Role of platelet-activating factor in reproduction:sperm function

Since its discovery nearly thirty years ago, platelet-activating factor has emerged as one of the more important lipidmediators known. Platelet-activating factor (PAF; 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine) exists en-dogenously as a mixture of molecular species with structural variants of the alkyl moiety. PAF is a novel potent signal-ing phospholipid that has unique pleiotropic biological properties in addition to platelet activation. PAF also plays a sig-nificant role in reproduction. PAF content in squirrel monkey sperm is significantly higher during the breeding seasonthan the non-breeding season. PAF content in human sperm has a positive correlation with seminal parameters and preg-nancy outcomes. High-fertility boars have significantly more PAF in their sperm than low-fertility boars. The enzymes(lyso-PAF-acetyltransferase and PAF-acetylhydrolase) necessary for PAF activation and deactivation are present insperm. PAF-acetylhydrolase may act as a 'decapacitation factor'. Removal of this enzyme during capacitation maypromote PAF synthesis increasing motility and fertilization. PAF also plays a significant role in the fertilization process,enhancing the fertilization rates of oocytes. Enhanced embryo development has also been reported in oocytes fertilizedwith PAF-treated sperm. PAF antagonists inhibit sperm motility, acrosome reaction, and fertilization, thus suggestingthe presence of receptors for PAF. The PAF-receptor is present on sperm, with altered transcript levels and distributionpatterns on abnormal cells. Whereas the exact mechanism of PAF in sperm function and reproduction is uncertain, itsimportance in normal fertility is substantial. The reproductive significance of PAF activity in sperm and fertility plus therole of PAF in the establishment of pregnancy requires further study.

Compound Kushen injection induces immediate hypersensitivity reaction through promoting the production of platelet-activating factor via de novo pathway

OBJECTIVE Compound Kushen injection(CKI)is a bis-herbal formulation extracted from Kushen(Radix Sophorae Flavescentis)and Baituling(Rhizoma Heterosmilacis Japonicae).Clinically,it is used as the adjuvant treatment of cancer.However,with the increased application,the cases of immediate hypersensitivity reactions(IHRs)also gradually rise.In this study,we investigated the underlying mechanism(s)and active constituent(s)for CKI-induced IHRs in experimental models.METHODS T helper 2(Th2)immunity-amplified mice were prepared by aluminum adjuvant.Anaphylactic shock was detected by measuring rectal thermometry in propranolol pretreated mice.For evaluating microvascular permeability,Evans blue extravasation assay was used.Platelet-activating factor(PAF),serum total IgE(tIgE)and mouse mast cell protease 1(MMCP1)were measured by ELISA.RESULTS The obtained results showed that CKI did not elevate serum tIgE and MMCP1 after consecutive immunization for five weeks,but could induce Evans blue extravasation(local)and cause obvious hypothermia(systemic)after a single injection.Further study showed that alkaloids in Kushen,especially matrine,were responsible for CKI-induced IHRs.Mechanism study showed that various PAF receptor antagonists could significantly counter CKI-induced IHRs locally or systemically.In cell system,CKI was able to promote PAF production in a non-cell-selective manner.In cell lysate,the effect of CKI on PAF production became stronger and could be abolished by blocking de novo pathway.CONCLUSION In conclusion,our study identifies,for the first time,that CKI is a PAF inducer.It causes non-immunologic IHRs,rather than IgE-dependent IHRs,by promoting PAF production through de novo pathway.Alkaloids in Kushen,especially matrine,are the prime culprits for IHRs.Our findings may provide a potential approach for preventing and treating CKI-induced IHRs.

