Inferior Frontal Sulcal Hyperintensity on Fluid-Attenuated Inversion Recovery Is Related to Cerebrospinal Fluid Clearance via Putative Meningeal Lymphatics.

Inferior frontal sulcal hyperintensity (IFSH) on FLAIR sequence may indicate elevated cerebrospinal fluid (CSF) wastes. The objective of this study was to investigate its association with the clearance function of putative meningeal lymphatic vessels (mLVs). We included patients who underwent FLAIR sequence and dynamic contrast MRI with intrathecal administration of contrast agent. The visibility of IFSH was quantitatively assessed by measuring the mean signal intensity of inferior frontal sulci on 2D FLAIR. The clearance function of putative mLVs was defined as the percentage change of signal unite ratio in the parasagittal dura from baseline to 4.5, 15 and 39 hours after intrathecal injection on dynamic contrast MRI. Additionally, imaging markers of cerebral small vessel disease, including white matter hyperintensities and enlarged perivascular spaces, were measured. Correlation analysis and linear regression were employed to verify the association of IFSH with the clearance function of mLVs. A total of 76 patients were included in the study. The visibility of IFSH was found to be associated with the percentage change of signal unite ratio in parasagittal dura from baseline to 15 and 39 hours in adjusted analyses. Furthermore, the visibility of IFSH was positively related to the age, scores of both periventricular and deep white matter hyperintensities, and the grade of enlarged perivascular spaces in centrum semiovale. These findings suggest that the visibility of IFSH on 2D FLAIR may serve as an indicator of clearance dysfunction of mLVs and may be implicated in the development of cerebral small vessel disease.

Impaired Meningeal Lymphatics and Glymphatic Pathway in Patients with White Matter Hyperintensity.

White matter hyperintensity (WMH) represents a critical global medical concern linked to cognitive decline and dementia, yet its underlying mechanisms remain poorly understood. Here, humans are directly demonstrated that high WMH burden correlates with delayed drainage of meningeal lymphatic vessels (mLVs) and glymphatic pathway. Additionally, a longitudinal cohort study reveals that glymphatic dysfunction predicts WMH progression. Next, in a rat model of WMH, the presence of impaired lymphangiogenesis and glymphatic drainage is confirmed, followed by elevated microglial activation and white matter demyelination. Notably, enhancing meningeal lymphangiogenesis through adeno-associated virus delivery of vascular endothelial growth factor-C (VEGF-C) mitigates microglial gliosis and white matter demyelination. Conversely, blocking the growth of mLVs with a VEGF-C trap strategy exacerbates these changes. The findings highlight the role of mLVs and glymphatic pathway dysfunction in aggravating brain white matter injury, providing a potential novel strategy for WMH prevention and treatment.

Data-driven clustering approach to identify novel clusters of high cognitive impairment risk among Chinese community-dwelling elderly people with normal cognition: A national cohort study.

Background: Cognitive impairment is a highly heterogeneous disorder that necessitates further investigation into the distinct characteristics of populations at varying risk levels of cognitive impairment. Using a large-scale registry cohort of elderly individuals, we applied a data-driven approach to identify novel clusters based on diverse sociodemographic features. Methods: A prospective cohort of 6398 elderly people from the Chinese Longitudinal Healthy Longevity Survey, followed between 2008-14, was used to develop and validate the model. Participants were aged ≥60 years, community-dwelling, and the Chinese version of the Mini-Mental State Examination (MMSE) score ≥18 were included. Sixty-nine sociodemographic features were included in the analysis. The total population was divided into two-thirds for the derivation cohort (n = 4265) and one-third for the validation cohort (n = 2133). In the derivation cohort, an unsupervised Gaussian mixture model was applied to categorise participants into distinct clusters. A classifier was developed based on the most important 10 factors and was applied to categorise participants into their corresponding clusters in a validation cohort. The difference in the three-year risk of cognitive impairment was compared across the clusters. Results: We identified four clusters with distinct features in the derivation cohort. Cluster 1 was associated with the worst life independence, longest sleep duration, and the oldest age. Cluster 2 demonstrated the highest loneliness, characterised by non-marital status and living alone. Cluster 3 was characterised by the lowest sense of loneliness and the highest proportions in marital status and family co-residence. Cluster 4 demonstrated heightened engagement in exercise and leisure activity, along with independent decision-making, hygiene, and a diverse diet. In comparison to Cluster 4, Cluster 1 exhibited the highest three-year cognitive impairment risk (adjusted odds ratio (aOR) = 3.31; 95% confidence interval (CI) = 1.81-6.05), followed by Cluster 2 and Cluster 3 after adjustment for baseline MMSE, residence, sex, age, years of education, drinking, smoking, hypertension, diabetes, heart disease and stroke or cardiovascular diseases. Conclusions: A data-driven approach can be instrumental in identifying individuals at high risk of cognitive impairment among cognitively normal elderly populations. Based on various sociodemographic features, these clusters can suggest individualised intervention plans.

