A Synergistic Therapeutic Scheme for Hyperglycemia and Nephrotic Disorders in Diabetes

We previously demonstrated that the utilization of an electrospun scaffold could boost functional outputs of transplanted islets. In this study, we aim to develop a drug-eluting scaffold with a payload of pioglitazone to simultaneously rein in hyperglycemia and recoup lost renal functions in diabetic mice that underwent islet transplantation. The in vivo proliferation of islets was measured by a non-invasive bio-imaging technology whereas the blood insulin, blood glucose and renal proteins were assayed. The local stimulation of transplanted islets by pioglitazone saw an accelerated in vivo proliferation without apoptosis caused by the drug-eluting scaffold. In addition, pioglitazone contributed to an increased secretion of insulin and C-peptide 2, giving rise to an accelerated rein-in of hyperglycemia and enhanced tolerance of sudden oral glucose challenge. Moreover, the accelerated decrease of blood creatinine, urine creatinine and blood urea nitrogen suggested that pioglitazone contributed to the recovery of renal functions compromised by diabetes. Our bioengineering strategy effectively ameliorated hyperglycemia and associated nephrotic disorders, and shed a new light on an engineering approach to combat diabetes

Quantitative DNA Methylation Analysis of DLGAP2 Gene Using Pyrosequencing in Schizophrenia With Tardive Dyskinesia: A Linear Mixed Model Approach

Tardive dyskinesia (TD) is a side effect of antipsychotic medications used to treat schizophrenia (SCZ) and other mental health disorders. No study has previously used pyrosequencing to quantify DNA methylation levels of the DLGAP2 gene; while the quantitative methylation levels among CpG sites within a gene may be correlated. To deal with the correlated measures among three CpG sites within the DLGAP2 gene, this study analyzed DNA methylation levels of the DLGAP2 gene using a linear mixed model (LMM) in a Chinese sample consisting of 35 SCZ patients with TD, 35 SCZ without TD (NTD) and 34 healthy controls (HCs) collected in Beijing, China. The initial analysis using the non-parametric Kruskal-Wallis test revealed that three groups (TD, NTD and HC) had significant differences in DNA methylation level for CpG site 2 (p = 0.0119). Furthermore, the average methylation levels among the three CpG sites showed strong correlations (all p values \u3c 0.0001). In addition, using the LMM, three groups had significant differences in methylation level (p = 0.0027); while TD, NTD and TD + NTD groups showed higher average methylation levels than the HC group (p = 0.0024, 0.0151, and 0.0007, respectively). In conclusion, the LMM can accommodate a covariance structure. The findings of this study provide first evidence of DNA methylation levels in DLGAP2 associated with SCZ with TD in Chinese population. However, TD just showed borderline significant differences to NTD in this study

A Synergistic Therapeutic Scheme for Hyperglycemia and Nephrotic Disorders in Diabetes

We previously demonstrated that the utilization of an electrospun scaffold could boost functional outputs of transplanted islets. In this study, we aim to develop a drug-eluting scaffold with a payload of pioglitazone to simultaneously rein in hyperglycemia and recoup lost renal functions in diabetic mice that underwent islet transplantation. The in vivo proliferation of islets was measured by a non-invasive bio-imaging technology whereas the blood insulin, blood glucose and renal proteins were assayed. The local stimulation of transplanted islets by pioglitazone saw an accelerated in vivo proliferation without apoptosis caused by the drug-eluting scaffold. In addition, pioglitazone contributed to an increased secretion of insulin and C-peptide 2, giving rise to an accelerated rein-in of hyperglycemia and enhanced tolerance of sudden oral glucose challenge. Moreover, the accelerated decrease of blood creatinine, urine creatinine and blood urea nitrogen suggested that pioglitazone contributed to the recovery of renal functions compromised by diabetes. Our bioengineering strategy effectively ameliorated hyperglycemia and associated nephrotic disorders, and shed a new light on an engineering approach to combat diabetes

A Pan-Cancer Analysis of UBE2S in Tumorigenesis, Prognosis, Pathway, Immune Infiltration and Evasion, and Therapy Response from an Immune-Oncology Perspective

