查看更多>>摘要：Background: Yiqi Tongluo Fang (YQTLF) is an effective prescription for the treatment of diabetic retinopathy (DR)， but its mechanism of action remains unclear。 Method: The content of YQTLF was determined using liquid and gas chromatography-mass spectrometry (LC-MS and GC-MS， respectively)。 Twenty-five Sprague Dawley (SD) rats were randomly selected as the normal control group。 One hundred SD streptozotocin-induced diabetes (type 1) rats were randomly divided into diabetic control， diabetic + insulin + calcium dobesilate (CaD)， and diabetic + insulin + YQTLF groups， with 25 rats in each group。 Bodyweight level was measured every 2 weeks。 After 12 weeks of gavage， the glucose levels， lipids， oxidative stress， inflammation， retinal histopathology， and the blood-retinal barrier were assessed in each group。 The p38 MAPK pathway was changed to explore its internal mechanism。 The measurement data were expressed as mean ± standard deviation， and different statistical methods were used according to a normal distribution， square error， or not。 Results: A total of 1024 valid peaks were identified in YQTLF using GC-MS。 YQTLF significantly lowered the fasting blood glucose levels in diabetic rats。 YQTLF early inhibited changes in retinal histology， capillaries， cells， and tight junction proteins (such as ZO-1， occludin， claudin-5， and VE-cadherin) before the formation and development of DR。 These findings correlated with the alleviation of glucolipid metabolism， inflammation， and oxidative stress。 The lncRNA MALAT1 and the PRC 2/p38 MAPK-related pathway， such as the expression of EZH2， SUZ12， EED， p38 MAPK， MMP-9， and VEGFR， were also correlated。 Conclusion: We have demonstrated the molecular and cellular mechanisms underlying the preventive and delayed development and formation of DR。 YQTLF prevents changes in dyslipidemia， retinal histology， capillaries， cells， and tight junction proteins。 These protective effects appear to be linked to its antioxidant and anti-inflammatory effects， which prevent the activation of intracellular signaling pathways， such as the lncRNA MALAT1 and PRC 2/p38 MAPK-related pathway。
查看更多>>摘要：Gastric mucosal injuries include focal and diffused injuries， which do and do not change the cell differentiation pattern。 Parietal cells loss is related to the occurrence of gastric mucosal diffused injury， with two phenotypes of spasmolytic polypeptide-expressing metaplasia and neuroendocrine cell hyperplasia， which is the basis of gastric cancer and gastric neuroendocrine tumor respectively。 Multiple ion channels and transporters are located and expressed in the parietal cells， which is not only regulate the gastric acid-base homeostasis， but also regulate the growth and development of parietal cells。 Therefore， alteration and dysregulation of ion channels and transporters in the parietal cells impairs the morphology and physiological functions of stomach， resulted in gastric diffused mucosal damage。 In this review， multiple ion channels and transporters in parietal cells， including K~+ channels， aquaporins， Cl- channels， Na~+/H~+ transporters， and Cl~-/HCO_3~- transporters are described， and their roles in gastric diffused mucosal injury are discussed。 We hope to drive researcher's attention to focus on the role of ion channels/transporters loss in the parietal cells induced gastric diffused mucosal injury。
查看更多>>摘要：Gastric cancer is a common gastrointestinal malignancy worldwide， with a high mortality rate and poor prognosis。 Esomeprazole (ESO) has been shown to have anticancer activity by affecting cell growth and autophagy and its mechanism in gastric cancer cells is evident。 The PI3K/AKT/FOXO3a pathway is central in cancers。 3-Methyladenine (3-MA)， a dual inhibitor of PI3K and autophagy， plays a synergistic role in combination with antitumor agents。 In this study， we assessed the role of ESO on the PI3K/AKT/FOXO3a pathway and the beneficial effects of ESO combined with 3-MA in gastric cancer cells。 Cell viability， proliferation， invasion， migration， apoptosis， autophagy， and protein expression were detected by CCK-8， EdU， Transwell， flow cytometry， immunofluorescence assay， and western blot。 ESO decreased cell viability in a concentration- and time-dependent manner and increased autophagy with upregulation of LC3II and P62。 Additionally， ESO inhibited the proliferation， migration， and invasion and induced the apoptosis of gastric cancer cells in a concentration-dependent manner。 ESO inhibited PI3K/AKT/FOXO3a signaling and EGFR and SKP2 expression concentration-dependent。 3-MA enhanced the antiproliferative activity of ESO and synergistically inhibited PI3K/FOXO3a signaling and the expression of EGFR but not SKP2。 Furthermore， pretreatment with the EGFR inhibitor AG1478 enhanced the antiproliferative activity of ESO in gastric cancer cells。 In conclusion， our results suggested that the PI3K inhibitor 3-MA promotes the antiproliferative activity of ESO in gastric cancer cells by synergistically downregulating EGFR via the PI3K/FOXO3a pathway。
