Effects of temporal changes in resting heart rate on future diabetes-related outcomes.

Background and aims: Most studies have analyzed the relationship between resting heart rate (RHR) measured at only one time point and future clinical events. The current study aims to investigate the impact of long-term RHR changes on future clinical outcomes in a decade-long cohort with type 2 diabetes mellitus (T2DM). Methods: The two-staged follow-up involved 2,513 T2DM participants. The first stage (2008-2014) intended to identify levels and trends in RHR changes, while the second stage (2014-2018) attempted to collect new occurrence records of clinical results. Cox proportional hazards models were applied to predict hazard ratios (HRs), along with 95% confidence interval (CI) for the correlation between RHR changes and future events. Results: There is no significant correlation between baseline RHR levels and long-term clinical events. According to the range of RHR change, compared with the stable RHR group, the adjusted HRs for cardiovascular events and all-cause death in the large increase group were 3.40 (95% CI: 1.33-8.71, p=0.010) and 3.22 (95% CI: 1.07-9.64, p=0.037), respectively. While the adjusted HRs for all-cause death and major adverse cardiac and cerebrovascular events (MACCE) in the moderate decrease group were 0.55 (95% CI: 0.31-0.96, p=0.037) and 0.51 (95% CI: 0.26-0.98, p=0.046). According to the trend of RHR, compared with the normal-normal group, the adjusted HRs for composite endpoint events and cerebrovascular events in the normal-high group were 1.64 (95% CI: 1.00-2.68, p=0.047) and 2.82 (95% CI: 1.03-7.76, p=0.043), respectively. Conclusion: Changes in RHR had predictive value for long-term clinical events in diabetic populations. Individuals with significantly elevated RHR over a particular period of time showed an increased risk of adverse events.

Gene delivery to breast cancer by incorporated EpCAM targeted DARPins into AAV2.

OBJECTIVE: The aim of this study is to evaluate an AAV vector that can selectively target breast cancer cells and to investigate its specificity and anti-tumor effects on breast cancer cells both in vitro and in vivo, offering a new therapeutic approach for the treatment of EpCAM-positive breast cancer. METHODS: In this study, a modified AAV2 viral vector was used, in which EpCAM-specific DARPin EC1 was fused to the VP2 protein of AAV2, creating a viral vector that can target breast cancer cells. The targeting ability and anti-tumor effects of this viral vector were evaluated through in vitro and in vivo experiments. RESULTS: The experimental results showed that the AAV2MEC1 virus could specifically infect EpCAM-positive breast cancer cells and accurately deliver the suicide gene HSV-TK to tumor tissue in mice, significantly inhibiting tumor growth. Compared to the traditional AAV2 viral vector, the AAV2MEC1 virus exhibited reduced accumulation in liver tissue and had no impact on tumor growth. CONCLUSION: This study demonstrates that AAV2MEC1 is a gene delivery vector capable of targeting breast cancer cells and achieving selective targeting in mice. The findings offer a potential gene delivery system and strategies for gene therapy targeting EpCAM-positive breast cancer and other tumor types.

[Testing Effectiveness of Localized Cognitive Stimulation Training With Musical Rhythm Courses Among Older People in Day Care Centers: A Pilot Study].

BACKGROUND: Staff caregivers of day care centers provide many activities for older people. However, there is a lack of a systematic curriculum based on Taiwanese culture to improve cognitive function, self-care ability, and depressive mood status in these individuals. PURPOSE: This study was designed to test the effectiveness of a series of localized cognitive stimulation training courses implemented by direct caregivers and aimed at improving cognitive function, self-care ability, and depressive mood in older people at day care centers. METHODS: This cluster-randomized controlled trial research was conducted over a four-month period. The participants were randomly assigned to the experimental, comparison, or control groups based on their day care center affiliation. The experimental group received a series of localized cognitive stimulation training sessions with musical rhythm courses from day care center direct caregivers. The cognitive function, self-care ability, and depression mood state of the three groups were then tested. RESULTS: The experimental group reported statistically significant changes in average scores for attention, feeding, and depressive mood. After controlling for time and degree of participation in activities, the comparison group reported a lower average score for cognitive function at timepoint 3. CONCLUSIONS / IMPLICATIONS FOR PRACTICE: The results of this study support caregivers at day care centers implementing a series of localized cognitive stimulation training course interventions to prevent declines in activities of daily living and cognitive function and ameliorate depressive mood in older adults. In the future, a larger sample size should be used to improve the effectiveness of the intervention.

