Publications by authors named "Yan Pan"

454 Publications

[Effect of staged acupuncture on serum irisin level and neurological rehabilitation in patients with ischemic stroke].

Zhongguo Zhen Jiu 2022 Aug;42(8):857-62

School of Nursing, Wenzhou Medical University, Wenzhou 325005, Zhejiang Province.

Objective: To observe the effect of staged acupuncture on serum irisin level, neurological deficit, balance ability and spasticity in patients with ischemic stroke.

Methods: Sixty patients with ischemic stroke were randomly divided into a staged acupuncture group and a routine acupuncture group, 30 cases in each group; another 30 healthy subjects were selected as a normal group. The patients with ischemic stroke were treated with aspirin (100 mg each time, once a day, changing to 50 mg for prophylactic dose after 4 weeks). The patients in the staged acupuncture group were treated with staged acupuncture (acupoints were selected according to the soft paralysis period, spasticity period and recovery period, sequelae period) and rehabilitation treatment, while the patients in the routine acupuncture group were treated with acupuncture of soft paralysis-period as the staged acupuncture group and rehabilitation treatment. All the treatment was given once a day, 5 times a week, 2 weeks as a course of treatment, and 4 consecutive courses of treatment were provided. Before treatment and at 2 weeks, 4 weeks, 6 weeks and 8 weeks into treatment, the serum irisin level was measured, and the scores of National Institutes of Health stroke scale (NIHSS), Fugl-Meyer assessment scale-balance (FM-B) and comprehensive spasticity scale (CSS) were compared, and the correlation between the serum irisin level and NIHSS and FM-B scores in the two groups was analyzed.

Results: Before treatment, the serum irisin levels in the two groups were lower than those in the normal group (<0.01). Compared before treatment, the serum irisin levels and FM-B scores were increased (<0.01), and the NIHSS scores were decreased at 2, 4, 6 and 8 weeks into treatment in the two groups (<0.01). At 4, 6 and 8 weeks into treatment, in the staged acupuncture group, the serum irisin levels and FM-B scores were higher than those in the routine acupuncture group (<0.01, <0.05), and the NIHSS scores were lower than those in the routine acupuncture group (<0.01). After treatment, the CSS scores in the two groups were increased first and then decreased. Compared before treatment, the CSS scores were increased at 2, 4, 6 and 8 weeks into treatment in the two groups (<0.01). At 4, 6 and 8 weeks into treatment, the CSS scores in the staged acupuncture group were lower than those in the routine acupuncture group (<0.01). The serum irisin level was negatively correlated with NIHSS score ( =-0.772, =0.000), and positively correlated with FM-B score ( =0.675, =0.000).

Conclusion: The severity of neurological deficit and balance ability are related to serum irisin level in patients with ischemic stroke. The staged acupuncture could increase the serum irisin level, improve the neurological function, balance ability and spasticity in patients with ischemic stroke.
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http://dx.doi.org/10.13703/j.0255-2930.20210823-k0006DOI Listing
August 2022

Impact of migration status on incidence of depression in the middle-aged and elderly population in China: Exploring healthy migrant and salmon bias hypotheses from a mental health perspective.

J Affect Disord 2022 Aug 1. Epub 2022 Aug 1.

Department of Medical Statistics, School of Public Health, Sun Yat-sen University, #74 Zhongshan Road 2, Guangzhou 510080, China; Center for Migrant Health Policy, Sun Yat-sen University, #74 Zhongshan Road 2, Guangzhou 510080, China. Electronic address:

Background: The healthy migrant and salmon bias hypotheses stipulate that those who are healthier are more likely to migrate (a selection effect) and unhealthy migrants have a greater tendency to return to their origin communities than healthier migrants. It remains unclear whether the hypotheses are relevant for mental health, although they have robust evidence for physical health. The current study expands the theoretical foundation underlying these hypotheses by exploring the impact of migration status on depression among the middle-aged and older population in China.

Method: Longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS) in 2011, 2013, 2015 and 2018 were used. Participants were divided into three groups, non-migrants, permanent migrants, and return-migrants according to their migration status. The Chinese version of 10-item Center for Epidemiologic Studies Depression Scale was used to assess clinically relevant depressive symptoms. Incidence were estimated by each migration status and compared across strata using log-rank tests. Cox regression models were fit to assess the relationship between migration status and depression incidence.

Results: A total of 9264 middle-aged and elderly participants were included, of whom 7047 (76.1 %) were non-migrants, 1065 (11.5 %) were permanent migrants, and 1152 (12.4 %) were return-migrants, respectively. Incidence rates of depression by different migration statuses were 76.6/10 person-years (73.7/10-79.7/10) in non-migrants, 62.9/10 person-years (55.9/10-70.6/10) in permanent migrants, and 67.3/10 person-years (60.7/10-74.5/10) in return-migrants. After controlling for covariates, only permanent migrants had significantly lower incidence of depression than non-migrants (HR: 0.85 (0.75, 0.96)). After stratifying by current place of residence, urban-permanent-migrants had a lower risk of depression than both rural and urban non-migrants, and the HRs and 95%CIs were 0.62(0.52-0.74) and 0.81(0.68-0.97).

Limitations: Migration statuses of participants may have changed over time, but due to the lack of raw data on migration status in 2013 and 2015, we used migration status at baseline. We were also not able to contextualize the migration experiences among those who migrated, and these trajectories may be heterogeneous.

Conclusion: Using depression as an indicator of mental health, the healthy migrant hypothesis was supported among middle-aged and elderly permanent migrants living in urban areas while the salmon bias hypothesis was not. Significant urban-rural inequities in mental health existed among different types of migrants. Especially among permanent migrants who have migrated and converted Hukou from their original registration place to their current residence.
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http://dx.doi.org/10.1016/j.jad.2022.07.048DOI Listing
August 2022

SDC1-dependent TGM2 determines radiosensitivity in glioblastoma by coordinating EPG5-mediated fusion of autophagosomes with lysosomes.

Autophagy 2022 Aug 1:1-19. Epub 2022 Aug 1.

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai, China.

Glioblastoma multiforme (GBM) is the most common brain malignancy insensitive to radiotherapy (RT). Although macroautophagy/autophagy was reported to be a fundamental factor prolonging the survival of tumors under radiotherapeutic stress, the autophagic biomarkers coordinated to radioresistance of GBM are still lacking in clinical practice. Here we established radioresistant GBM cells and identified their protein profiles using tandem mass tag (TMT) quantitative proteomic analysis. It was found that SDC1 and TGM2 proteins were overexpressed in radioresistant GBM cells and tissues and they contributed to the poor prognosis of RT. Knocking down and inhibited the fusion of autophagosomes with lysosomes and thus enhanced the radiosensitivity of GBM cells. After irradiation, TGM2 bound with SDC1 and transported it from the cell membrane to lysosomes, and then bound to LC3 through its two LC3-interacting regions (LIRs), coordinating the encounter between autophagosomes and lysosomes, which should be a prerequisite for lysosomal EPG5 to recognize LC3 and subsequently stabilize the STX17-SNAP29-VAMP8 QabcR SNARE complex assembly. Moreover, when combined with RT, cystamine dihydrochloride (a TGM2 inhibitor) extended the lifespan of GBM-bearing mice. Overall, our findings demonstrated the EPG5 tethering mode with SDC1 and TGM2 during the fusion of autophagosomes with lysosomes, providing new insights into the molecular mechanism and therapeutic target underlying radioresistant GBM. BafA: bafilomycin A; CQ: chloroquine; Cys-D: cystamine dihydrochloride; EPG5: ectopic P-granules 5 autophagy tethering factor; GBM: glioblastoma multiforme; GFP: green fluorescent protein; LAMP2: lysosomal associated membrane protein 2; LIRs: LC3-interacting regions; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; NC: negative control; RFP: red fluorescent protein; RT: radiotherapy; SDC1: syndecan 1; SNAP29: synaptosome associated protein 29; SQSTM1/p62: sequestosome 1; STX17: syntaxin 17; TGM2: transglutaminase 2; TMT: tandem mass tag; VAMP8: vesicle associated membrane protein 8; WT: wild type.
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http://dx.doi.org/10.1080/15548627.2022.2105562DOI Listing
August 2022

Genome-Wide Identification and Characterization of RNA/DNA Differences Associated with Infection in Wheat.