Evaluation of the hygiene status of teaching environment in primary and secondary schools in Beijing City from 2016 to 2020 / 中国学校卫生

Objective@#To understand the trend of changes of hygiene status in the teaching environment among primary and secondary schools in Beijing City during 2016-2020, so as to provide basis for further improving the teaching environment and campus hygiene conditions in primary and secondary schools.@*Methods@#A proportional systematic sampling method covered over 50% of schools selected annually in Beijing from 2016 to 2019, and 34% were selected in 2020. Two representative classrooms were selected from each selected school for testing based on their structure and other factors, with 6 196 classrooms supervised, from 2016 to 2020,1 330,1 312,1 384,1 322,848 classrooms were monitored for each year.@*Results@#From 2016 to 2020, the overall lighting qualification rate of classrooms (lighting coefficient 72.8%, window to floor area ratio 41.8%, rear wall reflectance ratio 42.2%, blackboard reflection ratio 37.4%), the overall qualification rate of average blackboard illumination and uniformity (50.6%, 34.9 %), and the overall qualification rate of desk and chair allocation (58.6%) were all below 80%. The overall qualification rate of per capita classroom area (87.5%), blackboard size (83.2%), average desk illumination ( 80.1% ), average desk illumination and uniformity (82.9%), the distance between lamp and desk (99.1%), carbon dioxide ( 86.6% ), temperature (84.9%), and noise (96.6%) were all above 80%. The following indicators, blackboard size, the distance between lamp and desk, average blackboard illumination, lighting coefficient, blackboard reflectance, rear wall reflectance, carbon dioxide, temperature, and noise ( χ 2=78.38, 9.71, 11.76, 320.59, 37.63, 58.45, 236.45, 1 347.56, 101.97), had statistically significance between years. Among those indicators, the qualified rates of blackboard size, blackboard reflectance, lighting coefficient, and noise had been increasing year by year ( χ 2 trend =69.98, 15.82, 240.02, 5.77) ( P <0.05). The qualified rates of per capita classroom area, window to floor area ratio, and blackboard reflection ratio in primary schools (81.6%, 39.8%, 36.3%) were all lower than those in secondary schools (94.9%, 44.5%, 40.3%) ( χ 2=246.32, 12.03, 10.51, P <0.05). The qualified rates of blackboard size, average blackboard illumination, average blackboard illumination and uniformity, and desk and chair allocation (89.3%, 55.6% , 36.0%, and 60.2%) were all higher than those in secondary schools (75.4%, 44.1%, 33.3%, and 56.5%) ( χ 2=209.33, 78.41, 4.44, 8.22) ( P <0.05). The qualified rates of average desk illumination and uniformity, average blackboard illumination, rear wall reflectance ratio, desk and chair allocation, carbon dioxide, temperature, and noise indicators in urban area (82.9%, 84.1% , 51.9%, 45.0%, 60.9%, 91.2%, 89.5%, 97.8%) were all higher than those in suburban area (77.3%, 81.7%, 49.2%, 39.5%, 56.3%, 82.3%, 80.4%, 95.5%) ( χ 2=31.16, 6.28, 4.36, 16.40, 13.39, 105.29, 98.23, 24.66， P <0.05). The qualified rates of the distance between lamp and desk, lighting coefficient, window to floor area ratio, blackboard size, blackboard reflection ratio, average blackboard illumination and uniformity, and per capita classroom area in urban areas (98.8%, 65.2%, 34.3%, 76.7%, 35.9%, 30.1%, 84.6%) were all lower than those in suburban areas (99.4%, 81.4%, 49.8%, 89.7%, 40.2%, 39.6%, 90.3%) ( χ 2=6.80, 171.67, 132.43, 188.46 , 12.45, 60.28, 44.82) ( P <0.05).@*Conclusions@#The main problems in the teaching environment of schools in Beijing are classroom lighting, as well as desk and chair allocation. The findings suggest technical rationality and operability of relevant standard should be considered when under revision, and standard training and supervision management should be strengthened, with the aim of teaching environment improvement.