Physiological Roles of Platelet-activating Factor in Mammalian and Human Reproduction

This review described origination, biosynthesis and functions of platelet-activating factor （PAF） in the reproductive system of mammals and human beings. The article mainly focused on biological roles of the phospholipid mediator in sperm fertilization and embryonic implantation. As an autocrine product of sperm and embryos, PAF markedly stimulates sperm motility and fertilization and serves as a capacitation factor in a ligand-receptor manner, After fertilization, embryo-derived PAF improves its own development, especially from fertilized ova to blastocyst stage and is thought to act as an embryo growth factor in the same manner as on sperm. Its mechanism of action was also clarified. At the end, it was presented some advances in its clinical application, followed by discussion of some issues possibly concerning in its current application.

Roles of BN52021 in platelet-activating factor pathway in inflammatory MS1 cells

AIM: To determine the effects of BN52021 on platelet-activating factor receptor (PAFR) signaling molecules under lipopolysaccharide (LPS)-induced inflammatory conditions in MS1 cells. METHODS: MS1 cells (a mouse pancreatic islet endothelial cell line) were grown in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum, 2 mmol/L glutamine and 100 μg/mL penicillin/streptomycin in 5% CO 2 at 37 ℃. After growth to confluency in media, the cells were processed for subsequent studies. The MS1 cells received 0, 0.1, 1 and 10 μg/mL LPS in this experiment. The viability/prolifera-tion of the cells induced by LPS was observed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay. Apoptosis and necrosis of the cells under the inflammatory condition described previously were observed using Hoechst 33342-propidium iodide staining. Adenylate cyclase (AC), phospholipase A 2 (PLA 2 ), phospholipase Cβ (PLCβ), protein tyrosine kinase (PTK), G protein-coupled receptor kinases (GRK) and p38-mitogen-activated protein kinase (p38 MAPK) mRNA in the PAFR signaling pathway were measured by real-time polymerase chain reaction. The protein expression level of phosphorylated AC (p-AC), phosphorylated PLA 2 (p-PLA 2 ), phosphorylated PTK (p-PTK), phosphorylated p38 MAPK (p-p38 MAPK), PLCβ and GRK was measured using Western blotting analysis. RESULTS: The activity of MS1 cells incubated with dif- ferent concentrations of LPS for 6 h decreased significantly in the 1 μg/mL LPS group (0.49 ± 0.10 vs 0.67 ± 0.13, P < 0.05) and 10 μg/mL LPS group (0.44 ± 0.10 vs 0.67 ± 0.13, P < 0.001), but not in 0.1 μg/mL group. When the incubation time was extended to 12 h (0.33 ± 0.05, 0.32 ± 0.03 and 0.25 ± 0.03 vs 0.69 ± 0.01) and 24 h (0.31 ± 0.01, 0.29 ± 0.03 and 0.25 ± 0.01 vs 0.63 ± 0.01), MS1 cell activity decreased in all LPS concentration groups compared with the blank control (P < 0.001). BN52021 significantly improved the cell activity when its concentration reached 50 μmol/L compared with the group that received LPS treatment alone, which was consistent with the results obtained from fluorescence staining. The mRNAs levels of AC (4.02 ± 0.14 vs 1.00 ± 0.13), GRK (2.63 ± 0.03 vs 1.00 ± 0.12), p38 MAPK (3.87 ± 0.07 vs 1.00 ± 0.17), PLA 2 (3.31 ± 0.12 vs 1.00 ± 0.12), PLCβ (2.09 ± 0.08 vs 1.00 ± 0.06) and PTK (1.85 ± 0.07 vs 1.00 ± 0.11) were up-regulated after LPS stimulation as compared with the blank control (P < 0.05). The up- regulated mRNAs including AC (2.35 ± 0.13 vs 3.87 ± 0.08), GRK (1.17 ± 0.14 vs 2.65 ± 0.12), p38 MAPK (1.48 ± 0.18 vs 4.30 ± 0.07), PLCβ (1.69 ± 0.10 vs 2.41 ± 0.13) and PLA 2 (1.87 ± 0.11 vs 2.96 ± 0.08)were significantly suppressed by BN52021 except for that of PTK. The level of p-AC (1.11 ± 0.12 vs 0.65 ± 0.08), GRK (0.83 ± 0.07 vs 0.50 ± 0.03), PLCβ (0.83 ± 0.16 vs 0.50 ± 0.10) and p-p38 MAPK (0.74 ± 0.10 vs 0.38 ± 0.05) was up-regulated after LPS stimulation as compared with the blank control (P < 0.05). The up-regulated proteins, including p-AC (0.65 ± 0.15 vs 1.06 ± 0.14), GRK (0.47 ± 0.10 vs 0.80 ± 0.06), PLCβ (0.47 ± 0.04 vs 0.80 ± 0.19) and p-p38 MAPK (0.30 ± 0.10 vs 0.97 ± 0.05), was significantly suppressed by BN52021, but p-PLA 2 and p-PTK protein level were not suppressed. CONCLUSION: BN52021 could effectively inhibit LPS-induced inflammation by down-regulating the mRNA and protein levels of AC, GRK, p38 MAPK, PLA 2 and PLCβ in the PAFR signaling pathway.