Altered GC- and AT-biased genotypes of Ophiocordyceps sinensis in the stromal fertile portions and ascospores of natural Cordyceps sinensis.

OBJECTIVE: To examine multiple genotypes of Ophiocordyceps sinensis in a semi-quantitative manner in the stromal fertile portion (SFP) densely covered with numerous ascocarps and ascospores of natural Cordyceps sinensis and to outline the dynamic alterations of the coexisting O. sinensis genotypes in different developmental phases. METHODS: Mature Cordyceps sinensis specimens were harvested and continuously cultivated in our laboratory (altitude 2,254 m). The SFPs (with ascocarps) and fully and semi-ejected ascospores were collected for histological and molecular examinations. Biochip-based single nucleotide polymorphism (SNP) MALDI-TOF mass spectrometry (MS) was used to genotype multiple O. sinensis mutants in the SFPs and ascospores. RESULTS: Microscopic analysis revealed distinct morphologies of the SFPs (with ascocarps) before and after ascospore ejection and SFP of developmental failure, which, along with the fully and semi-ejected ascospores, were subjected to SNP MS genotyping analysis. Mass spectra showed the coexistence of GC- and AT-biased genotypes of O. sinensis that were genetically and phylogenetically distinct in the SFPs before and after ejection and of developmental failure and in fully and semi-ejected ascospores. The intensity ratios of MS peaks were dynamically altered in the SFPs and the fully and semi-ejected ascospores. Mass spectra also showed transversion mutation alleles of unknown upstream and downstream sequences with altered intensities in the SFPs and ascospores. Genotype #5 of AT-biased Cluster-A maintained a high intensity in all SFPs and ascospores. An MS peak with a high intensity containing AT-biased Genotypes #6 and #15 in pre-ejection SFPs was significantly attenuated after ascospore ejection. The abundance of Genotypes #5‒6 and #16 of AT-biased Cluster-A was differentially altered in the fully and semi-ejected ascospores that were collected from the same Cordyceps sinensis specimens. CONCLUSION: Multiple O. sinensis genotypes coexisted in different combinations with altered abundances in the SFPs prior to and after ejection, the SFP of developmental failure, and the two types of ascospores of Cordyceps sinensis, demonstrating their genomic independence. Metagenomic fungal members present in different combinations and with dynamic alterations play symbiotic roles in different compartments of natural Cordyceps sinensis.

[Differential transcription of mating-type genes during sexual reproduction of natural Cordyceps sinensis].

