Objective:To screen interleukin(IL)-1β secretion-related membrane transporters by macrophage experiment in vitro and conventional knockout mice.Methods:THP-1 cell line was differentiated to obtain human THP-1-derived macrophages,and the primary macrophages were obtained from human peripheral blood.FVB wild-type mice with the same sex and age were used as the controls of MRP1 knockout mice.The macrophages in abdominal cavity and bone marrow of mice were cultivated.The cells were treated with ABCC1/MRP1,ABCG2/BCRP,ABCB1/P-gp,OATP1B1,and MATE transporter inhibitors,then stimulated by lipopolysaccharide and adenosine triphosphate.The secretion level of IL-iβ was detected by ELISA,Western blot,and immunofluorescence.Results:After inhibiting ABCC1/MRP1 transporter,the secretion of IL-1β decreased significantly,while inhibition of the other 4 transporters had no effect.In animal experiment,the level of IL-1 β secreted by macrophages in bone marrow of MRP1 knockout mice was significantly lower than control group(P＜0.05).Conclusion:ABCC1/MRP1 transporter is a newly discovered IL-1β secretion pathway,which is expected to become a new target for solving clinical problems such as cytokine release syndrome.

Objective To investigate the effects of exercise and complex environment on lipopolysaccharide(LPS)-induced dopaminergic neuron death in the substantia nigra of midbrain.Methods C57BL/6 mice were divided into control group,LPS group,LPS+swimming group and LPS+complex environment group,with 7 mice in each group.The mice in the LPS group were injected with LPS into the brain to establish an inflammatory model of Parkinson's disease and lived in cages for 2 weeks.Mice in LPS+swimming group were forced to swim for 15 minutes every day for 2 weeks after modeling.The mice in the LPS+complex environment group were placed in a complex environment for 2 weeks after modeling.The control group mice were not treated.After 14 days of modeling,behavioral experiments such as footprint,open field and rotating rod were performed on each group of mice to detect the autonomous exercise ability,exercise balance ability and depression level of mice.The expressions of tyrosine hydroxylase(TH)in substantia nigra was detected by immunohistochemical staining and Western blotting.The expressions of brain-derived neurotrophic factor(BDNF),Caspase-3,interleukin-1β(IL-1β),interleukin-6(IL-6)and tumor necrosis factor-α(TNF-α)in the substantia nigra of the midbrain were detected by Western blotting.The transcription levels of IL-1β,IL-6 and TNF-α in substantia nigra were detected by RT-PCR.Results Compared with the control group,the exercise ability and balance ability of mice in LPS group,LPS+swimming group and LPS+complex environment group decreased,the depression level increased(P＜0.001),the number of TH positive neurons and BDNF protein decreased significantly(P＜0.001),and the contents of Caspase-3,IL-1β,IL-6 and TNF-α increased significantly(P＜0.001).Compared with the LPS group,the exercise ability and balance ability of the mice in the LPS+swimming group and the LPS+complex environment group were restored,the depression level decreased significantly(P＜0.01),the survival number of TH positive neurons and the content of BDNF increased significantly(P＜0.01),Caspase-3,IL-1β,IL-6 and TNF-α reduced significantly(P＜0.01),and the phenomenon in the LPS+complex environment group was more significant.Conclusion Exercise and complex environment can inhibit LPS-induced central nervous system inflammation in mice,thereby reducing damage to midbrain substantia nigra neurons,and the inhibitory effect of LPS+complex environment group is more significant.

Drug discrimination is a behavioral pharmacological technique to study the discriminative stimulus effects of drug. Currently drug discrimination has been widely used in preclinical drug development of CNS drugs, the most extensive of which is psychodependent research in the field of drug abuse. This review describes in general the basic principles of drug discrimination, preliminarily elaborates on the relevant characteristics and applications of the subjective effects, time-course effect, stereo specificity, individual differences, and receptor mechanisms, and its development prospects for hallucinogens and cannabis drugs are also presented.

Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset, posing a serious threat to human physical and mental health. The cognitive impairments caused by AD are generally diffuse and overlap symptomatically with other neurodegenerative diseases. Moreover, the symptoms of AD are often covert, leading to missed opportunities for optimal treatment after diagnosis. Therefore, early diagnosis of AD is crucial. In vitro diagnostic biomarkers not only contribute to the early clinical diagnosis of AD but also aid in further understanding the disease's pathogenesis, predicting disease progression, and observing the effects of novel candidate therapeutic drugs in clinical trials. Currently, although there are numerous biomarkers associated with AD diagnosis, the complex nature of AD pathogenesis, limitations of individual biomarkers, and constraints of clinical detection methods have hindered the development of efficient, cost-effective, and convenient diagnostic methods and standards. This article provides an overview of the research progress on in vitro diagnostic biomarkers and detection methods related to AD in recent years.
Humans ; Alzheimer Disease/diagnosis* ; Neurodegenerative Diseases ; Early Diagnosis ; Cognitive Dysfunction ; Biomarkers

Objectives: To investigated the safety and efficacy of treating patients with acute non-ST-segment elevation myocardial infarction (NSTEMI) and elevated levels of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP) with levosimendan within 24 hours of first medical contact (FMC). Methods: This multicenter, open-label, block-randomized controlled trial (NCT03189901) investigated the safety and efficacy of levosimendan as an early management strategy of acute heart failure (EMS-AHF) for patients with NSTEMI and high NT-proBNP levels. This study included 255 patients with NSTEMI and elevated NT-proBNP levels, including 142 males and 113 females with a median age of 65 (58-70) years, and were admitted in the emergency or outpatient departments at 14 medical centers in China between October 2017 and October 2021. The patients were randomly divided into a levosimendan group (n=129) and a control group (n=126). The primary outcome measure was NT-proBNP levels on day 3 of treatment and changes in the NT-proBNP levels from baseline on day 5 after randomization. The secondary outcome measures included the proportion of patients with more than 30% reduction in NT-proBNP levels from baseline, major adverse cardiovascular events (MACE) during hospitalization and at 6 months after hospitalization, safety during the treatment, and health economics indices. The measurement data parameters between groups were compared using the t-test or the non-parametric test. The count data parameters were compared between groups using the χ² test. Results: On day 3, the NT-proBNP levels in the levosimendan group were lower than the control group but were statistically insignificant [866 (455, 1 960) vs. 1 118 (459, 2 417) ng/L, Z=-1.25,P=0.21]. However, on day 5, changes in the NT-proBNP levels from baseline in the levosimendan group were significantly higher than the control group [67.6% (33.8%,82.5%)vs.54.8% (7.3%,77.9%), Z=-2.14, P=0.03]. There were no significant differences in the proportion of patients with more than 30% reduction in the NT-proBNP levels on day 5 between the levosimendan and the control groups [77.5% (100/129) vs. 69.0% (87/126), χ²=2.34, P=0.13]. Furthermore, incidences of MACE did not show any significant differences between the two groups during hospitalization [4.7% (6/129) vs. 7.1% (9/126), χ²=0.72, P=0.40] and at 6 months [14.7% (19/129) vs. 12.7% (16/126), χ²=0.22, P=0.64]. Four cardiac deaths were reported in the control group during hospitalization [0 (0/129) vs. 3.2% (4/126), P=0.06]. However, 6-month survival rates were comparable between the two groups (log-rank test, P=0.18). Moreover, adverse events or serious adverse events such as shock, ventricular fibrillation, and ventricular tachycardia were not reported in both the groups during levosimendan treatment (days 0-1). The total cost of hospitalization [34 591.00(15 527.46,59 324.80) vs. 37 144.65(16 066.90,63 919.00)yuan, Z=-0.26, P=0.80] and the total length of hospitalization [9 (8, 12) vs. 10 (7, 13) days, Z=0.72, P=0.72] were lower for patients in the levosimendan group compared to those in the control group, but did not show statistically significant differences. Conclusions: Early administration of levosimendan reduced NT-proBNP levels in NSTEMI patients with elevated NT-proBNP and did not increase the total cost and length of hospitalization, but did not significantly improve MACE during hospitalization or at 6 months.
