P-glycoprotein (P-gp) is an ATP-dependent multidrug efflux pump that acts as a major obstacle for oral drug delivery and cancer therapy. Recent reports have provided evidence that excipients often used in pharmaceutical formulations, such as Pluronic and TPGS, also have inhibitory effects on P-glycoprotein. Because inhibition of efflux transporters by polymeric inhibitors may dramatically increase the bioavailability of P-gp substrates with negligible side effects, identification of the mechanism and their structure activity relationship is therefore of significant importance for pharmaceutical development. Other than competitive inhibition for traditional inhibitors, polymeric inhibitors may modify P-gp function through alterations on membrane fluidity, inhibition of P-gp ATPase, depletion of intracellular ATP and down-regulating of P-gp expression. In the present review, the inhibition mechanism of potential polymeric inhibitors and their structure activity relationship will be discussed along with a brief introduction to the established methodologies.

Objective To explore the treatment of incidental gallbladder carcinoma(UGC)discovered during laparoscopic cholecystectomy(LC). Methods The clinical data of 17 cases of incidental gallbladder (carcinoma) discovered during laparoscopic cholecystectomy were reviewed retrospectively. Results 11cases with Nevin stage I or stage II were treated by LC and 1 case with Nevin stage III and 3 cases with Nevin stage V were treated by LC and radical local lymphadenectomy. 2 cases with Nevin stage IV were treated by (cholecystectomy). UGC was incidently found in 0.6% of the cases. Cases with Nevin Stage I and II were (observed) for 5 years with no recurrence. A case with Nevin Stage III was found to have recurrence within one and a half years postoperatively and had a re-operation. The prognosis of patients with Nevin Stage IV and V was poor and they were dead within a year after operation. Conclusions The incidently found gallbladder carcinoma with Nevin Stage I and II disease can be radically resected with laparoscopic cholecystectomy. The incidently found gallbladder carcinoma with Nevin Stage III and IV disease needs to be radically resected, and if the resection margin is found to be free of tumour, the prognosis is enhanced. The ones with Nevin Stage V need to be treated by local lymphadenectomy and wedge-resection of liver.

Objective To explore whether perioperative bright light therapy could inhibit the occurrence of postoperative delirium in tumor patients undergoing open hepatobiliary surgery. Methods Totally120 elderly tumor patients scheduled for open hepatobiliary surgery and postoperative ICU treatment were recruited and randomized into bright light and control group with 60 cases per group in accordance with the random number table.Bright light was delivered to the patients at an intensity of 10 000 lux from 2 days before surgery to postoperative day 7.Each intervention began at 7 am and lasted for 2 hours.Delirium was screened using the Confusion Assessment Method for Intensive Care Unit(CAM-ICU) during the first 7 days after surgery. The differences in the incidence of postoperative delirium, the duration of delirium and the length of ICU as well as postoperative hospital stay were compared. Results Demographic characteristics and surgical outcomes were similar between groups. The incidence of postoperative delirium were 46.67%(28/60)and 23.33%(14/60)for control group and bright light group respectively with a significant difference (χ2=7.179,P=0.007). The difference was seen on postoperative days 3 (χ2=5.187, P = 0.023) and 4 (χ2=8.749,P = 0.003). The incidences of delirium on postoperative days 3 for bright light and control group were 5.08%(3/59)and 18.64%(11/59)respectively.On postoperative day 4, the incidences of delirium for bright light and control group were 0 (0/58) and 14.04% (8/57) respectively.There was no difference in the duration of delirium(χ2=1.248,P=0.264),the length of ICU stay (χ2=0.036,P=0.849)or the hospital stay(χ2=1.706,P=0.192). Conclusion Bright light is useful in preventing postoperative delirium in elderly tumor patients undergoing open hepatobiliary surgery.