Establishment and biological characterization of drug-resistant cells and identification of multidrug resistance in small-cell lung cancer / 中国药理学通报

Aim To establish NCI-H446/EP for small cell lung cancer resistant cells resistant to cisplatin and etoposide, and to evaluate their biological characteristics and multidrug resistance. Methods Nude mice were subcutaneously inoculated with NCI-H446 cells of SCLC to construct an in vivo model of xenograft tumor, and were given first-line EP regimen treatment for SCLC, inducing drug resistance in vivo, and stripping tumor tissue in vitro culture to obtain drug-resistant cells. The resistance coefficient, cell doubling time, cell cycle distribution, expression of multidrug resistance gene (MDR1), and drug resistance-related protein were detected in vitro, and the drug resistance to cisplatin and etoposide in vivo were verified. Results Mice with NCI-H446 tumors acquired resistance after eight weeks' EP regimen treatment, and the drug-resistant cell line NCI-H446/EP was obtained by isolation and culture in vitro. The resistance factors of this cell line to cisplatin, etoposide, SN38 and doxorubicin were 12.01, 18.36, 65.4 and 10.12, respectively. Compared with parental cells, the proportion of NCIH446/EP cells in Q

Characteristics and risk assessment of chilling injury on Morchella esculenta in Western Sichuan Plateau, China.

The development of precise climate risk zoning for chilling injury of Morchella esculenta can provide scientific basis for agricultural cultivation planning, dynamic assessment of chilling injury, and disaster prevention strategies. Based on meteorological data from 17 counties (cities) that located below the altitude of 3000 m in the Western Sichuan Plateau from 2011 to 2020, we analyzed the critical meteorological conditions for M. esculenta disasters in typical years. With the average yearly cold accumulation and cold injury frequency during the first day when the temperature remained stable between 5 ℃ and 10 ℃ during mushroom emergence as zoning indicators, we established a geographical spatial distribution model of the cold injury index, and then divided the risk level of M. esculenta cold injury in the Western Sichuan Plateau, evaluated the risk of cold injury. The results showed that the temperature index for chilling injury risk of M. esculenta in the study area was the daily minimum temperature ≤2.0 ℃. The daily average temperature <6.0 ℃ would cause slow growth or the cessation of growth, which was set as a warning indicator for chilling injury risk. Along the Dadu River and Minjiang River basins, the frequency of chilling injury on M. esculenta increased from south to north. Wenchuan, Maoxian, and Lixian had the fewest overall chilling injuries during the study period, whereas Jiulong, Yajiang, and Batang had the most. The duration for cold injury was mainly 1-3 d, followed by 4-5 d, and rarely for >5 d. The frequency of chilling injury lasting for more than 5 d in Xiangcheng, Batang, Jiulong, Yajiang, and Xiaojin was more than that lasting for 4-5 d. The annual average days of chilling injury of was 3.0-27.4 d, the daily average minimum temperature was -0.84-1.36 ℃, the extreme lowest temperature was -5.8-0.1 ℃, and the average accumulated cold was 0.16-9.64 ℃·d during the period of chilling injury. With the increases of elevation and latitude, the average days of chilling injury and the average accumulated cold increased. The largest duration of chilling injury was 3-20 d, the maximum accumulated cold was 0.44-13.34 ℃·d. The risk of chilling injury to M. esculenta increased from south to north and from low elevation to high elevation. The suitable planting areas were distributed in strips and branches along the direction of mountains and rivers, mainly in the flat areas of low mountains and valleys below the altitude of 2200 m, including Kangding, Luding, Danba, Wenchuan, Lixian, Maoxian, Jiuzhaigou, and Songpan.