Int J Mol Sci 2022 Jul 20;23(14). Epub 2022 Jul 20.

State Key Laboratory of Crop Stress Biology in Arid Areas, College of Agronomy, Northwest A&F University, Xianyang 712100, China.

RNA/DNA difference (RDD) is a post-transcriptional modification playing a crucial role in regulating diverse biological processes in eukaryotes. Although it has been extensively studied in plant chloroplast and mitochondria genomes, RDDs in plant nuclear genomes are not well studied at present. Here, we investigated the RDDs associated with fusarium head blight (FHB) through a novel method by comparing the RNA-seq data between Fusarium-infected and control samples of four wheat genotypes. A total of 187 high-confidence unique RDDs in 36 genes were identified, representing the first landscape of the FHB-responsive RDD in wheat. The majority (26) of these 36 RDD genes were correlated either positively or negatively with FHB levels. Effects of these RDDs on RNA and protein sequences have been identified, their editing frequency and the expression level of the corresponding genes provided, and the prediction of the effect on the minimum folding free energy of mRNA, miRNA binding, and colocation of RDDs with conserved domains presented. RDDs were predicted to induce modifications in the mRNA and protein structures of the corresponding genes. In two genes, TraesCS1B02G294300 and TraesCS3A02G263900, editing was predicted to enhance their affinity with and , respectively. To our knowledge, this study is the first report of the association between RDD and FHB in wheat; this will contribute to a better understanding of the molecular basis underlying FHB resistance, and potentially lead to novel strategies to improve wheat FHB resistance through epigenetic methods.
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http://dx.doi.org/10.3390/ijms23147982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9316857PMC
July 2022

Polarization Attack on Continuous-Variable Quantum Key Distribution with a Local Local Oscillator.

Entropy (Basel) 2022 Jul 18;24(7). Epub 2022 Jul 18.

Science and Technology on Communication Security Laboratory, Institute of Southwestern Communication, Chengdu 610041, China.

The estimation of phase noise of continuous-variable quantum key distribution protocol with a local local oscillator (LLO CVQKD), as a major process in quantifying the secret key rate, is closely relevant to the intensity of the phase reference. However, the transmission of the phase reference through the insecure quantum channel is prone to be exploited by the eavesdropper (Eve) to mount attacks. Here, we introduce a polarization attack scheme against the phase reference. Presently, in a practical LLO CVQKD system, only part of the phase reference pulses are measured to compensate for the polarization drift of the quantum signal pulses in a compensation cycle due to the limited polarization measurement rate, while the other part of the phase reference pulses are not measured. We show that Eve can control the phase noise by manipulating the polarization direction of the unmeasured phase reference to hide her attack on the quantum signal. Simulations show that Eve can obtain partial or total key rates information shared between Alice and Bob as the transmission distance increases. Improving the polarization measurement rate to 100% or monitoring the phase reference intensity in real-time is of great importance to protect the LLO CVQKD from polarization attack.
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http://dx.doi.org/10.3390/e24070992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9320017PMC
July 2022

Does direct settlement of intra-province medical reimbursements improve financial protection among middle-aged and elderly population in China? Evidence based on CHARLS data.

Soc Sci Med 2022 Jul 8;308:115187. Epub 2022 Jul 8.

Department of Medical Statistics, School of Public Health, Sun Yat-sen University, Guangzhou, China. Electronic address:

In low- and middle-income countries, social health insurance schemes are the main focus of efforts to achieve universal health coverage (UHC) by promoting access to health care and financial protection. Problems with financial protection in China are caused mainly by health insurance fragmentation and a rapid rise in medical expenditure. In this context, China implemented a policy of direct settlement of intra-provincial medical reimbursement in 2014. We evaluated the impact of the policy on financial protection with a population aged 45 and above based on the China Health and Retirement Longitudinal Study from 2011 to 2018. We estimated the policy effects using the difference-in-differences method, based on coarsened exact matching. We found that the policy significantly reduced the catastrophic health expenditures (CHEs) rate by approximately 10% in the population, whether middle-aged or elderly. Subgroup analyses indicated that middle-aged and elderly people living in western China and with lower household incomes received greater protection from the policy. The CHEs rate for the two age groups in western China was reduced by 16.26% and 20.12%, respectively. The CHEs rate was reduced by 24.51% and 17.32% for middle-aged individuals in the lowest and second household income quartiles, respectively, and by 21.31% for older adults in the second household income quartile. The new rural cooperative medical scheme exerted a smaller protective effect than urban medical insurance among the participants aged 60 and older. We found that in addition to optimizing health insurance schemes, more health care reform measures, such as adopting more efficient payment methods and rationalizing medical expenditures, should be combined to help reduce health inequities and accelerate progress toward achieving UHC and the Sustainable Development Goals.
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http://dx.doi.org/10.1016/j.socscimed.2022.115187DOI Listing
July 2022

Irradiation combined with PD-L1 and autophagy inhibition enhances the antitumor effect of lung cancer via cGAS-STING-mediated T cell activation.

iScience 2022 Aug 30;25(8):104690. Epub 2022 Jun 30.

Institute of Radiation Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Radiotherapy combined with immune checkpoint blockade has gradually revealed the superiority in the antitumor therapy; however, the contribution of host PD-L1 remains elusive. In this study, we found that the activation of CD8 T cells was strikingly increased in both irradiated PD-L1-expressing primary tumor and distant non-irradiated syngeneic tumor in PD-L1-deficient mouse host, and thus enhanced radiation-induced antitumor abscopal effect (ATAE) by activating cGAS-STING pathway. Notably, the autophagy inhibitors distinctively promoted dsDNA aggregation in the cytoplasm and increased the release of cGAS-STING-regulated IFN-β from irradiated cells, which further activated bystander CD8 T cells to release IFN-γ and contributed to ATAE. These findings revealed a signaling cascade loop that the cytokines released from irradiated tumor recruit CD8 T cells that in turn act on the tumor cells with amplified immune responses in PD-L1-deficient host, indicating a potential sandwich therapy strategy of RT combined with PD-L1 blockage and autophagy inhibition.
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http://dx.doi.org/10.1016/j.isci.2022.104690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9283938PMC
August 2022

Association between preoperative nutritional status, inflammation, and intestinal permeability in elderly patients undergoing gastrectomy: a prospective cohort study.

J Gastrointest Oncol 2022 Jun;13(3):997-1006

Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai, China.

Background: Malnutrition is relatively common among elderly patients with gastric cancer. This study sought to analyze whether preoperative nutritional status, inflammatory cytokines, and intestinal permeability were correlated in elderly gastric cancer patients undergoing surgery, and their effects on postoperative recovery.