Objective: To investigate the molecular mechanism and identify potential drugs for subthreshold depression (SD), and elucidate the detalied mechanism of Danzhi Xiaoyao powder (DZXY) in SD. Methods: Using RNA-sequencing, we identified differentially expressed genes (DEGs) in leukocytes of SD compared to healthy controls, deciphered their functions and pathways, and identified the hub genes of SD. We also assessed changes in leukocyte transcription factor activity in patients with SD using the TELiS platform. The Connectivity Map database was retrieved to screen candidate drugs for SD. Based on network pharmacology, we elucidated the “multi-component, multi-target, and multi-pathway” mechanism of DZXY in the treatment of SD. Results: We identified 1080 DEGs (padj <0.05 and |log2 (fold change)| ≥ 1 & protein coding) in the leukocytes of patients with SD. These DEGs, including hub genes, were primarily involved in immune and inflammatory response-related processes. Transcription factor activity analysis revealed similarities between the leukocyte transcriptome profile in SD and the conserved transcriptional response to adversities in immune cells. Connectivity Map analysis identified 28 potential drugs for SD treatment, particularly SB-202190 and TWS-119. Constructing the “Direct Compounds-Direct Targets-Pathways” network for DZXY and SD revealed the curative mechanisms of DZXY in SD, primarily including inflammatory response, lipid metabolism, immune response, and other processes. Conclusion These results provide new insights into the characteristics and functional changes of leukocytes in SD, partially illustrate the pathogenesis of SD, and suggest potential drugs for SD. The curative mechanisms of DZXY in SD are also partially elucidated.

Objective:To explore the effects of smart cloud follow-up platform in home care for elderly patients with pacemakers.Methods:Totally 120 elderly patients who received pacemaker implantation in a ClassⅢ Grade A hospital in Henan province between August 2018 and August 2019 were selected by convenient sampling. The 60 patients admitted from August 2018 to February 2019 were included into the control group, while the 60 patients admitted from March to August 2019 were selected into the experimental group. Patients in the experimental group received home care based on the cloud follow-up platform, while patients in the control group received routine continuing care at home. After 3 months of intervention, the complication rate, functional exercise compliance and quality of life were compared between the two groups using χ 2 test and t test. Results:Totally 59 patients in the experimental group and 58 patients in the control group completed the study. After intervention, the complication rate in the experimental group was 32.2% (19/59) , lower than 89.7% (52/58) in the control group, and the difference was statistically significant (χ 2=9.307, P< 0.05) ; the scores of physical exercise compliance after pacemaker implantation, postoperative precautions compliance and compliance of initiative advice seeking in the experimental group were (26.05±3.07) , (15.42±1.24) and (11.85±1.96) , higher than those in the control group (18.53±2.93) , (9.66±2.40) and (6.05±1.58) in the control group, and the differences were statistically significant ( t=13.548, 16.331, 17.558; P< 0.01) ; the total quality of life score in the experimental group was (161.12±9.94) , higher than (132.50±9.20) in the control group, and the difference was statistically significant ( t=16.149, P < 0.01) . Conclusions:The home management model based on the smart cloud follow-up platform improves home follow-up experience of elderly patients with pacemaker, the compliance of home functional exercises, and their quality of life.

Mammalian mitochondrial genome encodes a small set of tRNAs, rRNAs, and mRNAs. The RNA synthesis process has been well characterized. How the RNAs are degraded, however, is poorly understood. It was long assumed that the degradation happens in the matrix where transcription and translation machineries reside. Here we show that contrary to the assumption, mammalian mitochondrial RNA degradation occurs in the mitochondrial intermembrane space (IMS) and the IMS-localized RNASET2 is the enzyme that degrades the RNAs. This provides a new paradigm for understanding mitochondrial RNA metabolism and transport.
Cell Line ; Humans ; Mitochondrial Membranes ; metabolism ; Protein Transport ; RNA ; biosynthesis ; chemistry ; metabolism ; RNA Stability ; RNA, Mitochondrial ; Ribonucleases ; metabolism ; Tumor Suppressor Proteins ; metabolism

Mitochondrial dysfunctions play major roles in ageing. How mitochondrial stresses invoke downstream responses and how specificity of the signaling is achieved, however, remains unclear. We have previously discovered that the RNA component of Telomerase TERC is imported into mitochondria, processed to a shorter form TERC-53, and then exported back to the cytosol. Cytosolic TERC-53 levels respond to mitochondrial functions, but have no direct effect on these functions, suggesting that cytosolic TERC-53 functions downstream of mitochondria as a signal of mitochondrial functions. Here, we show that cytosolic TERC-53 plays a regulatory role on cellular senescence and is involved in cognition decline in 10 months old mice, independent of its telomerase function. Manipulation of cytosolic TERC-53 levels affects cellular senescence and cognition decline in 10 months old mouse hippocampi without affecting telomerase activity, and most importantly, affects cellular senescence in terc cells. These findings uncover a senescence-related regulatory pathway with a non-coding RNA as the signal in mammals.