mitochondrial pathway activity and inhibited chaperone-mediated autophagy in HT22 cells. Our findings indicate that E-64d may alleviate glutamate-induced damage via regulation of mitochondrial fission and apoptosis, as well as inhibition of chaperone-mediated autophagy. Thus, E-64d may be a promising therapeutic treatment for hippocampal injury associated with SE.

Gene expression signatures differentiating major depressive disorder from subsyndromal symptomatic depression.

Subsyndromal symptomatic depression (SSD) and major depressive disorder (MDD) have been classified as distinct diseases, due to their dissimilar gene expression profiles and responses to venlafaxine. To identify specific biomarkers of these two diseases, we conducted a secondary analysis of the gene expression signatures of SSD patients, MDD patients and healthy controls (n=8/group) from the study of Yi et al. Global, individual, specific, enrichment and co-expression analyses were used to compare the transcriptomic profiles of peripheral blood lymphocytes from the three groups. The global and individual analyses revealed that different genes were up- and downregulated in the SSD and MDD groups. Through our specific analysis, we identified 1719 and 3278 differentially expressed genes specifically associated with MDD and SSD, respectively. Enrichment and co-expression analyses demonstrated that the genes specific to MDD were enriched in pathways associated with hormone levels and immune responses, while those specific to SSD were associated with immune function. The specific hub gene for the MDD co-expression network was transmembrane protein 132B (TMEM132B), while the hub genes for SSD were actin-related protein 2/3 complex (ARPC2) and solute carrier family 5 member 5 (SLC5A5). This bioinformatic analysis has provided potential biomarkers that can distinguish SSD from MDD.

MicroRNA-195 predicts olanzapine response in drug-free patients with schizophrenia: A prospective cohort study.

BACKGROUND: Disturbances of microRNA-195 have been implicated in the pathogenesis of schizophrenia. However, microRNA-195 levels in schizophrenia are controversial. AIMS: To the best of our knowledge, this is the first study to examine microRNA-195 levels in untreated schizophrenia patients and their relationship to olanzapine response. METHODS: We recruited 81 untreated schizophrenia patients and 96 healthy controls. The patients received 2 months olanzapine treatment. MicroRNA-195 levels in peripheral blood mononuclear cells were measured using quantitative real-time polymerase chain reaction testing. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale. RESULTS: No significant differences in microRNA-195 levels were found between patients and healthy controls (p > 0.05). Olanzapine significantly reduced microRNA-195 levels after 2 months treatment (p = 0.003). Interestingly, microRNA-195 levels decreased significantly in responders (p = 0.010), but not in non-responders (p > 0.05). Both baseline microRNA-195 levels (p = 0.027, p = 0.030) and the reduction rate of microRNA-195 levels (p = 0.034, p = 0.044) were positively associated with the reduction rate of Positive and Negative Syndrome Scale total score and general psychopathological subscale score. Multiple stepwise regression analysis revealed that baseline microRNA-195 level was an independent contributor to the reduction in Positive and Negative Syndrome Scale total score and the general psychopathological subscale score (p = 0.018, p = 0.030). Finally, logistic regression analysis suggested that baseline microRNA-195 level can serve as a biomarker for response to olanzapine (p = 0.037). CONCLUSIONS: Our data indicate that microRNA-195 level may predict symptomatic improvement and olanzapine response in schizophrenia patients, suggesting that microRNA-195 should be considered as a potential therapeutic target for antipsychotics.

The interaction of NOS1AP, DISC1, DAOA, and GSK3B confers susceptibility of early-onset schizophrenia in Chinese Han population.

Although many major breakthrough had identificated potential susceptibility genes for schizophrenia, the aetiology of schizophrenia is still unknown. In the present study, we focused on the N-methyl-Daspartate receptors related genes nitric oxide synthase 1 adaptor gene (NOS1AP), disrupted in schizophrenia 1 gene (DISC1), d-amino acid oxidase activator gene (DAOA), and glycogen synthase kinase 3-beta gene (GSK3B). A family-based genetic association study (459 Han Chinese subjects in 153 nuclear families) using 3 single nucleotide polymorphisms in NOS1AP, 2 in DISC1, 1 in DAOA and 1 in GSK3B was conducted. We found rs12742393 have just positive trend with schizophrenia (SCZ) (p=0.07) after FDR correction. NOS1AP mRNA and serum levels were significantly elevated in SCZ patients (p<0.001; p<0.001) compared with healthy control. However, expression Quantitative Trait Loci (eQTL) analysis have demonstrated that rs12742393 genotype were not significantly associated with the NOS1AP mRNA expression. GMDR identified a significant seven-locus interaction model involving (NOS1AP-rs348624, rs12742393, rs1415263, DISC1-rs821633, rs1000731, DAOA-rs2391191and GSK3B- rs6438552) with a good testing accuracy (0.72). Our finding suggested statistically significant role of interaction of NOS1AP, DISC1, DAOA, and GSK3B polymorphisms (NOS1AP-rs348624, rs12742393, rs1415263, DISC1-rs821633, rs1000731, DAOA-rs2391191and GSK3B-rs6438552) in EOS susceptibility.