Background. Ubiquitin conjugating enzyme E2S (UBE2S), a member of the ubiquitin-conjugating enzyme family, is known to play a pivotal role in tumorigenesis and progression in some tumor types. However, whether UBE2S plays an irreplaceable role in the immune-oncology context of tumorigenesis, prognosis, pathogenesis, immune regulation, and therapeutic response through certain common molecular mechanisms remains to be defined. The present pan-cancer study was intended to decipher the landscape of UBE2S in pathologic, immunological, and therapeutic aspects across various cancers. Methods. Data used for UBE2S analysis were obtained from TCGA database. The pan-cancer analysis was mainly focused on the expression patterns, prognostic values, mutation landscapes, biological pathways, tumor microenvironment remodeling, and therapeutic resistance of UBE2S using multiple databases including cBioPortal, Cancer Cell Line Encyclopedia (CCLE) database, Tumor Immune Estimation Resource (TIMER), and Gene Expression Profiling Interactive Analysis (GEPIA). External experimental validation was conducted to delineate the association of UBE2S with tumor phenotypes through assays of proliferation, colony formation, and migration. Data processing, statistical analysis, and plotting were performed using R software and GraphPad Prism software. Results. UBE2S was aberrantly expressed in almost all human cancers, and elevated UBE2S expression was unfavorably associated with the clinical pathological stage and prognosis. DNA methylation and RNA modification were significantly correlated with the UBE2S expression level. The results of enrichment analysis revealed that UBE2S positively regulated MYC, G2M cell cycle, and DNA repair pathways and negatively regulated adipogenesis, fatty acid metabolism, and heme metabolism. In addition, UBE2S exhibited a significantly positive correlation with myeloid-derived suppressor cell MDSC and Th2 subsets in almost all tumors analyzed. UBE2S could confer immune evasion via coexpressed immunoinhibitors and T cell exhaustion. Notably, a higher UBE2S expression indicated a higher level of stemness, TMB, MSI, and MMR deficiency and DNA methyltransferases, as well as chemotherapeutic resistance in various cancers. Notably, in vitro functional validation showed that UBE2S knockdown attenuated the phenotypes of proliferation, clonogenicity, and migration in hepatocellular carcinoma cells. Conclusions. Our study provided meaningful clues to support UBE2S as an immune-oncogenic molecule and shed light on potential applications of UBE2S in cancer detection, prognostic prediction, and therapeutic response assessment.</jats:p

A study about drug combination therapy of <i>Schisandra sphenanthera</i> extract and Rapamycin in healthy subjects

To assess the effect of the drug combination of Schisandra sphenanthera extract (SchE) and Rapamycin (RAPA), 18 healthy subjects were given oral treatments of RAPA alone and with SchE. Pharmacokinetic investigations and indexes of hepatic and renal functions, as well as other indices of oral RAPA administration (2 mg), were performed both before and after the SchE treatment period. Whole-blood RAPA concentrations were determined by enzyme-linked immunosorbent assay. The research found that the mean whole-blood RAPA AUC0–∞, Cmax, and tmax increased almost 2-, 2.1-, and 1.3-fold, respectively, and CL/F (–38.0%) decreased almost 1.6-fold in these subjects when RAPA was administered with SchE compared with oral RAPA administered alone. The results of this study proved that SchE can increase the oral bioavailability of RAPA and will add important information to the interaction area between drugs and herbal products. </jats:p

The neural processing of the interaction between accentuation and lexical prediction during spoken sentence comprehension

Language comprehension requires integration of multiple cues, but the underlying mechanisms of how accentuation, as a significant prosodic feature, influences the processing of words with different levels of cloze probability remains unclear. This study exploits event-related potentials (ERPs) to examine the processing of accented and unaccented words with high-, medium-, and low-cloze probabilities embedded in the final position of highly constrained contexts during spoken sentence comprehension. Our results indicate that accentuation and cloze probability interact across the N400 and post-N400 positivity (PNP) time windows. Under the accented condition, N400 amplitudes gradually increased as cloze probability decreased. Conversely, under the unaccented condition, PNP amplitudes gradually increased as cloze probability decreased with a frontal distribution. These results suggest that the effect of predictability is influenced by accentuation, which is likely due to the processing speed and depth of the critical words, modulated by the amount of attentional resources allocated to them