Natural Cordyceps sinensis as an insect-fungal complex, which is developed after Ophiocordyceps sinensis infects a larva of Hepialidae family. Seventeen genotypes of O. sinensis have been identified in natural C. sinensis. This paper summarized the literature reports and GenBank database regarding occurrence and transcription of the mating-type genes of MAT1-1 and MAT1-2 idiomorphs in natural C. sinensis, in Hirsutella sinensis(GC-biased Genotype #1 of O. sinensis), to infer the mating pattern of O. sinensis in the lifecycle of natural C. sinensis. The mating-type genes and transcripts of MAT1-1 and MAT1-2 idiomorphs were identified in the metagenomes and metatranscriptomes of natural C. sinensis. However, their fungal sources are unclear because of co-colonization of several genotypes of O. sinensis and multiple fungal species in natural C. sinensis. The mating-type genes of MAT1-1 and MAT1-2 idiomorphs were differentially present in 237 H. sinensis strains, constituting the genetic control of the O. sinensis reproduction. Transcriptional control of the O. sinensis reproduction includes: differential transcription or silencing of the mating-type genes of MAT1-1 and MAT1-2 idiomorphs, and the MAT1-2-1 transcript with unspliced intron I that contains 3 stop codons. Research on the H. sinensis transcriptome demonstrated differential and complementary transcriptions of the mating-type genes of MAT1-1 and MAT1-2 idiomorphs in Strains L0106 and 1229, which may become mating partners to accomplish physiological heterothallism. The differential occurrence and transcription of the mating-type genes in H. sinensis are inconsistent with the self-fertilization hypothesis under homothallism or pseudohomothallism, but instead indicate the need of mating partners of the same H. sinensis species, either monoecious or dioecious, for physiological heterothallism, or heterospecific species for hybridization. Multiple GC-and AT-biased genotypes of O. sinensis were identified in the stroma, stromal fertile portion(densely covered with numerous ascocarps) and ascospores of natural C. sinensis. It needs to be further explored if the genome-independent O. sinensis genotypes could become mating partners to accomplish sexual reproduction. S. hepiali Strain FENG experienced differential transcription of the mating-type genes with a pattern complementary to that of H. sinensis Strain L0106. Additional evidence is needed to explore a hybridization possibility between S. hepiali and H. sinensis, whether they are able to break the interspecific reproductive isolation. Genotypes #13～14 of O. sinensis feature large DNA segment reciprocal substitutions and genetic material recombination between 2 heterospecific parental fungi, H. sinensis and an AB067719-type fungus, indicating a possibility of hybridization or parasexuality. Our analysis provides important information at the genetic and transcriptional levels regarding the mating-type gene expression and reproduction physiology of O. sinensis in the sexual life of natural C. sinensis and offers crucial reproductive physiology evidence, to assist in the design of the artificial cultivation of C. sinensis to supplement the increasing scarcity of natural resource.

Differential coexistence of multiple genotypes of Ophiocordyceps sinensis in the stromata, ascocarps and ascospores of natural Cordyceps sinensis.

OBJECTIVE: To examine the differential occurrence of Ophiocordyceps sinensis genotypes in the stroma, stromal fertile portion (SFP) densely covered with numerous ascocarps, and ascospores of natural Cordyceps sinensis. METHODS: Immature and mature C. sinensis specimens were harvested. Mature C. sinensis specimens were continuously cultivated in our laboratory (altitude 2,200 m). The SFPs (with ascocarps) and ascospores of C. sinensis were collected for microscopic and molecular analyses using species-/genotype-specific primers. Sequences of mutant genotypes of O. sinensis were aligned with that of Genotype #1 Hirsutella sinensis and compared phylogenetically using a Bayesian majority-rule method. RESULTS: Fully and semiejected ascospores were collected from the same specimens. The semiejected ascospores tightly adhered to the surface of the asci as observed by the naked eye and under optical and confocal microscopies. The multicellular heterokaryotic ascospores showed uneven staining of nuclei. The immature and mature stromata, SFPs (with ascocarps) and ascospores were found to differentially contain several GC- and AT-biased genotypes of O. sinensis, Samsoniella hepiali, and an AB067719-type fungus. The genotypes within AT-biased Cluster-A in the Bayesian tree occurred in all compartments of C. sinensis, but those within AT-biased Cluster-B were present in immature and mature stromata and SPFs but absent in the ascospores. Genotype #13 of O. sinensis was present in semi-ejected ascospores and Genotype #14 in fully ejected ascospores. GC-biased Genotypes #13-14 featured large DNA segment substitutions and genetic material recombination between the genomes of the parental fungi (H. sinensis and the AB067719-type fungus). These ascosporic offspring genotypes combined with varying abundances of S. hepiali in the 2 types of ascospores participated in the control of the development, maturation and ejection of the ascospores. CONCLUSION: Multiple genotypes of O. sinensis coexist differentially in the stromata, SFPs and 2 types of C. sinensis ascospores, along with S. hepiali and the AB067719-type fungus. The fungal components in different combinations and their dynamic alterations in the compartments of C. sinensis during maturation play symbiotic roles in the lifecycle of natural C. sinensis.