查看更多>>摘要：Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after Allogeneic Hematopoietic Stem Cell Transplant (allo-HSCT)。 Although a series of immunosuppressant agents are routinely used as the first-line prevention， the morbidity and mortality rate remains high in allo-HSCT recipients。 Our previous work indicated that combining Xuebijing (XBJ) with Cyclosporin A (CSA) is superior to CSA alone in preventing aGVHD。 However， it was not clear which compounds in XBJ may prevent aGVHD。 Whether the effective compounds in XBJ can be safely combined with CSA to prevent GVHD remain to be evaluated。 Here， we accessed whether the combination of four main components in XBJ (C0127) had the same efficacy as XBJ in preventing aGVHD。 In addition， the effectiveness of a novel combination therapy (C0127 + CSA) on aGVHD prophylaxis was evaluated using 16 s rRNA sequencing and RNA sequencing approaches in vitro and in vivo。 In aGVHD mice， C0127 enhanced the preventive effects of CSA including decreasing mortality， maintaining weight， reducing GVHD score and reducing the expression of IL-6 and TNF-α in serum。 Fatal GVHD is a frequent consequence of intestinal tract damage。 We found combining C0127 with CSA alleviated the gut damage and maintained the normal physiological function of intestine by H&E staining， intestinal permeability and short chain fatty acid (SCFA) assays。 Next， 16 S sequencing analysis of feces showed the combination treatment maintained the intestinal microbial diversity， normalized the intestinal microorganism and prevented flora disorder by reducing the relative abundances of Escherichia coli and Enterococcus。 Further， RNA-seq analysis of colonic epithelium revealed C0127 combined with CSA chiefly regulated chemokines and cytokines in IL-17 signaling pathway。 The combination treatment reduced the expression of G-CSF and its effector STAT3 (an axis that aggravated gut inflammation and flora disorder) in gut epithelium on mRNA and protein level。 These findings indicated that C0127 improved the prevention of CSA in aGVHD mice partially by protecting the gut from damage through normalizing G-CSF signaling， which regulates the intestinal microbiota and the integrity of the epithelial barrier。
Scott WyerDanyelle M. TownsendZhiwei YeAntonis Kourtidis...
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查看更多>>摘要：Since the discovery of the kahalalide family of marine depsipeptides in 1993， considerable work has been done to develop these compounds as new and biologically distinct anti-cancer agents。 Clinical trials and laboratory research have yielded a wealth of data that indicates tolerance of kahalalides in healthy cells and selective activity against diseased cells。 Currently， two molecules have attracted the greates level of attention， kahalalide F (KF) and isokahalalide F (isoKF， Irvalec， PM 02734， elisidepsin)。 Both compounds were originally isolated from the sarcoglossan mollusk Elysia rufescens but due to distinct structural characteristics it has been hypothesized and recently shown that the ultimate origin of the molecules is microbial。 The search for their true source has been a subject of considerable research in the anticipation of finding new analogs and a culturable expression system that can produce sufficient material through fermentation to be industrially relevant。
查看更多>>摘要：Alzheimer's disease (AD) is the most common neurodegenerative disease， with cognitive decline as the primary clinical feature。 According to epidemiological statistics， 50 million people worldwide are currently affected by Alzheimer's disease。 Although new drugs such as aducanumab have been approved for use in the treatment of AD， none of them have reversed the progression of AD。 MicroRNAs (miRNAs) are small molecule RNAs that exert their biological functions by regulating the expression of intracellular proteins， and differential abundance and varieties are found between the central and peripheral tissues of AD patients and healthy controls。 This article will summarise the changes of miRNAs in the AD process， and the potential role of diagnostic markers and therapeutic targets in AD will be explored。
Britt I. DrogemollerGalen E.B. WrightJessica TruemanKaitlyn Shaw...