Glymphatic function plays a protective role in ageing-related cognitive decline.

OBJECTIVE: The glymphatic pathway, characterised as a cerebral drainage system, influences cognitive function in neurodegenerative diseases; however, evidence is limited in a normal ageing population. The aim of this study was to investigate the effect of glymphatic function on ageing-related cognitive decline. METHODS: We retrospectively reviewed the Cognitive Impairment, Retinopathy, and Cerebrovascular Lesions in the Elderly (CIRCLE) study, and participants with multi-model magnetic resonance imaging (MRI) scans and Mini-Mental State Examinations (MMSE) were enrolled. Glymphatic function was evaluated via the diffusion tensor imaging along the perivascular space (DTI-ALPS) index. Regression models were used to estimate the impact of the DTI-ALPS index on cognitive decline cross-sectionally and longitudinally. We further analysed the mediation effect of the DTI-ALPS on age and cognitive function. RESULTS: A total of 633 participants were included in this study (48.2% female; mean age, 62.8 ± 8.9 years). The DTI-ALPS index was positively associated with cognitive function cross-sectionally (ß = 0.108, P = 0.003), and was an independent protective factor for cognitive decline longitudinally (odds ratio (OR) = 0.029, P = 0.007). The DTI-ALPS index declined progressively with ageing (r = -0.319, P <0.001), and the decrease was more pronounced after 65 years of age. Furthermore, the DTI-ALPS index mediated the relationship between age and MMSE score (ß = -0.016, P <0.001). The mediation effect accounted for 21.3%, which was higher in subjects aged over 65 years (25.3%) compared with those aged under 65 years (5.3%). CONCLUSION: Glymphatic function played a protective role in normal ageing-related cognitive decline, which may serve as a potential therapeutic target against cognitive decline in future.

Choroid Plexus Enlargement Exacerbates White Matter Hyperintensity Growth through Glymphatic Impairment.

OBJECTIVE: Choroid plexus (CP) is a key regulator in cerebrospinal fluid production, but its contribution to glymphatic clearance function and association with white matter hyperintensity (WMH) remains unclear. METHODS: This retrospective study included 2 prospective 3.0-T magnetic resonance imaging (MRI) cohorts. In cohort 1, patients with indications for lumbar puncture underwent 3-dimensional T1-weighted sequence (3D-T1) before and at 39 hours after intrathecal administration of contrast agent (glymphatic MRI). In cohort 2, patients with WMH were enrolled from the CIRCLE study and had a median follow-up time of 1.4 years. WMH and CP of the lateral ventricles were automatically segmented on T2 fluid-attenuated inversion recovery (FLAIR) and 3D-T1, respectively. CP volume was expressed as a ratio to intracranial volume. Glymphatic clearance was measured as signal percentage change from baseline to 39 hours at 8 brain locations based on glymphatic MRI in the first cohort, or as noninvasive diffusion tensor image analysis along the perivascular space (DTI-ALPS) index based on DTI in the second cohort. RESULTS: In cohort 1, a total of 52 patients were included. Higher CP volume was correlated with slower glymphatic clearance rate in all brain locations. In cohort 2, a total of 197 patients were included. Baseline CP volume was positively associated with WMH volume and its growth. Furthermore, DTI-ALPS index partially mediated the association of CP with both WMH load and growth. INTERPRETATIONS: Enlarged CP volume could be an indicator for larger growth of WMH, potentially involving impaired glymphatic clearance function. The exploration of CP may provide a novel perspective to clarify the mechanism of WMH pathogenesis, as well as other glymphatic-related disorders. ANN NEUROL 2023;94:182-195.