Medium optimization for high mycelial soluble protein content of Ophiocordyceps sinensis using response surface methodology.

Ophiocordyceps sinensis is widely utilized due to its pharmaceutical value. Mycelial protein forms a key active component of O. sinensis and determines the medicinal potential of fungus. Here, we describe the development of an optimized fermentation medium to obtain more mycelial soluble protein from O. sinensis using response surface methodology (RSM) and investigate the increased mycelial protein content using transcriptomics. The maximum mycelial protein content of 2.11% was obtained using a medium consisting of 20% beef broth, 0.10% peptone, 2% glucose, 0.15% yeast extract, 0.20% KH2PO4, and 0.02% MgSO4. Transcriptome analysis identified 790 differentially expressed genes (DEGs), including 592 up-regulated genes and 198 down-regulated genes, optimisation resulted in more up-regulated genes. The main DEGs were enriched in metabolic pathways, ABC transporters, starch and sucrose metabolism, tyrosine metabolism, and glutathione metabolism. In addition, some DEGs associated with mycelial protein enhancement such as tyrosinase (TYR), glutathione S-transferase (GST), glutamine synthetase (glnA), and ß-glucosidase may contribute to increased mycelial protein content. Real-time quantitative PCR (RT-qPCR) was used to confirm gene expression and the results support the accuracy of RNA-Seq and DEG analysis. This study provides an optimized fermentation method for enhancing the mycelial protein content of O. sinensis and a reference for the effective development of O. sinensis protein.

Role of Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma.

Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues and regulate tissue homeostasis in critical cellular processes. Recent advances in cell-cell junction research have led to critical discoveries. Cell-cell adhesion components are important for the invasion and metastasis of tumour cells, which are not only related to cell-cell adhesion changes, but they are also involved in critical molecular signal pathways. They are of great significance, especially given that relevant molecular mechanisms are being discovered, there are an increasing number of emerging biomarkers, targeted therapies are becoming a future therapeutic concern, and there is an increased number of therapeutic agents undergoing clinical trials. Oesophageal squamous cell carcinoma (ESCC), the most common histological subtype of oesophageal cancer, is one of the most common cancers to affect epithelial tissue. ESCC progression is accompanied by the abnormal expression or localisation of components at cell-cell junctions. This review will discuss the recent scientific developments related to the molecules at cell-cell junctions and their role in ESCC to offer valuable insights for readers, provide a global view of the relationships between position, construction, and function, and give a reference for future mechanistic studies, diagnoses, and therapeutic developments.

Exposure to ambient air pollutants with kidney function decline in chronic kidney disease patients.

Chronic kidney disease (CKD) has been a global public health problem with many adverse outcomes, but data are lacking regarding the relationship between air pollutants and risk of renal progression in patients with CKD. This study was to investigate whether 1-year average exposure to ambient air pollutants -CO, NO, NO2, SO2, O3, PM2.5, and PM10-is related to renal function deterioration among patients with CKD. A total of 5301 CKD patients were included in this study between October 2008 and February 2016. To estimate each patient's exposure to ambient air pollution, we used the 24-h ambient air pollution concentration monitoring data collected one year prior to renal progression or their last renal function assessment. Renal progression was considered when estimated glomerular filtration rate (eGFR) decreased more than 25% from the baseline eGFR. Cox proportional hazard regression was performed to calculate hazard ratios (HRs). Among 5301 patients with CKD, 1813 (34.20%) developed renal progression during the 30.48 ± 14.99-month follow-up. Patients with the highest quartile exposure to CO [HR = 1.53 (95% CI: 1.24, 1.88)], NO [HR = 1.38 (95% CI: 1.11, 1.71)], NO2 [HR = 1.63 (95% CI: 1.36, 1.97)], SO2 [HR = 2.27 (95% CI: 1.83, 2.82)], PM2.5 [HR = 7.58 (95% CI: 5.97, 9.62)], and PM10 [HR = 3.68 (95% CI: 2.84, 4.78)] had a significantly higher risk of renal progression than those with the lowest quartile exposure. In the multipollutant model, the analyses yielded to similar results. These results reinforce the importance of measures to mitigate air pollution and strategies to prevent worsening of kidney function in patients with CKD. One-year high exposure to ambient CO, NO, NO2, SO2, PM2.5, and PM10 is significantly associated with deteriorated kidney function in patients with CKD among Taiwanese adults.