Differential gene expression in patients with subsyndromal symptomatic depression and major depressive disorder.

BACKGROUND: Subsyndromal symptomatic depression (SSD) is a subtype of subthreshold depressive and can lead to significant psychosocial functional impairment. Although the pathogenesis of major depressive disorder (MDD) and SSD still remains poorly understood, a set of studies have found that many same genetic factors play important roles in the etiology of these two disorders. Nowadays, the differential gene expression between MDD and SSD is still unknown. In our previous study, we compared the expression profile and made the classification with the leukocytes by using whole-genome cRNA microarrays among drug-free first-episode subjects with SSD, MDD and matched healthy controls (8 subjects in each group), and finally determined 48 gene expression signatures. Based on these findings, we further clarify whether these genes mRNA was different expressed in peripheral blood in patients with SSD, MDD and healthy controls (60 subjects respectively). METHOD: With the help of the quantitative real-time reverse transcription-polymerase chain reaction (RT-qPCR), we gained gene relative expression levels among the three groups. RESULTS: We found that there are three of the forty eight co-regulated genes had differential expression in peripheral blood among the three groups, which are CD84, STRN, CTNS gene (F = 3.528, p = 0.034; F = 3.382, p = 0.039; F = 3.801, p = 0.026, respectively) while there were no significant differences for other genes. CONCLUSION: CD84, STRN, CTNS gene may have significant value for performing diagnostic functions and classifying SSD, MDD and healthy controls.

The survival rate and larynx preservation in elderly cancer patients who received surgical operation: A retrospective cohort study.

BACKGROUND: To investigate the efficiency of surgical operation for patients over 70 years with hypopharyngeal cancer. MATERIALS AND METHODS: A retrospective analysis of the medical records from 68 patients over 70 years-old with hypopharyngeal cancer who underwent different therapeutic regimen between 2000 and 2009 was conducted. 36 of 68 patients underwent larynx preservation. All patients were treated with surgical operation and adjuvant radiotherapy. A Kaplan-Meier method was employed to calculate the survival rate. RESULTS: Overall 3 year-and 5 year-survival rates were 48.6% and 29.4% respectively. For patients who underwent larynx preservation, 5 year-survival rate was 30.5%, which was decreased compared to 3 year-survival rate (46.9%) However, 3 year- and 5 year-survival rates in patients without larynx preservation were 46.9% and 28.1% respectively, suggesting that no statistically significant difference of survival rates was found between patients with or without larynx preservation (P > 0.05). A majority of patients who receive larynx preservation exhibited normal breathing and eating abilities and could present an intelligible speech. 16 of 36 patients who preserved larynx and 14 of 32 patients who underwent laryngectomy showed postoperative complication. No significant difference was observed in these two treatments, indicating larynx preservation is not a factor for inducing complication. CONCLUSION: This study provides evidence that the quality of life for elderly patients with hypopharyngeal cancer can be improved by optimizing the therapeutic regimen based on the physical condition of each patient.

[Observe the origin of antrochoanal polyp and the comparison of the curative effect of antrochoanal polyp].

OBJECTIVE: To explore the curative effect and origin of antrochoanal polyp (ACP) with various approaches. METHOD: Fifty-seven patients with ACP were included in the study. All the ACP patients were examined by preoperative endoscopy and computer tomographic (CT) scans. The patients were treated by various endoscopic approaches including endoscopic middle meatus antrostomy, inferior meatus antrostomy combined with endoscopic middle meatus antrostomy or endoscopic medial maxillectomy combined with endoscopic middle meatus antrostomy respectively. The relationship between polyp location in middle meatus and lesions in the antrum was explored during the surgery. Pathological examination was carried out and patients were regularly followed up after operation. RESULT: Fifty-seven ACP develops from antral cyst. In 22 cases of endoscopic middle meatus antrostomy, two patients relapsed. In 17 cases of inferior meatus antrostomy combined with endoscopic middle meatus antrostomy, one patients relapsed. In 18 cases of endoscopic medial maxillectomy combined with endoscopic middle meatus antrostomy, no one relapsed. CONCLUSION: Our data indicated that the ACP mainly originates in antral cyst, and capsule wall herniates to middle meatus through the antral ostium. ACP are common in unilateral, rare in both sides. The endoscopic approaches of middle meatus antrostomy and inferior meatus antrostomy combined with endoscopic middle meatus antrostomy might guarantee good prognosis. If the cyst is on the anterior wall of maxillary sinus, the approach of endoscopic medial maxillectomy can obtain a better vision and completely remove the lesions.