Male ; Female ; Humans ; Aged ; Natriuretic Peptide, Brain ; Simendan/therapeutic use* ; Non-ST Elevated Myocardial Infarction ; Heart Failure/drug therapy* ; Peptide Fragments ; Arrhythmias, Cardiac ; Biomarkers ; Prognosis

Objective: To analyze whether the upper airway of patients with catathrenia has obstructive manifestations using nasal resistance, craniofacial, and upper airway imaging methods, which could benefit the exploration of the etiology and treatment options. Methods: From August 2012 to September 2019, a total of 57 patients with catathrenia in the Department of Orthodontics at Peking University Hospital of Stomatology were included in the study, including 22 males and 35 females, aged (31.1±10.9) years, with a body mass index of (21.7±2.7) kg/m². All the patients were diagnosed by full-night polysomnography at the Sleep Division, Peking University People's Hospital, of which 10 patients were combined with obstructive sleep apnea hypopnea syndrome (OSAHS). The median groaning index of patients was 4.8 (1.8, 13.0) events/h. Nasal resistance and cone-beam CT were conducted on the patients, and measurements were performed on the craniofacial structures, upper airway, and surrounding soft tissues, compared with non-snoring normal occlusion individuals' references published by the same research team (144 college students recruited at Peking University and 100 non-snoring young adults with normal occlusion recruited at six universities in Beijing). Results: The total nasal resistance of patients with catathrenia was (0.26±0.08) Pa·cm^-3·s^-1. The patients had overall well-developed mandibular hard tissues. However, the patients were found with increased FH/BaN (steep anterior cranial base plane), increased MP/FH (forward rotation of the mandible); increased U1/NA and L1/MP (proclined upper and lower incisors). The sagittal diameter of the velopharynx [(19.2±4.5) mm] was significantly larger than the normal reference (t=8.44, P<0.001), while the sagittal diameter at the hypopharynx [(17.4±6.4) mm] was statistically smaller than the normal reference (t=-2.79, P=0.006). Catarhrenia patients combined with OSAHS presented longer soft palate, tongue, and lower hyoid bone than those with primary catathrenia. Conclusions: In patients with catathrenia, the overall craniofacial characteristics are well-developed skeletal structures, lower nasal resistance, proclined upper and lower incisors, wide upper sagittal development of the upper airway and narrow hypopharynx. Groaning sounds might be related to the narrowing of the hypopharynx during sleep.

The electrophysiological activity of the gastrointestinal tract and the mechanical anti-reflux structure of the gastroesophageal junction are the basis of the anti-reflux function of the stomach. Proximal gastrectomy destroys the mechanical structure and normal electrophysiological channels of the anti-reflux. Therefore, the residual gastric function is disordered. Moreover, gastroesophageal reflux is one of the most serious complications. The emergence of various types of anti-reflux surgery through the mechanism of reconstructing mechanical anti-reflux barrier and establishing buffer zone, and the preservation of, the pacing area and vagus nerve of the stomach, the continuity of the jejunal bowel, the original gastroenteric electrophysiological activity of the gastrointestinal tract, and the physiological function of the pyloric sphincter, are all important measures for gastric conservative operations. There are many types of reconstructive approaches after proximal gastrectomy. The design based on the anti-reflux mechanism and the functional reconstruction of mechanical barrier, and the protection of gastrointestinal electrophysiological activities are important considerations for the selected of reconstructive approaches after proximal gastrectomy. In clinical practice, we should consider the principle of individualization and the safety of radical resection of tumor to select a rational reconstructive approaches after proximal gastrectomy.