Time Trends in Psoriasis and Psoriatic Arthritis Incidence from 2002 to 2016 in Taiwan: An Age-Period-Cohort Analysis.

BACKGROUND: Psoriatic disease is a chronic inflammatory disease that is associated with morbidity and a poor quality of life. However, studies on the trends of psoriatic disease incidence are limited. We examined trends in psoriasis and psoriatic arthritis from 2002 to 2016 in Taiwan and distinguished the effects of age, period, and cohort on those trends. METHODS: Data from the National Health Insurance Research Database were analyzed for the annual incidence of psoriasis and psoriatic arthritis. An age-period-cohort model was designed in order to investigate the effects of each age, period, and birth cohort on the incidence. RESULTS: From 2002 to 2016, the incidence of psoriasis significantly decreased from 43.33 to 23.14 per 100,000 persons. The incidence of psoriatic arthritis significantly increased from 3.57 to 5.22 per 100,000 persons. In the age-period-cohort analysis, the net age effect on the incidence of psoriasis and psoriatic arthritis increased with advancing age (6-fold and 7.7-fold difference, respectively). CONCLUSION: The age-period-cohort analysis revealed that the incidence of psoriasis and psoriatic arthritis is associated with older age and early birth cohorts. Elderly individuals in Taiwan may be at a higher risk of developing new-onset psoriasis and psoriatic arthritis.

ß-Ecdysterone Enhanced Bone Regeneration Through the BMP-2/SMAD/RUNX2/Osterix Signaling Pathway.

Bone defects are a global public health problem. However, the available methods for inducing bone regeneration are limited. The application of traditional Chinese herbs for bone regeneration has gained popularity in recent years. ß-ecdysterone is a plant sterol similar to estrogen, that promotes protein synthesis in cells; however, its function in bone regeneration remains unclear. In this study, we investigated the function of ß-ecdysterone on osteoblast differentiation and bone regeneration in vitro and in vivo. MC3T3-E1 cells were used to test the function of ß-ecdysterone on osteoblast differentiation and bone regeneration in vitro. The results of the Cell Counting Kit-8 assay suggested that the proliferation of MC3T3-E1 cells was promoted by ß-ecdysterone. Furthermore, ß-ecdysterone influenced the expression of osteogenesis-related genes, and the bone regeneration capacity of MC3T3-E1 cells was detected by polymerase chain reaction, the alkaline phosphatase (ALP) test, and the alizarin red test. ß-ecdysterone could upregulate the expression of osteoblastic-related genes, and promoted ALP activity and the formation of calcium nodules. We also determined that ß-ecdysterone increased the mRNA and protein levels of components of the BMP-2/Smad/Runx2/Osterix pathway. DNA sequencing further confirmed these target effects. ß-ecdysterone promoted bone formation by enhancing gene expression of the BMP-2/Smad/Runx2/Osterix signaling pathway and by enrichment biological processes. For in vivo experiments, a femoral condyle defect model was constructed by drilling a bone defect measuring 3 mm in diameter and 4 mm in depth in the femoral condyle of 8-week-old Sprague Dawley male rats. This model was used to further assess the bone regenerative functions of ß-ecdysterone. The results of micro-computed tomography showed that ß-ecdysterone could accelerate bone regeneration, exhibiting higher bone volume, bone surface, and bone mineral density at each observation time point. Immunohistochemistry confirmed that the ß-ecdysterone also increased the expression of collagen, osteocalcin, and bone morphogenetic protein-2 in the experiment group at 4 and 8 weeks. In conclusion, ß-ecdysterone is a new bone regeneration regulator that can stimulate MC3T3-E1 cell proliferation and induce bone regeneration through the BMP-2/Smad/Runx2/Osterix pathway. This newly discovered function of ß-ecdysterone has revealed a new direction of osteogenic differentiation and has provided novel therapeutic strategies for treating bone defects.