Methods: This study was a single-center prospective cohort study. Patients aged 65-90 years who underwent gastrectomy were included. Preoperative nutritional status was assessed by the Mini Nutritional Score (MNA), Nutritional Risk Screening-2002 (NRS2002), body mass index (BMI), free fatty acids (FFAs), albumin, and prealbumin concentrations. Intestinal permeability was assessed by D-lactate and intestinal fatty acid-binding protein (i-FABP). The inflammatory factors included interleukin (IL)-6, IL-10, neutrophil, and lymphocyte counts. The time to first defecation, time to first liquid diet, length of hospital stay (LOS), and postoperative complications were recorded.

Results: A total of 134 patients were included. According to the MNA, 50.7% and 32.1% of the cohort had mild to moderate malnutrition, and severe malnutrition, respectively. According to the NRS2002, 38.8% of the patients scored >4 points. I-FABP was significantly negatively correlated with albumin (r=-0.409, P<0.001) and prealbumin (r=-0.397, P<0.001), and significantly positively correlated with MNA (r=0.291, P=0.001), the NRS2002 (r=0.284, P=0.001), and LOS (r=0.245, P=0.004). D-lactate was significantly negatively correlated with BMI (r=-0.229, P=0.008), albumin (r=-0.426, P<0.001), and prealbumin (r=-0.358, P<0.001), and significantly positively correlated with the NRS2002 (r=0.187, P=0.030), time to first defecation (r=0.264, P=0.002), and LOS (r=0.409, P<0.001). There were significant differences in BMI, prealbumin, FFAs, i-FABP, time to first defecation, and time to first fluid diet (P<0.05) among groups based on MNA score. The multivariate logistic analysis showed that D-lactate was an independent risk factor of postoperative complications [odds ratio (OR) =1.354, 95% confidence interval (CI): 1.099-1.669, P=0.004].

Conclusions: The preoperative intestinal permeability indicators (i.e., D-lactate and i-FABP) are significantly correlated with some nutritional indicators and postoperative recovery indicators. The preoperative D-lactate level is an independent risk factor of postoperative complications, suggesting that altered gut barrier function before surgery could to some extent influence postoperative recovery in the elderly.
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http://dx.doi.org/10.21037/jgo-22-367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9274063PMC
June 2022

DRD3 Ser9Gly polymorphism and treatment response to antipsychotics in schizophrenia: A meta-analysis.

Neurosci Lett 2022 Aug 11;786:136788. Epub 2022 Jul 11.

Molecular Biology Laboratory, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310013, China. Electronic address:

The association between dopamine D3 receptor (DRD3) Ser9Gly polymorphism and treatment response to antipsychotic drugs (APDs) in schizophrenia (SCZ) has been widely reported with inconsistent results, thus we performed an updated meta-analysis to derive a more precise estimation of the relationship. PubMed, Cochrane Library, Medline, Embase, CNKI, Weipu and Wanfang databases were searched for eligible studies published until March 2022. Odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of the associations in four genetic models. A total of 13 studies with 1769 patients were included in this meta-analysis. Our findings suggested that Ser9Gly polymorphism was significantly associated with treatment response to APDs in SCZ in allele model (Ser vs Gly, OR = 0.72, 95 % CI = 0.58-0.89, P = 0.002), recessive model (Ser/Ser vs Ser/Gly + Gly/Gly, OR = 0.55, 95 % CI = 0.36-0.86, P = 0.008) and co-dominant model (Ser/Ser vs Gly/Gly, OR = 0.57, 95 % CI = 0.33-0.99, P = 0.045) in Caucasians, but not in Asians. meta-regression revealed that the associations were not confounded by mean age, male ratio and treatment duration (P > 0.05). In summary, our results indicated the DRD3 Ser9Gly may influence the efficacy of APDs in specific genetic models, of which Ser allele and Ser/Ser genotype contributed to poor treatment response in Caucasians.
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http://dx.doi.org/10.1016/j.neulet.2022.136788DOI Listing
August 2022

Experimental demonstration of high-rate discrete-modulated continuous-variable quantum key distribution system.

Opt Lett 2022 Jul;47(13):3307-3310

A high-rate continuous-variable quantum key distribution (CV-QKD) system based on high-order discrete modulation is experimentally investigated. With the help of the novel system scheme, effective digital signal processing (DSP) algorithms and advanced analytical security proof methods, the transmission results of 5.059 km, 10.314 km, 24.490 km, and 50.592 km are achieved for 1 GBaud optimized quantum signals. Correspondingly, the asymptotic secret key rates (SKRs) are 292.185 Mbps, 156.246 Mbps, 50.491 Mbps, and 7.495 Mbps for discrete Gaussian (DG) 64QAM, and 328.297 Mbps, 176.089 Mbps, 51.304 Mbps, and 9.193 Mbps for DG 256QAM, respectively. Under the same parameters, the achieved SKRs of DG 256QAM is almost same as ideal Gaussian modulation. In this case, the demonstrated high-rate discrete-modulated CV-QKD system has the application potential for high-speed security communication under tens of kilometers.
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http://dx.doi.org/10.1364/OL.456978DOI Listing
July 2022

Enhanced extracellular raw starch-degrading α-amylase production in Bacillus subtilis by promoter engineering and translation initiation efficiency optimization.

Microb Cell Fact 2022 Jun 27;21(1):127. Epub 2022 Jun 27.

School of Life Sciences, Anhui University, Hefei, 230601, Anhui, People's Republic of China.

Background: A raw starch-degrading α-amylase from Pontibacillus sp. ZY (AmyZ1), previously screened by our laboratory, showed a promising application potential for starch-processing industries. However, the AmyZ1 secretory production still under investigation, which seriously restricts its application in the starch-processing industry. On the other hand, Bacillus subtilis is widely used to achieve the extracellular expression of target proteins.

Results: AmyZ1 secretory production was achieved in B. subtilis and was enhanced by promoter engineering and translation initiation efficiency optimization. First, based on the different phase-dependent promoters, the dual-promoter P-P was constructed by combining dual-promoter engineering and promoter modification. The corresponding strain BZd34 showed an extracellular AmyZ1 activity of 1437.6 U/mL during shake flask cultivation, which was 3.11-fold higher than that of the original strain BZ1 (P). Then, based on translation initiation efficiency optimization, the best strain BZd343 containing optimized 5'-proximal coding sequence (opt3) produced the highest extracellular α-amylase activity of 1691.1 U/mL, which was 3.65-fold higher than that of the strain BZ1. Finally, cultivation of BZd343 in 3-L fermenter exhibited an extracellular AmyZ1 activity of 14,012 U/mL at 48 h, with productivity of 291.9 U/mL·h.

Conclusions: This is the first report of recombinant expression of AmyZ1 in B. subtilis and the expression level of AmyZ1 represents the highest raw starch-degrading α-amylase level in B. subtilis to date. The high-level expression of AmyZ1 in this work provides a foundation for its industrial production. The strategies used in this study also provide a strategic reference for improving the secretory expression of other enzymes in B. subtilis.
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http://dx.doi.org/10.1186/s12934-022-01855-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9235159PMC
June 2022

Artemisinin and Its Derivate Alleviate Pulmonary Hypertension and Vasoconstriction in Rodent Models.

Oxid Med Cell Longev 2022 17;2022:2782429. Epub 2022 Jun 17.

Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, China.