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查看更多>>摘要：Background: Ondansetron is a highly effective antiemetic for the treatment of nausea and vomiting。 However， this medication has also been associated with QT prolongation。 Pharmacogenomic information on therapeutic response to ondansetron exists， but no investigation has been performed on genetic factors that influence the cardiac safety of this medication。 Methods: Three patient groups receiving ondansetron were recruited and followed prospectively (pediatric post-surgical patients n = 101; pediatric oncology patients n = 98; pregnant women n = 62)。 Electrocardiograms were conducted at baseline， and 5- and 30-min post-ondansetron administration， to determine the effect of ondansetron treatment on QT interval。 Pharmacogenomic associations were assessed via analyses of comprehensive CYP2D6 genotyping and genome-wide association study data。 Results: In the entire cohort， 62 patients (24。1%) met the criteria for prolonged QT， with 1。2% of the cohort exhibiting unsafe QT prolongation。 The most significant shift from baseline occurred at five minutes post-ondansetron administration (P = 9。8 x 10~-4 )。 CYP2D6 activity score was not associated with prolonged QT。 Genome-wide analyses identified novel associations with a missense variant in TLR3 (rs3775291; P = 2。00 x 10~-7) and a variant linked to the expression of SLC36A1 (rs34124313; P = 1。97 x 10~-7)。 Conclusions: This study has provided insight into the genomic basis of ondansetron-induced cardiac changes and has emphasized the importance of genes that have been implicated in serotonin-related traits。 These biologically-relevant findings represent the first step towards understanding this adverse event with the overall goal to improve the safety of this commonly used antiemetic medication。
查看更多>>摘要：The post-translational glycosylation of proteins by O-linked α-mannose is conserved from bacteria to humans。 Due to advances in high-throughput mass spectrometry-based approaches， a variety of glycoproteins are identified to be O-mannosylated。 Various proteins with O-mannosylation are involved in biological processes， providing essential necessity for proper growth and development。 In this review， we summarize the process and regulation of O-mannosylation。 The multi-step O-mannosylation procedures are quite dynamic and complex， especially when considering the structural and functional inspection of the involved enzymes。 The widely studied O-mannosylated proteins in human include α-Dystroglycan (α-DG)， cadherins， protocadherins， and plexin， and their aberrant O-mannosylation are associated with many diseases。 In addition， O-mannosylation also contributes to diverse functions in lower eukaryotes and prokaryotes。 Finally， we present the relationship between O-mannosylation and gut microbiota (GM)， and elucidate that O-mannosylation in microbiome is of great importance in the dynamic balance of GM。 Our study provides an overview of the processes of O-mannosylation in mammalian cells and other organisms， and also associated regulated enzymes and biological functions， which could contribute to the understanding of newly discovered O-mannosylated glycoproteins。
Anders Kirkegaard JensenKaterina ChatzidionysiouChristopher Kirkegaard TorpAnne Sofie S?rensen...
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查看更多>>摘要：Introduction: Immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA) is a relatively new disease entity caused by ICI agents during cancer therapy。 Reactive arthritis (ReA) is a well-known disease entity caused by urogenital or gastrointestinal bacterial infection or pneumonia。 In this sense， ICI-IA and ReA are both defined by a reaction to a well-specified causal event。 As a result， comparing these diseases may help to determine therapeutic strategies。 Methods: We compared ICI-IA and ReA with special focus on pharmacological management。 Specifically regarding treatment， we conducted a literature search of studies published in the PubMed database。 Inclusion criteria were studies on treatment with non-steroidal anti-inflammatory drugs (NSAIDs)， glucocorticoids (GC)， or disease modifying antirheumatic drugs (DMARDs) in ICI-IA or ReA。 During systematic selection， 21 studies evaluating ICI-IA and 14 studies evaluating ReA were included。 Results: In ICI-IA， prospective and retrospective studies have shown effects of non-steroidal anti-inflammatory drugs (NSAIDs)， glucocorticoid (GC)， sulfasalazine (SSZ)， methotrexate (MTX)， hydroxychloroquine (HCQ) and TNFi。 In ReA， retrospective studies evaluated NSAIDs and GC。 A randomized controlled trial reported the effect of SSZ， and a retrospective study reported the effect of MTX and SSZ in combination with tumor necrosis factor alpha inhibition (TNFi)。 For both entities， small case reports show treatment effects of interleukin 6 receptor inhibition (IL-6Ri)。 Discussion: This literature review identified both similarities and differences regarding the pathogenesis and clinical features of ReA and ICI-IA。 Studies on treatment reported effectiveness of NSAIDs， GC， MTX， SSZ and TNFi in both diseases。 Further， small case reports showed effects of IL-6Ri。
查看更多>>摘要：Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders that develop in early life due to interaction between several genetic and environmental factors and lead to alterations in brain function and structure。 During the last decades， several mechanisms have been placed to explain the pathogenesis of autism。 Unfortunately， these are reported in several studies and reviews which make it difficult to follow by the reader。 In addition， some recent molecular mechanisms related to ASD have been unrevealed。 This paper revises and highlights the major common molecular mechanisms responsible for the clinical symptoms seen in people with ASD， including the roles of common genetic factors and disorders， neuroinflammation， GABAergic signaling， and alterations in Ca~+2 signaling。 Besides， it covers the major molecular mechanisms and signaling pathways involved in initiating the epileptic seizure， including the alterations in the GABAergic and glutamate signaling， vitamin and mineral deficiency， disorders of metabolism， and autoimmunity。 Finally， this review also discusses sleep disorder patterns and the molecular mechanisms underlying them。
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