Molecular chaperone heat shock protein 70 inhibitors suppress conditioned place preference induced by morphine exposure in male rats.

Previous studies have indicated a role for molecular chaperone heat shock protein 70 (Hsp70) in the development of behavioural sensitization to morphine in rodents, suggesting that Hsp70 expression following morphine exposure is involved in molecular changes that may underlie addiction vulnerability. The current study was carried out to investigate the role of Hsp70 in the positive reinforcing properties of morphine using conditioned place preference (CPP) in male rats. An unbiased CPP procedure of three phases (pre-conditioning: d1-d3; conditioning: d4-d6; and testing: d7) was used. During the conditioning phase, morphine injections (5 mg/kg, subcutaneously) were administered to induce significant place preference. To explore the effect of Hsp70 on the development and expression of morphine CPP, Hsp70 inhibitors (PES, KNK437 and methylene blue) were administered into the lateral ventricle prior to either morphine conditioning sessions or a morphine challenge on the test day. Furthermore, Hsp70 expression within the mesocorticolimbic system was measured after the treatment with KNK437, a transcriptional inhibitor. We found that PES and KNK437, respectively, injected intracerebroventricularly dose-dependently attenuated both the development and expression of morphine CPP. Methylene blue treatment demonstrated an attenuation of the development, but had no effect on the expression of morphine CPP. Following KNK437 treatment, Hsp70 expression was significantly inhibited in the shell of nucleus accumbens (NAc) during both the development and expression of morphine CPP. The findings suggest that Hsp70 in the NAc shell plays an important role in the reinforcing effects of morphine and may be involved in the development of morphine dependence.

Respect in the Eyes of Non-Urban Elders: Using Qualitative Interviews to Distinguish Community Elders' Perspective of Respect in General and Healthcare Services.

This study aimed to describe the connotation of respect for community elders in daily situations, and discuss the elderly's views on respect for healthcare services. A qualitative research design was conducted to interview elders from a non-urban area in Changhua, Taiwan. Study sites were Lukang and Ershui. A total of 52 people were interviewed, with an average age of 75 years old. Based on Grounded theory, the thematic analysis method was used to analyze data. This study found that respect from the perspective of the elderly can be divided into three categories: (1) verbal expression, (2) non-verbal behavior, and (3) behavior combined with appropriate language. We found that elders use the performance of healthcare service providers to discuss respect in the field of healthcare services. Respect can also be shown in the physical environment in healthcare settings. This study found that, for the community elders, respect is an individual's subjective feelings regarding the process of interpersonal interaction. Compared to daily life, the respect of the elderly for the healthcare setting has increased the element of the environment. In addition, it was found that elderly people have lower expectations and requirements for respect in healthcare settings.

Connexin 43 affects thoracic ossification of ligamentum flavum by regulating the p38 MAPK-RUNX2 signaling pathway.