The actions,detection and synthesis of platelet-activating factor (PAF) in mammalian pregnancy

Platelet-activating factor (PAF) exhibits a variety of biological activities and it be thought to involved in various pathophysiological process. In this paper, some studies were summarized about those roles ofPAF in a variety productive processes of female of mammalian that inctude fertilization, implantation and parturition, and that was involved in the concentration, synthesis, deiradation and some assay methods of PAF. Therelationship between PAF and early pregnancy factor (EPF) was reviewed.

Platelet-activating factor mediates hydrogen peroxide induced endothelial-leukocyte adhesion

The effects of hydrogen peroxide（H2O2）on endothelial-polymorphonuclear leuko-cyte（EC-PMN）adhesion and their mechanisms were studied in cultured bovine pulmonaryartery endothelial monolayers in vitro.H2O2 at various concentrations(10-3,10-2,10-1mol/Lrespectively)stimulated EC-dependent PMN adhesion,of which 10-2mol/L H2O2 was the mostpotent one,increasing adhesion to 2.3 times that of the control.Pretreatment of PMNs with SRI63-441,a platelet-activating factor（PAF）receptor antagonist,had no inhibition effect on H2O2induced EC-PMN adhesion.Pretreatment of ECs with SRI 63-441 before H2O2 exposure signifi-cantly decreased PMN adherence to ECs.Pretreatment of ECs with phospholipase A2 inhibitorp-bromophenacyl-bromide or calmodulin antagonist chlorpromazine and calcium ion chelate EG-TA obviously decreased H2O2 induced increment of EC-PMN adhesion.These results suggestthat H2O2 may activate ECs,causing the inflow of extracellular calcium or the release of calciumfrom intracellular deposits.Increased intracellar Ca2+may bind with calmodulin to activate phos-pholipase A2,thus initiating PAF synthesis and promoting EC-PMN adhesion.

Effects of platelet-activating factor on endothelial cell monolayer permeability under hydrostatic perfusion in vitro

A simple and rapid method was established to study vascular permeability by in vitroperfused endothelial cell monolayers cultured on micropore filter membrane.It can be used todetermine filtration coefficient （Kf） to small molecules and osmotic reflection coefficient （σ） toproteins of the endothelial monolayer.Hanks’ balanced salt solution （HBSS） or 5g/L albuminin HBSS was used to perfuse the confluent endothelial monolayer at the hydrostatic pressure of2.45kPa （25cm H2O）.Control Kf values were 10.1±0.75 and 3.6±0.75μl·min-1·cm-2·kPa（-1）（±,n=3） respectively for the perfusion of HBSS and albumin HBSS,suggesting that al-bumin may decrease endothelial monolayer permeability to water and small molecules.After ex-posure of endothelial monolayer to 10-8mol/L platelet-activating factor （PAF） for 30min,Kfvalues increased to 193.1% and 133.3% respectively.Protein clearance rate (μl.min-1·cm-2)and osmotic reflection coefficient of the control endothelial monolayer were 8.0±3.22 and 0.37±0.09 respectively and those of the PAF treated endothelial monolayer 12.2±2.95μl·min-1·cm-2 and 0.18±0.06,revealing increased permeability to albumin.Computer-assisted imageprocessing demonstrated that PAF treatment decreased cell area while increased cell form factorand intercellular space,suggesting that endothelial cells retracted and rounded,which may bean important mechanism of PAF-induced increase of vascular permeability.