[The options of surgery and laryngeal preservation for hypopharyngeal cancer patients more than 65 years old].

OBJECTIVE: To study the effectiveness of preserving laryngeal function for senile hypopharyngeal cancer patientsolder than 65. METHOD: The clinical data of 58 surgery cases of senile hypopharyngeal cancer patients more than 65 years old were colleted and analyzed. Thirty-one cases preserved the laryngeal function, while the rest did not. Perfect preoperative preparation was done before surgery. Surgical resection specimens were sent to frozen-section examination. When the negative incisal margin was confirmed, the defect was repaired by the appilication of local stitching, ribbon muscle flap, major myocutaneous flaps, split thickness skin and replacement of esophagus by stomach. Radical radiotherapy was used after surgery. Survival rate was calculated by the Kaplan-Meier method. Chi-square test was used to compare complications of the two groups. RESULT: The 3 years and 5 years survival rate for all cases were 48.3% (28/58) and 27.6% (16/58), respectively. For patients with laryngeal function preservation, the 3 years and 5 years survival rate were 51.6% (16/31), 29.0% (9/31), respectively. For cases without laryngeal function preservation, the 3 years survival rate and 5 years survival rate were 44.4% (12/ 27), 25.9% (7/27), respectively. The result showed no obvious difference in survival rate between two groups (P > 0.05). Surgery complication rate were 45.2% (14/31) and 40.7% (11/27), without obvious differences between the two groups (P > 0.05). CONCLUSION: It is feasible for senile hypopharyngeal cancer patients to choose suitable operation based on their physical conditions and the tumor extension. The key issues include well perioperative treatment management, correct indications grasp, and intraoperative repair skills improvement.

Association of schizophrenia with the rs821633 polymorphism in the DISC1 gene among Han Chinese.

BACKGROUND: Previous studies report that various single nucleotide polymorphisms (SNP) in the Disrupted-in Schizophrenia 1 (DISC1) gene are closely associated with schizophrenia, but there are no studies that assess the relationship of age of onset of schizophrenia with these SNPs. OBJECTIVE: Investigate the relationship between the rs821633 SNP in the DISC1 gene and the occurrence and age of onset of schizophrenia in Han Chinese. METHODS: We used the TaqMan genotyping technology to examine the rs821633 SNP in the DISC1 gene among 315 individuals who developed schizophrenia prior to 19 years of age ('early-onset'), 407 individuals who developed schizophrenia when 19 years of age or older ('late-onset'), and 482 healthy controls. We used survival analyses to investigate the relationship between the rs821633(C) risk allele and the age of onset of schizophrenia. RESULTS: Compared to the prevalence in healthy controls, the prevalence of the C/C genotype of rs821633 and of the C allele in rs821633 were significantly greater in individuals with early-onset schizophrenia (X (2)=7.17, df=1, p=0.007; X (2)=7.20, df=2, p=0.032) and significantly greater in individuals with late-onset schizophrenia (X (2)=5.36, df=1, p=0.022; X (2)=6.58, df=2, p=0.041). However, there were no significant differences in the prevalence of the C/C genotype or the C allele between individuals with early-onset and late-onset schizophrenia. Kaplan-Meier survival analyses found no significant association between the rs821633(C) risk allele and age of onset in schizophrenia. CONCLUSION: We confirm the association of polymorphism in the rs821633 SNP in the DISC1 gene with schizophrenia among Han Chinese, but we found no association between the rs821633(C) risk allele and the age of onset in individuals with schizophrenia.

Platinum-based chemotherapy plus cetuximab first-line for Asian patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck: Results of an open-label, single-arm, multicenter trial.

BACKGROUND: The purpose of this study was to assess the efficacy, safety, and pharmacokinetics of cisplatin-based chemotherapy plus cetuximab as first-line treatment in Chinese and Korean patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). METHODS: Patients (n = 68) received cetuximab weekly plus 3-week cycles of cisplatin/5-fluorouracil (5-FU) chemotherapy for up to 6 cycles. The primary endpoint was overall response rate. RESULTS: The overall response rate was 55.9%, including 2 complete responses (CRs). Median overall survival (OS) was 12.6 months and median progression-free survival (PFS) was 6.6 months. Grade 3/4 adverse events (AEs) were reported in 41 (60.3%) patients. The safety profile was in line with previous clinical experience. The pharmacokinetic profile was in line with that observed with cetuximab in white and Japanese patients. CONCLUSION: The efficacy, safety, and pharmacokinetic findings from this study support the use of first-line platinum-based chemotherapy plus cetuximab in Chinese and Korean patients with recurrent and/or metastatic SCCHN (ClinicalTrials.gov NCT01177956).