This study aimed to investigate the role of connexin 43 (CX43) in thoracic ossification of ligamentum flavum (TOLF) based on the p38 mitogen-activated protein kinase (p38MAPK)-runt-related transcription factor 2 (RUNX2) pathway. Immunohistochemistry was used to detect CX43 expression in TOLF and non-TOLF patients, fibroblasts of TOLF were isolated and induced osteogenic differentiation, and CX43 expression was detected by western blot analysis (WB). In addition, si-CX43 was used to intervene CX43, and SB203580 was used to inhibit the p38MAPK. The expressions of bone differentiation marker protein were detected by WB, and the ossification ability was analyzed by alizarin red staining. The interaction between RUNX2 and CX43 was identified by dual-luciferase reporter assay. Results found that CX43 was highly expressed during TOLF, and si-CX43 could inhibit the expression of alkaline phosphatase (ALP) and osteopontin (OPN), as well as inhibit TOLF and the p38MAPK-RUNX2 pathway. In addition, SB203580 showed a synergistic effect with si-CX43 to further inhibit TOLF and the expression of RUNX2. The dual-luciferase reporter assay confirmed that RUNX2 could bind to the CX43 promoter. In conclusion, CX43 promotes TOLF, which may be mediated by p38MAPK-RUNX2, and RUNX2 binds to the CX43 promoter to form a positive feedback regulatory loop during TOLF.

Mu-opioid receptors in septum mediate the development of behavioural sensitization to a single morphine exposure in male rats.

Behavioural sensitization (BS) is characterized by enhanced psychomotor responses to a dose of substance of abuse after prior repeated exposure. We previously reported that BS can be induced by a single injection of morphine in rats, whereas septal nuclei are specifically involved in the development phase of BS. Here, we demonstrated that intra-LS or intra-MS microinjections also incubated BS to a systemic morphine injection in a cross-sensitization fashion, whereas inactivation of either subdivision of septal nuclei (LS: lateral septum; MS: medial septum) can negate this ability of morphine. Then, non-selective (naloxone) and selective (µ-, δ- and κ-)opioid receptor antagonists were directly delivered into LS or MS, respectively, ahead of a morphine microinjection, whereas only µ-opioid receptors in both LS and MS play indispensable roles in mediating the BS development. Finally, there was a pronounced elevation in the levels of the monoamines (i.e. dopamine, homovanillic acid, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid) in the septum, 8 h after a morphine injection detected with a HPLC-ECD method, suggesting that dopaminergi and serotoninergic systems are implicated in the BS formation. Our studies demonstrated that septal nuclei critically participate in the BS development. Essentially, µ- instead of δ- or κ-opioid receptors in LS and MS mediate sensitization to opiates.

Observing time effect of SSRIs on suicide risk and suicide-related behaviour: a network meta-analysis protocol.

INTRODUCTION: Suicide is a serious problem worldwide and 90% cases are associated with pre-existing or underlying mental illness. As a common treatment for depressive symptoms that suicidal people may receive, selective serotonin reuptake inhibitors (SSRIs) have been linked to a possible increase in suicide rates. Studies focusing on SSRIs and suicide have produced inconsistent results, suggesting that use of SSRIs decreases, increases, has no effect on suicide rates, or that the effect of SSRIs on suicide is age-dependent. This protocol of network meta-analysis aims to precisely evaluate the time effects of SSRIs by observing weekly changes of suicidality in the first 2 months of the treatment, and consequently, to explore whether the effect of the SSRIs on suicide varies depending on the stages of the treatment; if so, we will identify the turning point. METHODS AND ANALYSIS: We will search in the following databases: PubMed, Web of science, China National Knowledge Infrastructure and Wanfang Data, from dates of inception to 9 July 2021, with language restricted to English and Chinese. Studies focusing on the time effect of SSRIs on suicide will be retrieved. Then, the study selection process will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline, and the quality assessment will be conducted with Cochrane Collaboration's tool. Two researchers will work independently on data extraction using a standardised data extraction spreadsheet. Any disagreement between two researchers will be discussed and determined by a third researcher. ETHICS AND DISSEMINATION: This work does not require ethics approval as it will be based on published studies. This review will be published in peer-reviewed journals. PROSPERO REGISTRATION NUMBER: CRD42021244779.

L-Type Amino Acid Transporter 1 Regulates Cancer Stemness and the Expression of Programmed Cell Death 1 Ligand 1 in Lung Cancer Cells.