Background: Pulmonary arterial hypertension (PAH) is a complex pulmonary vasculature disease characterized by progressive obliteration of small pulmonary arteries and persistent increase in pulmonary vascular resistance, resulting in right heart failure and death if left untreated. Artemisinin (ARS) and its derivatives, which are common antimalarial drugs, have been found to possess a broad range of biological effects. Here, we sought to determine the therapeutic benefit and mechanism of ARS and its derivatives treatment in experimental pulmonary hypertension (PH) models.

Methods: Isolated perfused/ventilated lung and isometric tension measurements in arteries were performed to test pulmonary vasoconstriction and relaxation. Monocrotaline (MCT) and hypoxia+Su5416 (SuHx) were administered to rats to induce severe PH. Evaluation methods of ARS treatment and its derivatives in animal models include echocardiography, hemodynamics measurement, and histological staining. , the effect of these drugs on proliferation, viability, and hypoxia-inducible factor 1 (HIF1) was examined in human pulmonary arterial smooth muscle cells (hPASMCs).

Results: ARS treatment attenuated pulmonary vasoconstriction induced by high K solution or alveolar hypoxia, decreased pulmonary artery (PA) basal vascular tension, improved acetylcholine- (ACh-) induced endothelial-dependent relaxation, increased endothelial nitric oxide (NO) synthase (eNOS) activity and NO levels, and decreased levels of NAD(P)H oxidase subunits (NOX2 and NOX4) expression, NAD(P)H oxidase activity, and reactive oxygen species (ROS) levels of pulmonary arteries (PAs) in MCT-PH rats. NOS inhibitor, L-NAME, abrogated the effects of ARS on PA constriction and relaxation. Furthermore, chronic application of both ARS and its derivative dihydroartemisinin (DHA) attenuated right ventricular systolic pressure (RVSP), Fulton index (right ventricular hypertrophy), and vascular remodeling of PAs in the two rat PH models. In addition, DHA inhibited proliferation and migration of hypoxia-induced PASMCs.

Conclusions: In conclusion, these results indicate that treatment with ARS or DHA can inhibit PA vasoconstriction, PASMC proliferation and migration, and vascular remodeling, as well as improve PA endothelium-dependent relaxation, and eventually attenuate the development and progression of PH. These effects might be achieved by decreasing NAD(P)H oxidase generated ROS production and increasing eNOS activation to release NO in PAs. ARS and its derivatives might have the potential to be novel drugs for the treatment of PH.
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http://dx.doi.org/10.1155/2022/2782429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9232380PMC
June 2022

Qualitative Distribution of Endogenous Cholesteryl Esters in Plasma of Humans and Three Rodent Species Using Stepwise UPLC-Q-Exactive-MS.

Curr Med Sci 2022 Jun 21. Epub 2022 Jun 21.

School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.

Objective: Cholesteryl esters (CEs) are composed of various fatty acyl chains attached to the hydroxyl groups of cholesterol, and abnormalities in their metabolism are related to many diseases. This study aimed to develop an ultrahigh-performance liquid chromatography-quadrupole exactive mass spectrometry (UPLC-Q-Exactive MS) method to identify the CEs in plasma.

Methods: First, the MS fragmentation patterns were investigated using seven commercial CE standards. Then, the CEs in plasma were characterized through the accurate mass data of precursor ions and characteristic product ions. A strategy of step-by-step m/z scans in a narrow range was proposed to identify more trace CEs by the full-scan data-dependent MS/MS (ddMS2) mode.

Results: A total of 50 CE species consisting of 55 regioisomers were identified in human plasma. Among them, two species were reported for the first time.

Conclusion: This study is the most comprehensive identification of CE species in human plasma to date. These results will contribute to the in-depth profiling of CEs in human plasma and provide guidance for animal model selection when studying lipid-related diseases.
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http://dx.doi.org/10.1007/s11596-022-2577-5DOI Listing
June 2022

Preoperative Nutritional Status and Risk Factors Associated with Delayed Discharge in Geriatric Patients Undergoing Gastrectomy: A Single-Center Retrospective Study.

Appl Bionics Biomech 2022 3;2022:8263986. Epub 2022 Jun 3.

Department of Anesthesiology, Zhongshan Hospital Fudan University, Shanghai 200032, China.

Objective: Preoperative malnutrition is an independent risk factor for postoperative complications and survival for gastric cancer patients. The study is aimed at investigating the prevalence of malnutrition, perioperative nutritional support, and the risk factors associated with delayed discharge of geriatric patients undergoing gastrectomy.

Methods: A retrospective study of gastric cancer patients (age ≥ 65) who underwent gastrectomy at Zhongshan Hospital from January 2018 to May 2020 was conducted. Clinical data, including demographic information, medical history, surgery-related factors, and perioperative nutritional management, were collected and analyzed. Postoperative complications were assessed according to the Clavien-Dindo grading system, and the prognostic nutritional index (PNI) was calculated. The risk factors affecting the prolongation of postoperative hospital stay were analyzed.

Results: A total of 783 patients were reviewed. The overall frequency of malnutrition was 31.3% (249/783). The albumin, prealbumin, and hemoglobin levels were lower in the malnutrition group than in the well-nourished group. The proportion of patients who received preoperative total parenteral nutritional support in the malnutrition group was significantly higher than in the well-nourished group (12.4% vs. 3.7%, < 0.001). All patients received postoperative parenteral nutrition (PN); the proportion of patients who received total nutrient admixture (TNA) in the malnutrition group was lower than in the well-nourished group (22.1% vs. 33.5%, = 0.001). No significant difference was found in the duration of postoperative nutrition between groups ( > 0.05). The malnutrition group was associated with a higher rate of postoperative complications ( < 0.001). Univariate and multivariate regressions revealed that age > 70 years (OR = 1.216, 95% CI 1.048-1.411, = 0.010), operation time > 180 min (OR = 1.431, 95% CI 1.237-1.656, < 0.001), PNI < 44.5 (OR = 1.792, 95% CI 1.058-3.032, = 0.030), and postoperative complications (OR = 2.191, 95% CI 1.604-2.991, < 0.001) were significant risk factors associated with delayed discharge.

Conclusion: Malnutrition is relatively common in elderly patients undergoing gastrectomy. Advanced age, duration of surgery, lower levels of PNI, and postoperative complications were risk factors associated with delay discharge. Elderly gastric cancer patients with risk factors urgently require specific attention for reducing hospital stay.
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http://dx.doi.org/10.1155/2022/8263986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9187457PMC
June 2022

Protein-Ligand Identification and Inhibitory Effects of Cathine on 11 Major Human Drug Metabolizing Cytochrome P450s.

Int J Toxicol 2022 Jun 4:10915818221103790. Epub 2022 Jun 4.

Division of Biomedical Sciences, School of Pharmacy, 69861University of Nottingham Malaysia, Semenyih, Malaysia.