Serum platelet-activating factor level of patients with cerebral infarction from TIA and its correlation with coagulation function and inflammatory response

Objective: To study the serum platelet-activating factor (PAF) level of patients with cerebral infarction from transient ischemic attack (TIA) and its correlation with coagulation function and inflammatory response. Methods: TIA patients who were hospitalized in Neurology Department of Foshan Second People's Hospital between September 2016 and July 2017 were selected and divided into simple TIA group and cerebral infarction group according to the progression into cerebral infarction or not within 1 week;healthy subjects who received physical examination during the same period were selected as the control group. Serum levels of PAF, coagulation function indexes and inflammation indexes were detected. Results: Serum PAF, FVIII, vWF, TNF-α, hs-CRP, MCP-1 and IL-17 contents of cerebral infarction group and simple TIA group were significantly higher than those of control group while PT, APTT and TT levels were significantly shorter than those of control group;serum PAF, FVIII, vWF, TNF-α, hs-CRP, MCP-1 and IL-17 contents of cerebral infarction group were significantly higher than those of simple TIA group while PT, APTT and TT levels were significantly shorter than those of simple TIA group;serum FVIII, vWF, TNF-α, hs-CRP, MCP-1 and IL-17 contents of TIA patients with high PAF content were significantly higher than those of TIA patients with low PAF content while PT, APTT and TT levels were significantly shorter than those of TIA patients with low PAF content. Conclusion: Excessively generated PAF can promote TIA progression to cerebral infarction by activating coagulation pathway and inflammatory response.

Therapy for acute pancreatitis with platelet-activating factor receptor antagonists

Acute pancreatitis (AP) causes release of platelet- activating factor (PAF), which induces systemic effects that contribute to circulatory disturbances and multiple organ failure. PAF is a cell surface secretion of bioactive lipid, which could produce physiological and pathological effects by binding to its cell surface receptor called platelet-activating factor receptor (PAF-R). Studies showed that PAF participates in the occurrence and development of AP and administration of platelet-activating factor receptor antagonists (PAF-RAs) could significantly reduce local and systemic events after AP. PAF has also been implicated as a key mediator in the progression of severe AP, which can lead to complications and unacceptably high mortality rates. Several classes of PAF-RA show PAF- RAs significant local and systemic effects on reducing inflammatory changes. As a preventive treatment, PAF-RA could block a series of PAF-mediated inflammatory injury and thus improve the prognosis of AP. This review introduces the important role of PAF-RA in the treatment of AP.

Role of platelet-activating factor in pathogenesis of acute pancreatitis

Platelet-activating factor(PAF)is a potentproinflammatory phospholipid mediator that belongsto a family of biologically active,structurally relatedalkyl phosphoglycerides with diverse pathologicaland physiological effects.This bioactive phospholipidmediates processes as diverse as wound healing,physiological inflammation,angiogenesis,apoptosis,reproduction and long-term potentiation.PAF actsby binding to a specific G protein-coupled receptorto activate multiple intracellular signaling pathways.Since most cells both synthesize and release PAFand express PAF receptors,PAF has potent biologicalactions in a broad range of cell types and tissues.Inappropriate activation of this signaling pathway isassociated with many diseases in which inflammationis thought to be one of the underlying features.Acutepancreatitis(AP)is a common inflammatory disease.The onset of AP is pancreatic autodigestion mediatedby abnormal activation of pancreatic enzyme caused bymultiple agents,which subsequently induce pancreaticand systemic inflammatory reactions.A number ofexperimental pancreatitis and clinical trials indicatethat PAF does play a critical role in the pathogenesisof AP.Administration of PAF receptor antagonist cansignificantly reduce local and systemic events that occurin AP.This review focuses on the aspects that are morerelevant to the pathogenesis of AP.