The l-type amino acid transporter 1 (LAT1) is a membranous transporter that transports neutral amino acids for cells and is dysregulated in various types of cancer. Here, we first observed increased LAT1 expression in pemetrexed-resistant non-small cell lung cancer (NSCLC) cells with high cancer stem cell (CSC) activity, and its mRNA expression level was associated with shorter overall survival in the lung adenocarcinoma dataset of the Cancer Genome Atlas database. The inhibition of LAT1 by a small molecule inhibitor, JPH203, or by RNA interference led to a significant reduction in tumorsphere formation and the downregulation of several cancer stemness genes in NSCLC cells through decreased AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) activation. The treatment of the cell-permeable leucine derivative promoted AKT/mTOR phosphorylation and reversed the inhibitory effect of JPH203 in the reduction of CSC activity in pemetrexed-resistant lung cancer cells. Furthermore, we observed that LAT1 silencing caused the downregulation of programmed cell death 1 ligand 1 (PD-L1) on lung cancer cells. The PD-L1+/LAT1+ subpopulation of NSCLC cells displayed great CSC activity with increased expression of several cancer stemness genes. These data suggest that LAT1 inhibitors can serve as anti-CSC agents and could be used in combination with immune checkpoint inhibitors in lung cancer therapy.

Synbiotics Containing Nanoprebiotics: A Novel Therapeutic Strategy to Restore Gut Dysbiosis.

A new formulation, nanoprebiotics [e.g., phthalyl pullulan nanoparticles (PPNs)], was demonstrated to enhance the antimicrobial activity of probiotics [e.g., Lactobacillus plantarum (LP)] in vitro through intracellular stimulation better than that by backbone prebiotics, which are commonly used. In this study, we aimed to investigate whether this combination would exert distinct effects as synbiotics in vivo. Synbiotics combinations of LP, pullulan, and PPNs were used as experimental treatments in a dysbiosis-induced murine model, and their restorative effect was assessed using pathogen Escherichia coli K99 challenge. Our results showed that the E. coli infection was suppressed markedly in the experimental group fed with synbiotics containing PPNs. In addition, the decrease in serum endotoxin level after synbiotics treatment suggested the reinforcement of the gut barrier. Comparison of treatment groups, including a normal control group, showed that synbiotics containing PPNs increased microbial diversity, which is a representative parameter of healthy status. Furthermore, distinct from probiotics treatment alone, synbiotics showed additive effects of enrichment of several well-known beneficial bacteria such as Lactobacillus, Bifidobacterium, and other butyrate-producing bacteria including Faecalibacterium. Collectively, our results indicate that synbiotics containing PPNs are effective at restoring gut dysbiosis, suppressing pathogenic infection, and increasing microbial diversity, suggesting that synbiotics with nanoprebiotics have the potential to be a novel strategy for ameliorating gut dysbiosis and infectious diseases.

Neck circumference and waist circumference associated with cardiovascular events in type 2 diabetes (Beijing Community Diabetes Study 23).

Obesity increases the risk of developing cardiovascular disease and other metabolic diseases. We intended to compare three different anthropometric indicators of obesity, in predicting the incidence of cardiovascular events in Chinese type 2 diabetes. Beijing Community Diabetes Study was a prospective multi-center study conducted in Beijing community health centers. Type 2 diabetes patients from fourteen community health centers were enrolled at baseline. The primary endpoint was cardiovascular events. The upper quartile of neck circumference (NC) was set as greater NC. A total of 3299 diabetes patients were enrolled. In which, 941 (28.52%) had cardiovascular disease at baseline. Logistic analysis showed that central obesity (waist circumference (WC) above 90 cm in men and 85 cm in women) and greater NC were all related to baseline cardiovascular disease (adjusted OR = 1.49, and 1.55). After 10-year follow-up, 340 (10.31%) had cardiovascular events. Compared with patients without cardiovascular events, those having cardiovascular events had higher BMI, larger WC and NC. Cox regression analysis showed that greater WC and NC were all associated with the occurrence of cardiovascular events (adjusted HR = 1.41, and 1.38). A higher NC and WC might increase the risk of cardiovascular events by about 40% in type 2 diabetes patients in Beijing communities.