Humans ; Stomach Neoplasms/surgery* ; Gastrectomy ; Gastroesophageal Reflux ; Esophagogastric Junction/surgery* ; Pylorus/pathology*

Alzheimer's disease (AD) is a neurodegenerative disease with insidious onset, posing a serious threat to human physical and mental health. The cognitive impairments caused by AD are generally diffuse and overlap symptomatically with other neurodegenerative diseases. Moreover, the symptoms of AD are often covert, leading to missed opportunities for optimal treatment after diagnosis. Therefore, early diagnosis of AD is crucial. In vitro diagnostic biomarkers not only contribute to the early clinical diagnosis of AD but also aid in further understanding the disease's pathogenesis, predicting disease progression, and observing the effects of novel candidate therapeutic drugs in clinical trials. Currently, although there are numerous biomarkers associated with AD diagnosis, the complex nature of AD pathogenesis, limitations of individual biomarkers, and constraints of clinical detection methods have hindered the development of efficient, cost-effective, and convenient diagnostic methods and standards. This article provides an overview of the research progress on in vitro diagnostic biomarkers and detection methods related to AD in recent years.
Humans ; Alzheimer Disease/diagnosis* ; Neurodegenerative Diseases ; Early Diagnosis ; Cognitive Dysfunction ; Biomarkers

Objective: To provide scientific evidence for early lung cancer screening, to analyze the incidence of pulmonary nodules among petroleum company staffs in Sichuan-Chongqing Area. Methods: In January 2021 , 6002 petroleum company staffs in Sichuan-Chongqing Area which scanned by low-dose spiral computed tomography (LDCT) of chest in medical examination center in 2020 were retrospectively collected as objects. Their imaging and clinical data were collected. χ(2) test was used to analyze the differences in the detection rates of lung nodules and suspected lung cancer nodules among workers in petroleum company staffs of different genders, ages and types of work. Results: Among the 6002 objects, 3853 (64.2%) were male and 2149 (35.8%) were female, with an average age of (47.25±12.13) years old. A total of 431 cases (7.2%) of pulmonary nodules and 57 cases (0.9%) of suspected lung cancer nodules were detected. 45 cases were followed up with surgical treatment, and 41 cases (91.1%) of lung cancer were diagnosed by postoperative pathology. There were significant differences in the detection rates of pulmonary nodules and suspected lung cancer nodules between different age groups (χ(2)=51.23, 18.81 , P<0.001). The detection rates of pulmonary nodules in the age groups 51-60 years old and ≥61 years old were higher than those in the age groups≤40 years old and 41-50 years old (P<0.05). The detection rate of suspected lung cancer nodules in the age group≥ 61 years old was higher than those in the age groups≤40 years old, 41-50 years old and 51-60 years old (P< 0.05) . And the detection rate of suspected lung cancer pulmonary nodules in oil workers was higher than that of ordinary workers (P<0.05) . Among female objects, the detection rate of pulmonary nodules in oil workers was higher than that in ordinary workers (χ(2)=8.09, P=0.004) . The detection rate of pulmonary nodules in oil workers aged ≥61 years old was higher than ordinary workers (χ(2)=37.94, P<0.001) . Among male objects, the detection rate of suspected lung cancer pulmonary nodules in oil workers was higher than that in ordinary workers (χ(2)=8.42, P=0.004) . The detection rates of suspected lung cancer pulmonary nodules in oil workers aged 51-60 years old and ≥61 years old groups were higher than those of ordinary workers (χ(2)=4.70, 8.74; P=0.030, 0.003) . Conclusion: LDCT is suitable for early lung cancer screening for petroleum company staffs. During the clinical screening process, LDCT should be used as a routine physical examination item for petroleum workers older than 51 years old.