Synthesis of platelet-activating factor and its receptor expression in Kupffer cells in rat carbon tetrachloride-induced cirrhosis

AIM:To determine the platelet-activating factor (PAF) synthesis and its receptor expression in Kupffer cells in rat carbon tetrachloride-induced cirrhosis. METHODS:Kupffer cells, isolated from the livers of control and CCl4-induced cirrhotic rats, were placed in serum-free medium overnight. PAF saturation binding, ET-1 saturation and competition binding were assayed. ET-1 induced PAF synthesis, mRNA expression of PAF, preproendothelin-1, endothelin A (ETA) and endothelin B (ETB) receptors were also determined. RESULTS:A two-fold increase of PAF synthesis (1.42 ± 0.14 vs 0.66 ± 0.04 pg/μg DNA) and a 1.48-fold increase of membrane-bound PAF (1.02 ± 0.06 vs 0.69 ± 0.07 pg/μg DNA) were observed in activated Kupffer cells of cirrhotic rats. The application of ET-1 to Kupffer cells induced PAF synthesis in a concentration-dependent manner in both cirrhotic and normal rats via ETB receptor, but PAF synthesis in the activated Kupffer cells was more effective than that in the normal Kupffer cells. In activated Kupffer cells, PAF receptor expression and PAF binding capacity were markedly enhanced. Activated Kupffer cells raised the [125I]-ET-1 binding capacity, but changed neither the affinity of the receptors, nor the expression of ETA receptor. CONCLUSION:Kupffer cells in the course of CCl4-induced cirrhosis are the main source of increased PAF. ET-1 is involved endogenously in stimulating the PAF synthesis in activated Kupffer cells via ETB receptor by paracrine. ETA receptor did not appear in activated Kupffer cells, which may exacerbate the hepatic and extrahepatic complications of cirrhosis.

Platelet-activating factor in cirrhotic liver and hepatocellular carcinoma

瞄准：激活血小板的因素(PAF ) 是一个支持 inflammatory 和 angiogenic 类脂化合物调停人。这里，我们试图调查 PAF 的层次， lyso-PAF ( PAF 先锋)，磷脂酶 A ( 2 )( PLA ( 2 )，产生 lyso-PAF 的酶的活动)， acetylhydrolase 活动(啊哈， PAF 降级的酶)并且在硬变肝和肝细胞癌( HCC )的 PAF 受体( PAF-R )抄本。方法：有 HCC 的 29 个病人在这研究被注册。肝硬化在十四个病人是在场的，七没有肝疾病。织物 PAF 层次被血小板聚集试金调查。Lyso-PAF 在它的化学乙酰化作用以后被估计进 PAF。啊哈被降级决定[(3 ) H ]-PAF。PLA (2 ) 层次被 EIA 估计。PAF-R 抄本用 RT-PCR 被调查。结果：PAF 和 PAF-R 抄本的提高的数量(白血球类型) 1 作为与非肝脏硬化症的相比在肝脏硬化症的纸巾被发现。PAF 和 PAF-R 抄本的更高的数量(织物类型) 1 和 2 作为与非肿瘤纸巾相比在 HCC 纸巾被发现。PLA (2 ) ， lyso-PAF 和啊哈层次没在肝脏硬化症的纸巾和 HCC 被改变。结论：当 PAF 的角色在肝生理学当前是未知的时，这研究在在 HCC 期间在硬变肝并且在 angiogenic 反应发现的煽动性的网络建议它的潜在的参与。

Determination of platelet-activating factor by reverse phase high-performance liquid chromatography and its application in viral hepatitis