Cathine is the stable form of cathinone, the major active compound found in khat () plant. Khat was found to inhibit major phase I drug metabolizing cytochrome P450 (CYP) enzyme activities and . With the upsurge of khat consumption and the potential use of cathine to combat obesity, efforts should be channelled into understanding potential cathine-drug interactions, which have been rather limited. The present study aimed to assess CYPs activity and inhibition by cathine in a high-throughput fluorescence-based enzyme assay and molecular docking analysis to identify how cathine interacts within various CYPs' active sites. The half maximal inhibitory concentration (IC) values of cathine determined for CYP2A6 and CYP3A4 were 80 and 90 μM, while CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP2J2 and CYP3A5 showed no significant inhibition. Furthermore, in K analysis, the Lineweaver-Burk plots depicted non-competitive mixed inhibition of cathine on both CYP2A6 and CYP3A4 with K value of 63 and 100 μM, respectively. Cathine showed negligible time-dependent inhibition on CYPs. Further, molecular docking studies showed that cathine was bound to CYP2A6 via hydrophobic, hydrogen and π-stacking interactions and formed hydrophobic and hydrogen bonds with active site residues in CYP3A4. Both molecular docking prediction and outcome are in agreement, granting more detailed insights for predicting CYPs metabolism besides the possible cathine-drug interactions. Cathine-drug interactions may occur with concomitant consumption of khat or cathine-containing products with medications metabolized by CYP2A6 and CYP3A4.
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http://dx.doi.org/10.1177/10915818221103790DOI Listing
June 2022

[Saxagliptin alleviates kidney injury in diabetic rats by down-regulating the expression of mammalian target of rapamycin (mTOR)].

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2022 May;38(5):406-411

Department of Nephrology, The First Affiliated Hospital of Bengbu Medical College, Bengbu 233000, China. *Corresponding author, E-mail:

Objective To investigate the effect of saxagliptin (Sax) against kidney injury in diabetic rats and its mechanisms. Methods SD male rats were fed for 2 weeks, among which 14 rats were selected randomly and given intraperitoneal injection of streptozotocin (STZ) to establish the type 2 diabetes mellitus (T2DM) model, and then were randomly divided into T2DM group and Sax group after the model was successfully established; 6 rats were selected as normal control (NC) group randomly. The rats of Sax group were given the saxagliptin solution. The rats of NC and T2DM groups were injected with the same amount of sodium carboxymethyl cellulose solution. After 8 weeks of continuous gastric administration, the rats were sacrificed and their blood and kidney tissues were collected. Glucose (G1u), albumin (ALB), aspartate transaminase (AST), alanine transaminase (ALT), serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), serum total cholesterol (TC), triglycerides (TG) were detected by automatic biochemical analyzer. HE, PAS, Masson staining and transmission electron microscopy were performed to observe the morphological changes of renal. Immunohistochemical staining was used to detect the protein expression level of mammalian target of rapamycin (mTOR), interleukin 1 (IL-1), IL-6, tumor necrosis factor α (TNF-α) in renal tissues. Results Compared with the NC group, the levels of biochemical indicators such as G1u, ALB, AST, ALT, Scr, BUN, UA, TC, and TG showed significant increase; the number of glomerular mesangial cells also increased, and the mesangial matrix hyperplasia, mTOR, IL-1, IL-6, TNF-α protein expression levels exhibited significant increase in T2DM group. Compared with T2DM group, Sax group showed decreased levels of biochemical indicators such as G1u, ALB, AST, ALT, Scr, BUN, UA, TC, and TG and improved renal pathological damage performance, together with a profound reduction in mTOR, IL-1, IL-6, TNF-α protein expression level. Conclusion Sax may suppress inflammatory response and reduce renal injury in diabetic rats by down-regulating mTOR expression.
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May 2022

A Novel Neutrophil-Based Biomarker to Monitor Disease Activity and Predict Response to Infliximab Therapy in Patients With Ulcerative Colitis.

Front Med (Lausanne) 2022 27;9:872831. Epub 2022 Apr 27.

Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

Background: Ulcerative colitis (UC) is characterized by refractory and recurrent mucosal inflammation, leading to a substantial healthcare burden. Diagnostic biomarkers predicting disease activity and treatment response remain elusive. To evaluate the application value of a novel neutrophil-based index (the neutrophil-to-albumin ratio, NAR) as a novel diagnostic biomarker in patients with UC and a predictive marker for disease activity and response to infliximab (IFX) therapy.

Methods: Clinical characteristics and laboratory parameters of enrolled subjects (patients with UC and healthy controls) were retrieved from the electronic medical record database of our hospital. Serum cytokine and fecal calprotectin levels were measured by enzyme-linked immunosorbent assay (ELISA). Mucosal expression levels of inflammatory agents were measured by quantitative RT-PCR (qRT-PCR).

Results: We found that NAR, which had not yet been explored in UC, was significantly increased in patients with UC ( = 146) compared to that in controls ( = 133) (1.95 ± 0.41 vs. 1.41 ± 0.23, < 0.0001). NAR showed a positive association with the disease activity and inflammatory load in patients with UC. Pre-treatment NAR was significantly lower in IFX responders than that in non-responders (2.18 ± 0.29 vs. 2.44 ± 0.21, = 0.0118), showing a significant ability to discriminate initial responders from primary non-responders to IFX induction therapy (AUC = 0.7866 = 0.0076). Moreover, pre-treatment NAR predicted postinduction serum IFX trough level.

Conclusion: Our study provides evidences to utilize NAR in the diagnosis, activity monitoring, and IFX response prediction in patients with UC.
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http://dx.doi.org/10.3389/fmed.2022.872831DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9092064PMC
April 2022

Green Recycling Supplier Selection of Shared Bicycles: Interval-Valued Pythagorean Fuzzy Hybrid Weighted Methods Based on Self-Confidence Level.

Int J Environ Res Public Health 2022 04 20;19(9). Epub 2022 Apr 20.

Department of Mathematics, Riphah Institute of Computing and Applied Sciences, Riphah International University, Lahore 54000, Pakistan.

In the face of practical problems such as the increasing demand for shared bicycles and the number of faulty vehicles which are hard to handle and repair in time, shared bicycles operators tend to outsource recycling services to suppliers. To solve the problem of recycling supplier selection, this paper constructs a novel evaluation index system involving the three traditional dimensions and introduces an interval-valued Pythagorean fuzzy (IVPF) hybrid weighted decision-making model based on the self-confidence level. Subsequently, the self-confidence IVPF hybrid weighted average geometric operator and self-confidence IVPF ordered hybrid weighted average geometric operator are proposed by integrating the self-confidence level of experts, the superiority of the weighted and geometric average rules. The significant merit of the developed operators is that they can incorporate the self-confidence level of the expert as well as effectively combine the characteristics of the weighted and geometric average mechanism. A multi-attribute decision-making (MADM) framework is then constructed by using the proposed aggregation approach. Finally, on the basis of the established evaluation index system, a case concerning the green recycling supplier selection of shared bicycles is applied to display the superiority and practicability of the presented method.
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http://dx.doi.org/10.3390/ijerph19095024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9104403PMC
April 2022

Luminescence properties of BaYbF:Er nanocrystals embedded in glass ceramics for optical thermometry.

RSC Adv 2021 Jun 28;11(37):22798-22804. Epub 2021 Jun 28.

School of Mathematics and Physics, Anhui University of Technology Maanshan 243000 China

Transparent glass ceramics (GCs) containing BaYbF:Er nanocrystals were successfully fabricated by a traditional melt-quenching method. The formation of BaYbF nanocrystals was confirmed by X-ray diffraction, transmission electron microscopy, and selected area electron diffraction. Compared with the precursor glass, the enhanced emission intensity and lifetime of GCs indicate that the Er ions incorporate into the BaYbF nanocrystals after crystallization. The color tuning properties with doping under 980 nm excitation have been systematically discussed. It was found that the red/green ratio increased with Er ion doping and the corresponding color changed from greenish-yellow to yellow-green. Furthermore, the temperature-dependent luminescence properties were studied in detail by the fluorescence intensity ratio (FIR) technique. The monotonic change of FIR with temperature indicates that this material is suitable for temperature sensing. At a temperature of 450 K, the relative sensitivity of the prepared sample reached its maximal value of 0.20% K. The results show that the GCs containing BaYbF:Er nanocrystals are candidate materials for temperature sensing.
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http://dx.doi.org/10.1039/d1ra04038cDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9034377PMC
June 2021

MircroRNA Let-7a-5p in Airway Smooth Muscle Cells is Most Responsive to High Stretch in Association With Cell Mechanics Modulation.