Adult ; Early Detection of Cancer/methods* ; Female ; Humans ; Lung Neoplasms/diagnosis* ; Male ; Mass Screening/methods* ; Middle Aged ; Multiple Pulmonary Nodules/diagnostic imaging* ; Petroleum ; Retrospective Studies ; Tomography, Spiral Computed

Objective: To analyze the effects of transient receptor potential vanilloid type 4 (TRPV4) activation on the function and endothelial-to-mesenchymal transition (EndMT) of human umbilical vein endothelial cells (HUVECs), as well as to explore the effects of TRPV4 activation on blood perfusion and survival of rat perforator flap and the mechanism. Methods: The experimental research methods were used. The 3^rd to 6^th passages of HUVECs were used for experiments and divided into 0.5 μmol/L 4α-phorbol 12, 13-didecanoate (4αPDD) group, 1.0 μmol/L 4αPDD group, 3.0 μmol/L 4αPDD group, 10.0 μmol/L 4αPDD group, and phosphate buffer solution (PBS) group, which were cultivated in corresponding final molarity of 4αPDD and PBS, respectively. The cell proliferation activity at 6 and 12 h of culture was detected using cell counting kit-8 (CCK-8). Another batch of cells was acquired and divided into PBS group, 1 μmol/L 4αPDD group, and 3 μmol/L 4αPDD group, which were treated similarly as described before and then detected for cell proliferation activity at 6, 12, 24, and 48 h of culture. The residual scratch area of cells at post scratch hour (PSH) 12, 24, and 48 was detected by scratch test, and the percentage of the residual scratch area was calculated. The number of migrated cells at 24 and 48 h of culture was detected by Transwell experiment. The tube-formation assay was used to measure the number of tubular structures at 4 and 8 h of culture. The protein expressions of E-cadherin, N-cadherin, Slug, and Snail at 24 h of culture were detected by Western blotting. All the sample numbers in each group at each time point in vitro experiments were 3. A total of 36 male Sprague-Dawley rats aged 8 to 10 weeks were divided into delayed flap group, 4αPDD group, and normal saline group according to the random number table, with 12 rats in each group, and iliolumbar artery perforator flap models on the back were constructed. The flap surgical delay procedure was only performed in the rats in delayed flap group one week before the flap transfer surgery. Neither rats in 4αPDD group nor normal saline group had flap surgical delay; instead, they were intraperitoneally injected with 4αPDD and an equivalent mass of normal saline, respectively, at 10 min before, 24 h after, and 48 h after the surgery. The general state of flap was observed on post surgery day (PSD) 0 (immediately), 1, 4, and 7. The flap survival rates were assessed on PSD 7. The flap blood perfusion was detected by laser speckle contrast imaging technique on PSD 1, 4, and 7. The microvascular density in the flap's choke vessel zone was detected by immunohistochemical staining. All the sample numbers in each group at each time point in vivo experiments were 12. Data were statistically analyzed with analysis of variance for factorial design, analysis of variance for repeated measurement, one-way analysis of variance, least significant difference t test, and Bonferroni correction. Results: At 6 and 12 h of culture, there were no statistically significant differences in cell proliferation activity in the overall comparison among PBS group, 0.5 μmol/L 4αPDD group, 1.0 μmol/L 4αPDD group, 3.0 μmol/L 4αPDD group, and 10.0 μmol/L 4αPDD group (P>0.05). At 6, 12, 24, and 48 h of culture, there were no statistically significant differences in cell proliferation activity in the overall comparison among PBS group, 1 μmol/L 4αPDD group, and 3 μmol/L 4αPDD group (P>0.05). At PSH 12, the percentages of the residual scratch area of cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group were close to that in PBS group (P>0.05). At PSH 24 and 48, compared with those in PBS group, the percentages of the residual scratch area of cells in 3 μmol/L 4αPDD group were significantly decreased (with t values of 2.83 and 2.79, respectively, P<0.05), while the percentages of the residual scratch area of cells in 1 μmol/L 4αPDD group showed no significant differences (P>0.05). At 24 h of culture, the number of migrated cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group were close to that in PBS