AIM: To detect the platelet-activating factor (PAF) and the plasma or serum levels of tumor necrosis factor-α (TNF-α) malondialdehyde (MDA), endotoxin (ET) and to discuss their significance in various types of viral hepatitis.METHODS: PAF, TNF-α, MDA, and ET levels in 60 controls, 16 cases of acute viral hepatitis, 71 cases of chronic viral hepatitis, 19 cases of severe viral hepatitis were detected by reverse phase high-performance liquid chromatography (rHPLC), bio-assay, ELISA, thiobarbituric acid (TBA), and limulus lysate test (LLT), respectively.RESULTS: The rHPLC was more sensitive and specific than bio-assay (r = 0.912, P<0.01). The plasma levels of PAF, TNF-α, MDA, and ET in patients with viral hepatitis were higher than those in controls (P<0.01).CONCLUSION: rHPLC is more reliable and accurate for the detection of PAF.

Creation of reversed phase high-performance liquid chromatographic technique to assay platelet-activating factor

Objective: To establish a new assay for platelet-activating factor (PAF), to compare it with bio-assay; and to discuss its significance in some elderly people diseases such as cerebral infarction and coronary heart disease. Methods: To measure PAF levels in 100 controls, 23 elderly patients with cerebral infarction and 65 cases with coronary heart disease by reversed phase high-performance liquid chromatographic technique (rHPLC). Results:rHPLC is more convenient, sensitive,specific, and less confusing, compared with bio-assay. The level of plasma PAF in patients with cerebral infarction was higher than that in the controls (P<0.01), and in patients with coronary heart disease. Conclusion: Detection of PAF with rHPLC is more reliable and more accurate. The new assay has important significance in PAF research.

Association of Platelet-Activating Factor Receptor Gene rs5938(G/T) and rs313152(T/C) Polymorphisms with Coronary Heart Disease and Blood Stasis Syndrome in A Chinese Han Population

Objective: To explore the association of the platelet-activating factor receptor(PAFR) gene rs5938, rs313152 and rs76744145 polymorphisms with coronary heart disease(CHD) and blood stasis syndrome(BSS) of CHD in Chinese Han population. Methods: A total of 570 CHD patients(299 with BSS and 271 with non-BSS) and 317 controls were enrolled. The PAFR gene rs5938, rs313152 and rs76744145 polymorphisms were genotyped using the multiplex SNaP shot technology. The statistical analysis was conducted using a multiple variable logistic regression model. Results: Significant differences were detected in the genotypes frequency distributions of the rs5938(P<0.01), but not the rs313152(P>0.05), between the controls and CHD patients. Individuals with an rs5938 or rs313152 mutated allele had a low risk for CHD [adjusted odds ratio(aOR)=0.35, 95% confidence interval(CI): 0.23 to 0.56, P<0.01; aOR=0.65, 95% CI: 0.46 to 0.91, P<0.05, respectively]. After the CHD patients were stratified as BSS or non-BSS according to their Chinese medicine patterns, the rs5938 polymorphism mutated alleles had a significant association with a low risk for BSS of CHD(aOR=0.32, 95% CI: 0.18 to 0.57, P<0.01) and non-BSS of CHD(aOR=0.31, 95% CI: 0.17 to 0.55, P<0.01). The rs313152 polymorphism was associated with a low risk for BSS(aOR=0.51, 95% CI: 0.33 to 0.79, P<0.01), but not for non-BSS(aOR=1.22, 95% CI: 0.81 to 1.85, P>0.05). Furthermore, the interaction effect of the rs5938 and rs313152 polymorphisms for BSS of CHD was significantly based on an aOR value associated with the combination of the rs5938 GT genotype with the rs313152 TC genotype of 0.27(95% CI: 0.1 to 0.7, P<0.01). Conclusion: The PAFR gene rs5938 or rs313152 polymorphisms might be a potential biomarker for susceptibility to CHD, especially to BSS of CHD in Chinese Han population.