Front Physiol 2022 25;13:830406. Epub 2022 Mar 25.

Changzhou Key Laboratory of Respiratory Medical Engineering, Institute of Biomedical Engineering and Health Sciences, Changzhou University, Changzhou, China.

High stretch (strain >10%) can alter the biomechanical behaviors of airway smooth muscle cells which may play important roles in diverse lung diseases such as asthma and ventilator-induced lung injury. However, the underlying modulation mechanisms for high stretch-induced mechanobiological responses in ASMCs are not fully understood. Here, we hypothesize that ASMCs respond to high stretch with increased expression of specific microRNAs (miRNAs) that may in turn modulate the biomechanical behaviors of the cells. Thus, this study aimed to identify the miRNA in cultured ASMCs that is most responsive to high stretch, and subsequently investigate in these cells whether the miRNA expression level is associated with the modulation of cell biomechanics. MiRNAs related to inflammatory airway diseases were obtained via bioinformatics data mining, and then tested with cultured ASMCs for their expression variations in response to a cyclic high stretch (13% strain) simulating ventilator-imposed strain on airways. Subsequently, we transfected cultured ASMCs with mimics and inhibitors of the miRNA that is most responsive to the high stretch, followed by evaluation of the cells in terms of morphology, stiffness, traction force, and mRNA expression of cytoskeleton/focal adhesion-related molecules. 29 miRNAs were identified to be related to inflammatory airway diseases, among which let-7a-5p was the most responsive to high stretch. Transfection of cultured human ASMCs with let-7a-5p mimics or inhibitors led to an increase or decrease in aspect ratio, stiffness, traction force, migration, stress fiber distribution, mRNA expression of -smooth muscle actin (SMA), myosin light chain kinase, some subfamily members of integrin and talin. Direct binding between let-7a-5p and ItgαV was also verified in classical model cell line by using dual-luciferase assays. We demonstrated that high stretch indeed enhanced the expression of let-7a-5p in ASMCs, which in turn led to changes in the cells' morphology and biomechanical behaviors together with modulation of molecules associated with cytoskeletal structure and focal adhesion. These findings suggest that let-7a-5p regulation is an alternative mechanism for high stretch-induced effect on mechanobiology of ASMCs, which may contribute to understanding the pathogenesis of high stretch-related lung diseases.
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http://dx.doi.org/10.3389/fphys.2022.830406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8990250PMC
March 2022

Spatial and temporal variations of metal fractions in paddy soil flooding with acid mine drainage.

Environ Res 2022 09 4;212(Pt A):113241. Epub 2022 Apr 4.

School of Environment and Energy, South China University of Technology, Guangzhou, 510006, PR China; The Key Lab of Pollution Control and Ecosystem Restoration in Industry Clusters, Ministry of Education, South China University of Technology, Guangzhou, 510006, PR China. Electronic address:

Environmental release of acid mine drainage (AMD) poses a potential threat to the environment and human health due to its high content of heavy metals. The impact of AMD flooding on unpolluted soil leads to serious pollution over time via a complex process, related to the geochemical behavior of toxic metals that so far has only been partially investigated. Here, a soil column study was conducted to investigate the migration of Cu and Cd fractions in unpolluted paddy soil following treatment with AMD collected from the Dabaoshan Mining area. Tessier's sequential extraction was performed to fractionate the metals at various depths over time. After 160 days of experimental flooding, the soil pH stabilized at 2.52 at a column depth of 5 cm. The fractions of Cu and Cd that were highly mobile increased significantly during AMD flooding. For Cd, the latter already occurred on day 67. At a depth of 20 cm, the total content of Cu maximally increased from initially 26.89 mg kg to 696.96 mg kg on day 160, while the content of Cd maximally increased from 0.22 mg kg to 391.30 mg kg on day 67. Reduced partition index analysis conformed that the mobility of both Cu and Cd significantly increased in contaminated soil during continuous AMD flooding. Scanning electron microscopy coupled with energy dispersive spectroscopy (SEM-EDS) identified a changed distribution of the elements in the soil, with Fe appearing to have aggregated. The correlation analysis between Cu and Cd in pore water and in different fractions in the soil's solid phase identified a dynamic distribution of these metals in certain geochemical components during their migration. The results of this study contribute to a scientific foundation to describe the geochemical behavior of heavy metals in soil subject to AMD flooding.
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http://dx.doi.org/10.1016/j.envres.2022.113241DOI Listing
September 2022

CircUBE2Q2 promotes differentiation of cattle muscle stem cells and is a potential regulatory molecule of skeletal muscle development.

BMC Genomics 2022 Apr 6;23(1):267. Epub 2022 Apr 6.

State Key Laboratory for Conservation and Utilization of Subtropical Agro-bioresources, Animal Reproduction Institute, Guangxi University, Nanning, 530004, Guangxi, China.

Background: The growth and development of muscle stem cells (MuSCs) are significant events known to affect muscle plasticity, disease, meat production, and meat quality, which involves the types and functions of mRNA and non-coding RNA. Here, MuSCs were cultured from Guangxi fetal cattle. RNA sequencing was used to analyze the RNA expression of mRNA and non-coding RNAs during the cell proliferation and differentiation phases.

Results: Two thousand one hundred forty-eight mRNAs and 888 non-coding RNAs were differentially expressed between cell proliferation and differentiation phases, including 113 miRNAs, 662 lncRNAs, and 113 circRNAs. RT-qPCR verified the differential expression levels of mRNAs and non-coding RNAs, and the differentially expressed circUBE2Q2 was subsequently characterized. Expression profile analysis revealed that circUBE2Q2 was abundant in muscle tissues and intramuscular fat. The expression of cricUBE2Q2 was also significantly upregulated during MuSCs myogenic differentiation and SVFs adipogenic differentiation and decreased with age in cattle muscle tissue. Finally, the molecular mechanism of circUBE2Q2 regulating MuSCs function that affects skeletal muscle development was investigated. The results showed that circUBE2Q2 could serve as a sponge for miR-133a, significantly promoting differentiation and apoptosis of cultured MuSCs, and inhibiting proliferation of MuSCs.

Conclusions: CircUBE2Q2 is associated with muscle growth and development and induces MuSCs myogenic differentiation through sponging miR-133a. This study will provide new clues for the mechanisms by which mRNAs and non-coding RNAs regulate skeletal muscle growth and development, affecting muscle quality and diseases.
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http://dx.doi.org/10.1186/s12864-022-08518-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8985345PMC
April 2022

Network pharmacology combined with metabolomics and lipidomics to reveal the hypolipidemic mechanism of in hyperlipidemic mice.

Food Funct 2022 Apr 20;13(8):4714-4733. Epub 2022 Apr 20.

Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan 430030, China.