group (P>0.05). At 48 h of culture, the number of migrated cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD groups were significantly greater than that in PBS group (with t values of 6.20 and 9.59, respectively, P<0.01). At 4 h of culture, the numbers of tubular structures of cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group were significantly greater than that in PBS group (with t values of 4.68 and 4.95, respectively, P<0.05 or <0.01). At 8 h of culture, the numbers of tubular structures of cells in 1 μmol/L 4αPDD and 3 μmol/L 4αPDD groups were similar to that in PBS group (P>0.05). At 24 h of culture, compared with those in PBS group, the protein expression level of E-cadherin of cells in 3 μmol/L 4αPDD group was significantly decreased (t=5.13, P<0.01), whereas there was no statistically significant difference in the protein expression level of E-cadherin of cells in 1 μmol/L 4αPDD group (P>0.05); the protein expression level of N-cadherin of cells in 3 μmol/L 4αPDD group was significantly increased (t=4.93, P<0.01), whereas there was no statistically significant difference in the protein expression level of N-cadherin of cells in 1 μmol/L 4αPDD group (P>0.05); the protein expression levels of Slug of cells in 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group were significantly increased (with t values of 3.85 and 6.52, respectively, P<0.05 or P<0.01); and the protein expression level of Snail of cells in 3 μmol/L 4αPDD group was significantly increased (t=4.08, P<0.05), whereas there was no statistically significant difference in the protein expression level of Snail of cells in 1 μmol/L 4αPDD group (P>0.05). There were no statistically significant differences in the protein expression levels of E-cadherin, N-cadherin, Slug, or Snail of cells between 1 μmol/L 4αPDD group and 3 μmol/L 4αPDD group (P>0.05). The general condition of flaps of rats in the three groups was good on PSD 0. On PSD 1, the flaps of rats in the three groups were basically similar, with bruising and swelling at the distal end. On PSD 4, the swelling of flaps of rats in the three groups subsided, and the distal end turned dark brown and necrosis occurred, with the area of necrosis in flaps of rats in normal saline group being larger than the areas in 4αPDD group and delayed flap group. On PSD 7, the necrotic areas of flaps of rats in the 3 groups were fairly stable, with the area of necrosis at the distal end of flap of rats in delayed flap group being the smallest. On PSD 7, the flap survival rates of rats in 4αPDD group ((80±13)%) and delayed flap group ((87±9)%) were similar (P>0.05), and both were significantly higher than (70±11)% in normal saline group (with t values of 2.24 and 3.65, respectively, P<0.05 or P<0.01). On PSD 1, the overall blood perfusion signals of rats in the 3 groups were basically the same, and the blood perfusion signals in the choke vessel zone were relatively strong, with a certain degree of underperfusion at the distal end. On PSD 4, the boundary between the surviving and necrotic areas of flaps of rats in the 3 groups became evident, and the blood perfusion signals in the choke vessel zone were improved, with the normal saline group's distal hypoperfused area of flap being larger than the areas in delayed flap group and 4αPDD group. On PSD 7, the blood perfusion signals of overall flap of rats had generally stabilized in the 3 groups, with the intensity of blood perfusion signal in the choke vessel zone and overall flap of rats in delayed flap group and 4αPDD group being significantly greater than that in normal saline group. On PSD 7, the microvascular density in the choke vessel zone of flap of rats in 4αPDD group and delayed flap group were similar (P>0.05), and both were significantly higher than that in normal saline group (with t values of 4.11 and 5.38, respectively, P<0.01). Conclusions: After activation, TRPV4 may promote the migration and tubular formation of human vascular endothelial cells via the EndMT pathway, leading to the enhanced blood perfusion of perforator flap and microvascular density in the choke vessel zone, and therefore increase the flap survival rate.
Animals ; Cadherins ; Endothelial Cells ; Humans ; Male ; Necrosis ; Perforator Flap ; Rats ; Rats, Sprague-Dawley ; Saline Solution ; TRPV Cation Channels