Platelet-activating factor receptor affects food intake and body weight

“Let’s Move!”is a comprehensive initiative,launched by the First Lady,Michelle Obama,dedicates to solving problems of obesity,which is growing in child.The life behaviors do affect obesity;however,the mechanistic insight in molecular level is still not clear.In this study,by continually monitoring mouse body weight under chow and high fat western diets as well as metabolic,physical activity and food intake behaviors assessed in a CLAMS Comprehensive Lab Animal Monitoring System,we demonstrated that the platelet-activating factor receptor(PTAFR)contributes to modification of life behaviors.PTAFR does not affect metabolism of ingested dietary fat and carbohydrate in young animals;however,Ptafr ablation dramatically increased weight gain without affecting adipose tissue accumulation.Ptafr/mice possess new habits that increased food intake and decreased movement.Our studies suggest that regulation of PTAFR activity may be a novel strategy to control obesity in children or young adults.

Significant risk factors for intensive care unit-acquired weakness:A processing strategy based on repeated machine learning

BACKGROUND Intensive care unit-acquired weakness(ICU-AW)is a common complication that significantly impacts the patient's recovery process,even leading to adverse outcomes.Currently,there is a lack of effective preventive measures.AIM To identify significant risk factors for ICU-AW through iterative machine learning techniques and offer recommendations for its prevention and treatment.METHODS Patients were categorized into ICU-AW and non-ICU-AW groups on the 14th day post-ICU admission.Relevant data from the initial 14 d of ICU stay,such as age,comorbidities,sedative dosage,vasopressor dosage,duration of mechanical ventilation,length of ICU stay,and rehabilitation therapy,were gathered.The relationships between these variables and ICU-AW were examined.Utilizing iterative machine learning techniques,a multilayer perceptron neural network model was developed,and its predictive performance for ICU-AW was assessed using the receiver operating characteristic curve.RESULTS Within the ICU-AW group,age,duration of mechanical ventilation,lorazepam dosage,adrenaline dosage,and length of ICU stay were significantly higher than in the non-ICU-AW group.Additionally,sepsis,multiple organ dysfunction syndrome,hypoalbuminemia,acute heart failure,respiratory failure,acute kidney injury,anemia,stress-related gastrointestinal bleeding,shock,hypertension,coronary artery disease,malignant tumors,and rehabilitation therapy ratios were significantly higher in the ICU-AW group,demonstrating statistical significance.The most influential factors contributing to ICU-AW were identified as the length of ICU stay(100.0%)and the duration of mechanical ventilation(54.9%).The neural network model predicted ICU-AW with an area under the curve of 0.941,sensitivity of 92.2%,and specificity of 82.7%.CONCLUSION The main factors influencing ICU-AW are the length of ICU stay and the duration of mechanical ventilation.A primary preventive strategy,when feasible,involves minimizing both ICU stay and mechanical ventilation duration.

Are TrkB receptor agonists the right tool to fulfill the promises for a therapeutic value of the brain-derived neurotrophic factor?

Brain-derived neurotrophic factor signaling via its receptor tro pomyosin receptor kinase B regulates several crucial physiological processes.It has been shown to act in the brain,promoting neuronal survival,growth,and plasticity as well as in the rest of the body where it is involved in regulating for instance aspects of the metabolism.Due to its crucial and very pleiotro pic activity,reduction of brain-derived neurotrophic factor levels and alterations in the brain-derived neurotrophic factor/tropomyosin receptor kinase B signaling have been found to be associated with a wide spectrum of neurological diseases.Howeve r,because of its poor bioavailability and pharmacological properties,brain-derived neurotrophic factor itself has a very low therapeutic value.Moreover,the concomitant binding of exogenous brain-derived neurotrophic factor to the p75 neurotrophin receptor has the potential to elicit several unwanted and deleterious side effects.Therefo re,developing tools and approaches to specifically promote tropomyosin receptor kinase B signaling has become an important goal of translational research.Among the newly developed tools are different categories of tropomyosin receptor kinase B receptor agonist molecules.In this review,we give a comprehensive description of the diffe rent tro pomyosin receptor kinase B receptor agonist drugs developed so far and of the res ults of their application in animal models of several neurological diseases.Moreover,we discuss the main benefits of tropomyosin receptor kinase B receptor agonists,concentrating especially on the new tropomyosin receptor kinase B agonist antibodies.The benefits observed both in vitro and in vivo upon application of tropomyosin receptor kinase B receptor agonist drugs seem to predominantly depend on their general neuroprotective activity and their ability to promote neuronal plasticity.Moreover,tro pomyosin receptor kinase B agonist antibodies have been shown to specifically bind the tropomyosin receptor kinase B receptor and not p75 neurotrophin receptor.Therefore,while,based on the current knowledge,the tropomyosin receptor kinase B receptor agonists do not seem to have the potential to reve rse the disease pathology per se,promoting brainderived neurotrophic factor/tro pomyosin receptor kinase B signaling still has a very high therapeutic relevance.