(AR), the dried rhizome of (Sam) Juzep, is effective in treating hyperlipidemia, but the mechanisms involved require further exploration. This study evaluated the hypolipidemic properties of AR using an integrated strategy combining network pharmacology with metabolomics and lipidomics. Firstly, a hyperlipidemia mouse model induced by a high-fat diet was established to evaluate the therapeutic effects of AR. Secondly, plasma metabolomics and lipidomics were used to identify differential metabolites and lipids, and metabolic pathway analysis was performed using MetaboAnalyst. Thirdly, network pharmacology, based on the metabolic profile of AR , was used to discover potential therapeutic targets. Finally, key targets were obtained through a compound-target-metabolite network, which was verified by molecular docking and quantitative real-time PCR (qPCR). Biochemistry analysis and histological examinations showed that AR exerted hypolipidemic effects on hyperlipidemic mice. Seventy potential biomarkers for the AR treatment of hyperlipidemia were identified by metabolomics and lipidomics, which were mainly involved in lipid metabolism, energy metabolism and amino acid metabolism. Eighteen potentially active compounds were identified in the plasma of mice after oral administration of AR, which were associated with 83 potential therapeutic targets. The PPAR signaling pathway was considered a crucial signaling pathway of AR against hyperlipidemia by KEGG analysis. The joint analysis showed that 6 upstream key targets were regulated by AR, including ALB, TNF, IL1B, MMP9, PPARA and PPARG. Molecular docking showed that active compounds of AR had high binding affinity with these key targets. qPCR further demonstrated that AR could reverse the mRNA expression of these key targets in hyperlipidemic mice. This study integrates network pharmacology with metabolomics and lipidomics to reveal the regulatory effects of AR on endogenous metabolites and validates key therapeutic targets, and represents the most systematic and in-depth study on the hypolipidemic activity of AR.
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http://dx.doi.org/10.1039/d1fo04386bDOI Listing
April 2022

Cytochromes P450: Role in Carcinogenesis and Relevance to Cancers.

Curr Drug Metab 2022 Mar 28. Epub 2022 Mar 28.

School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur, Malaysia.

Cancer is a leading factor of mortality globally. Cytochrome P450 (CYP) enzymes play a pivotal role in the biotransformation of both endogenous and exogenous compounds. Evidence from numerous epidemiological, animal, and clinical studies points to instrumental role of CYPs in cancer initiation, metastasis, and prevention. Substantial research has found that CYPs are involved in activating different carcinogenic chemicals in the environment, such as polycyclic aromatic hydrocarbons and tobacco-related nitrosamines. Electrophilic intermediates produced from these chemicals can covalently bind to DNA, inducing mutation and cellular transformation that collectively result in cancer development. While bioactivation of procarcinogens and promutagens by CYPs has long been established, the role of CYP-derived endobiotics in carcinogenesis has emerged in recent years. Eicosanoids derived from arachidonic acid via CYP oxidative pathways have been implicated in tumorigenesis, cancer progression and metastasis. The purpose of this review is to update on the current state of knowledge about the cancer molecular mechanism involving CYPs with focus on the biochemical and biotransformation mechanisms in the various CYP-mediated carcinogenesis, and the role of CYP-derived reactive metabolites, from both external and endogenous sources, on cancer growth and tumour formation.
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http://dx.doi.org/10.2174/1389200223666220328143828DOI Listing
March 2022

Deficiency of Integrin 4 Results in Increased Lung Tissue Stiffness and Responds to Substrate Stiffness Modulating RhoA Activity.

Front Cell Dev Biol 2022 3;10:845440. Epub 2022 Mar 3.

School of Basic Medicine, Central South University, Changsha, China.

The interaction between extracellular matrix (ECM) and epithelial cells plays a key role in lung development. Our studies found that mice with conditional integrin 4 (ITGB4) knockout presented lung dysplasia and increased stiffness of lung tissues. In accordance with our previous studies regarding the functions of ITGB4 in bronchial epithelial cells (BECs), we hypothesize that the decreased ITGB4 expression during embryonic stage leads to abnormal ECM remodeling and increased tissue stiffness, thus impairing BECs motility and compromising lung development. In this study, we examined lung tissue stiffness in normal and ITGB4 deficiency mice using Atomic Force Microscopy (AFM), and demonstrated that ITGB4 deficiency resulted in increased lung tissue stiffness. The examination of ECM components collagen, elastin, and lysyl oxidase (LOX) family showed that the expression of type VI collagen, elastin and LOXL4 were significantly elevated in the ITGB4-deficiency mice, compared with those in normal groups. Airway epithelial cell migration and proliferation capacities on normal and stiff substrates were evaluated through video-microscopy and flow cytometry. The morphology of the cytoskeleton was detected by laser confocal microscopy, and RhoA activities were determined by fluorescence resonance energy transfer (FRET) microscopy. The results showed that migration and proliferation of ITGB4 deficiency cells were noticeably inhibited, along decreased cytoskeleton stabilization, and hampered RhoA activity, especially for cells cultured on the stiff substrate. These results suggest that decreased ITGB4 expression results in increased lung tissue stiffness and impairs the adaptation of bronchial epithelial cells to substrate stiffness, which may be related to the occurrence of broncho pulmonary dysplasia.
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http://dx.doi.org/10.3389/fcell.2022.845440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8926985PMC
March 2022

Clinical Significance of Novel Neutrophil-Based Biomarkers in the Diagnosis and Prediction of Response to Infliximab Therapy in Crohn's Disease.

Front Immunol 2022 4;13:865968. Epub 2022 Mar 4.

Department of Gastroenterology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China.

With the increasing incidence and prevalence, Crohn's disease (CD) has become one of the most challenging diseases in both diagnosis and treatment of gastroenterology. Evaluation of the disease activity and mucosal healing guides clinical decisions regarding subsequent therapy for CD. In this study, we enrolled a total of 144 patients with CD and 239 healthy controls were enrolled. Clinical characteristics and laboratory parameters of enrolled subjects were retrieved from the electronic medical record database of our hospital. Serum cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA). Mucosa expression levels of inflammatory agents were measured by quantitative RT-PCR (qRT-PCR). We identified two neutrophil-based indexes, the neutrophil-to-albumin ratio (NAR) and neutrophil-to-bilirubin ratio (NBR), both of which had not yet been explored in CD or UC. NAR and NBR were significantly increased in patients with CD compared to those in healthy controls, and both indexes showed significantly positive correlations with CD activity and inflammatory load. In note, NAR and NBR showed better performance than blood neutrophil percentage, serum albumin, or bilirubin alone in these scenarios. More importantly, both NAR and NBR discriminated CD patients who completely or partially responded to infliximab (IFX) induction therapy from those with primary non-response. Our observations suggest that NAR and NBR may serve as promising biomarkers in the diagnosis and prediction of response to IFX therapy in CD.
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http://dx.doi.org/10.3389/fimmu.2022.865968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931310PMC
May 2022

Normothermic ex vivo lung perfusion outperforms conventional cold preservation in a deceased rat lung.

Ann Transl Med 2022 Jan;10(2):99

Department of Pharmacology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.

Background: Utilization rate of donor lungs in China is constrained by the inefficiency of conventional cold preservation (COLD) in lung transplantation. We assessed the performance of normothermic ex vivo lung perfusion (EVLP) in lung donors following cardiac death (DCD) with fresh EVLP perfusate.

Methods: A total of 24 adult Sprague-Dawley (SD) rats were randomized into three groups (EVLP, COLD, and control groups) with 8 rats each. Fresh EVLP perfusate was prepared for lung perfusion. The pH, electrolyte concentration, perfusate penetration pressure during irrigation, physiological function, integrity of barrier function, pathological changes, and expressions of inflammation-related cytokines of donor lungs were examined.