Biological factors driving colorectal cancer metastasis

Approximately 20%of colorectal cancer(CRC)patients present with metastasis at diagnosis.Among Stage I-III CRC patients who undergo surgical resection,18%typically suffer from distal metastasis within the first three years following initial treatment.The median survival duration after the diagnosis of metastatic CRC(mCRC)is only 9 mo.mCRC is traditionally considered to be an advanced stage malignancy or is thought to be caused by incomplete resection of tumor tissue,allowing cancer cells to spread from primary to distant organs;however,increa-sing evidence suggests that the mCRC process can begin early in tumor development.CRC patients present with high heterogeneity and diverse cancer phenotypes that are classified on the basis of molecular and morphological alterations.Different genomic and nongenomic events can induce subclone diversity,which leads to cancer and metastasis.Throughout the course of mCRC,metastatic cascades are associated with invasive cancer cell migration through the circulatory system,extravasation,distal seeding,dormancy,and reactivation,with each step requiring specific molecular functions.However,cancer cells presenting neoantigens can be recognized and eliminated by the immune system.In this review,we explain the biological factors that drive CRC metastasis,namely,genomic instability,epigenetic instability,the metastatic cascade,the cancer-immunity cycle,and external lifestyle factors.Despite remarkable progress in CRC research,the role of molecular classification in therapeutic intervention remains unclear.This review shows the driving factors of mCRC which may help in identifying potential candidate biomarkers that can improve the diagnosis and early detection of mCRC cases.

Sorl1 knockout inhibits expression of brain-derived neurotrophic factor:involvement in the development of late-onset Alzheimer's disease

Sortilin-related receptor 1(SORL1)is a critical gene associated with late-onset Alzheimer’s disease.SORL1 contributes to the development and progression of this neurodegenerative condition by affecting the transport and metabolism of intracellularβ-amyloid precursor protein.To better understand the underlying mechanisms of SORL1 in the pathogenesis of late-onset Alzheimer s disease,in this study,we established a mouse model of SorI1 gene knockout using cluste red regularly inters paced short palindro mic repeats-associated protein 9 technology.We found that Sorl1-knocko ut mice displayed deficits in learning and memory.Furthermore,the expression of brain-derived neurotrophic factor was significantly downregulated in the hippocampus and co rtex,and amyloidβ-protein deposits were observed in the brains of 5orl1-knockout mice.In vitro,hippocampal neuronal cell synapses from homozygous Sorl1-knockout mice were impaired.The expression of synaptic proteins,including Drebrin and NR2B,was significantly reduced,and also their colocalization.Additionally,by knocking out the Sorl1 gene in N2a cells,we found that expression of the N-methyl-D-aspartate receptor,NR2B,and cyclic adenosine monophosphate-response element binding protein was also inhibited.These findings suggest that SORL1 participates in the pathogenesis of late-onset Alzheimer s disease by regulating the N-methyl-D-aspartate receptor NR2B/cyclic adenosine monophosphate-response element binding protein signaling axis.