Results: The pH, electrolyte concentration, osmotic pressure of the perfusate were kept stable for 4 hours after EVLP was administered. Pulmonary arterial pressure (PAP), pulmonary venous pressure (PVP), pulmonary venous oxygenation index (PaO/FiO), and end carbon dioxide partial pressure (PCO) in the EVLP group were all within acceptable limits. After 4 hours, the oxygenation index was significantly higher in the EVLP group compared with that of the COLD group (P=0.0032). The EVLP group had a decreased wet/dry weight ratio (P=0.0155) and Evans blue dye content (P=0.0075) compared to that of the COLD group. Pathological examination showed more obvious lung damage in the COLD group than in the EVLP group. However, there was no difference in protein expression of high mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) between the EVLP group and the COLD group.

Conclusions: Fresh lung perfusate could be used for EVLP to protect and repair donor lungs. Normothermic EVLP performed better than conventional cold preservation. EVLP might be powerful for lung quality maintenance and may have potential for anti-inflammation.
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http://dx.doi.org/10.21037/atm-22-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848380PMC
January 2022

Yield of baseline imaging for distant metastases in high-risk primary melanoma.

J Surg Oncol 2022 Jun 9;125(8):1312-1317. Epub 2022 Mar 9.

Victorian Melanoma Service, Alfred Health, Melbourne, Victoria, Australia.

Background: The yield of baseline imaging in patients presenting with higher risk primary tumours, at least American Joint Committee on Cancer 8th edition stage IIC or III melanoma, is unclear.

Methods: This retrospective study included patients referred to the Victorian Melanoma Service from January 2017 to April 2020, diagnosed with at least stage IIC or stage III melanoma. Patients with a T4b tumour and no sentinel lymph node biopsy were included as 'T4bNX'.

Results: One hundred and sixty-four patients (median age 65 years) with baseline imaging (T4bNX: 19, IIC: 30, IIIA: 21, IIIB: 43, IIIC: 50, IIID: 1) were included. The majority were male (73%), and those with T4bNX melanoma tended to be older (median age 79 years). Distant metastases were detected in 21% (4/19) of T4bNX, 3% (1/30) of stage IIC, 0% (0/21) of stage IIIA, and 6% (6/94) of stages IIIB-D melanoma patients. All stage III patients with distant metastases had palpable lymphadenopathy a presentation. Two patients had brain metastases, both of whom had T4bNX melanoma and synchronous extra-cranial metastases.

Conclusions: Compared to stage IIC, baseline imaging detects higher rates of extra-cranial distant disease in stages IIIB-D and T4bNX melanoma. Intracranial imaging has greater yield in patients with distant extra-cranial disease.
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http://dx.doi.org/10.1002/jso.26846DOI Listing
June 2022

Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS).

Eur J Med Chem 2022 Mar 19;232:114201. Epub 2022 Feb 19.

Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA. Electronic address:

Tuberculosis (TB) is one of the world's most deadly infectious diseases resulting in nearly 1.3 million deaths annually and infecting nearly one-quarter of the population. para-Aminosalicylic acid (PAS), an important second-line agent for treating drug-resistant Mycobacterium tuberculosis, has moderate bioavailability and rapid clearance that necessitate high daily doses of up to 12 g per day, which in turn causes severe gastrointestinal disturbances presumably by disruption of gut microbiota and host epithelial cells. We first synthesized a series of alkyl, acyloxy and alkyloxycarbonyloxyalkyl ester prodrugs to increase the oral bioavailability and thereby prevent intestinal accumulation as well as undesirable bioactivation by the gut microbiome to non-natural folate species that exhibit cytotoxicity. The pivoxyl prodrug of PAS was superior to all of the prodrugs examined and showed nearly quantitative absorption. While the conceptually simple prodrug approach improved the oral bioavailability of PAS, it did not address the intrinsic rapid clearance of PAS mediated by N-acetyltransferase-1 (NAT-1). Thus, we next modified the PAS scaffold to reduce NAT-1 catalyzed inactivation by introduction of groups to sterically block N-acetylation and fluorination of the aryl ring of PAS to attenuate N-acetylation by electronically deactivating the para-amino group. Among the mono-fluorinated analogs prepared, 5-fluoro-PAS, exhibited the best activity and an 11-fold decreased rate of inactivation by NAT-1 that translated to a 5-fold improved exposure as measured by area-under-the-curve (AUC) following oral dosing to CD-1 mice. The pivoxyl prodrug and fluorination at the 5-position of PAS address the primary limitations of PAS and have the potential to revitalize this second-line TB drug.
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http://dx.doi.org/10.1016/j.ejmech.2022.114201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8941652PMC
March 2022

[Effect of moxibustion with wheat-grain-sized moxa cones on uterine natural killer cells and deci-dualization in rats with thin endometrium].

Zhen Ci Yan Jiu 2022 Feb;47(2):101-7

College of Acupuncture-moxibustion and Health-rehabilitation, Nanjing University of Chinese Medicine, Nanjing 210000, China; Xuzhou Medical University, Xuzhou 221000, Jiangsu Province.

Objective: To observe the effect of moxibustion at "Shenshu"(BL23) and "Guanyuan" (CV4) on decidua-lization and uterine natural killer cells in rats with thin endometrium, so as to explore its mechanism underlying promotion of embryo implantation.

Methods: Female SD rats were randomly divided into normal control, model and wheat-grain-sized moxa cone moxibustion (moxibustion) groups, with 14 rats in each group. The thin endometrium model was established by bilaterally intrauterine perfusion of 95% ethanol (first) and saline (later) during estrus. For rats of the moxibustion group, the ignited wheat-grain-sized moxa cones were applied to bilateral BL23 and CV4, with 7 moxa cones for each acupoint, once a day, continuously for 3 estrous cycles. Then the male and female rats were raised in the same cage. On the 5 day of pregnancy, the rats were killed under anesthesia and the uterus tissue was collected for measuring the endometrium thickness and the numbers of blood vessels and glands after H.E. staining, detecting the levels of the proportion of natural killer cells with flow cytometry. After the uterine natural killer cells were sorted by the immunomagnetic bead method, the expression levels of insulin-like growth factor binding protein (IGFBP-1), interferon(INF-γ), tumor necrosis factor(TNF-α), transforming growth factor(TGF-β), interleukin 4(IL-4) and IL-10 mRNAs were detected by using fluorescence quantitative real-time PCR.

Results: Compared with the normal control group, the endometrium thickness, number of glands and blood vessels, and the expression levels of IGFBP-1, TGF-β, IL-4 and IL-10 mRNAs were significantly decreased (<0.01, <0.05), while the expression levels of IFN-γ and TNF-α mRNAs were significantly increased (<0.05,<0.01) in the model group. In contrast to the model group, the endometrium thickness, number of glands and blood vessels, and the expression levels of IGFBP-1, TGF-β, IL-4 and IL-10 mRNAs were significantly increased (<0.05, <0.01), while the expression levels of IFN-γ and TNF-α mRNAs were considerably down-regulated (<0.05, <0.01) in the moxibustion group. No significant difference was found among the 3 groups in the proportion of natural killer cells in the endometrium (>0.05).

Conclusion: Moxibustion of BL23 and CV4 with wheat-grain-sized moxa cones can improve the degree of thin endometrial decidualization, which may be related with its functions in regulating the levels of cytokines secreted from natural killer cells in the uterus.
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http://dx.doi.org/10.13702/j.1000-0607.201304DOI Listing
February 2022
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