Effect of chemogenetic manipulation of PVN corticotropin-releasing factor-expressing neurons on excitability of presympathetic neurons in SHR / 中国药理学通报

Aim To observe the effect of corticotropin-releasing factor ( CRF) -expressing neurons on presympathetic neurons in hypothalamic paraventricular nucleus ( PVN) of normotensive Wistar Kyoto ( WKY) rats or spontaneously hypertensive rats (SHR) , and to elucidate the underlying neuronal circuit mechanism of central sympathetic hyperexcitability. Methods The expression levels of CRF protein in WKY rats and SHR PVN were determined by Western blot. Meanwhile, the WKY and SHR PVN CRF-expressing neurons and presympathetic neurons were observed by immunofluo-rescent staining. Adult WKY rats and SHR were used in this study. By microinjection of Cre-dependent ade-no-associated viruses ( AAV) that specifically recognized the CRF promoter and AAV of chemogenetics into the PVN, CRF-expressing neurons expressed designer receptors exclusively activated by designer drugs (DREADDs). Human M3 muscarinic DREADD coupled to Gq receptor ( hM3 Dq) was specifically expressed in PVN CRF-expressing neurons in WKY rats, while human M4 muscarinic DREADD coupled to Gi receptor ( hM4Di) was specifically expressed in PVN CRF-expressing neurons in SHR. Clozapine-N-oxide (CNO) , as a designer ligand, would couple to excitatory hM3Dq or inhibitory hM4Di to regulate the excitability of PVN CRF-expressing neurons. Then the PVN presympathetic neurons were retrogradely labeled by microinjection of fluosecent tracer into the intermedio-lateral column (IML) of spinal cord. Lastly, whole cell patch clamp was used to determine the effect of CNO (10 jjumol L~ ) on spontaneous excitatory postsynaptic currents ( sEPSCs) and current-evoked firing of PVN presympathtic neurons of WKY rats and SHR. Results The expression of CRF protein in the PVN of SHR was significantly higher than that of WKY rats, and the activity and number of CRF-expressing neurons in the PVN of SHR were increased. PVN CRF-expressing neurons were expressed with chemogenetic DREADDs and PVN presympathetic neurons were retrogradely labeled with fluorescent tracer in WKY rats and SHR. In SHR expressed with chemogenetic inhibitory hM4Di-mCherry of PVN CRF-expressing neurons, bath application of CNO to the brain slices resulted in a significant decrease in sEPSCs frequency, but no change in their amplitude of labeled PVN presympathetic neurons. In contrast, in WKY rats expressed with excitatory hM3Dq-eGFP of PVN CRF-expressing neurons, CNO had no obvious effect on the sEPSCs frequency and amplitude in PVN presympathetic neurons. Furthermore, bath application of CNO had no significant effect on current-evoked firing of PVN presympathetic neurons of either WKY rats with hM3Dq-eGFP expression in CRF neurons or SHR with hM4Di-mCherry expression in CRF neurons. Conclusions The activity and number of PVN CRF-expressing neurons are increased in SHR, and CRF-expressing neurons enhance the excitability of presympathetic neurons, which acts as a regulatory neuronal microcircuit between CRF neurons and presympathetic neurons in the PVN.

Relationship between coagulation status, autoantibodies, and conception method with subchorionic hematoma / 中华妇产科杂志

Objective: To investigate the relationship between subchorionic hematoma (SCH) and coagulation status, autoantibodies, and conception method. Methods: A total of 100 pregnant women diagnosed with SCH from June 2020 to December 2021 in the Third Affiliated Hospital of Zhengzhou University were included in the SCH group, while 100 healthy pregnant women during the same period were selected as the control group. The coagulation status (including platelet, prothrombin time, thrombin time, activated partial thromboplastin time, fibrinogen, antithrombin Ⅲ, fibrin degradation products, D-dimer, homocysteine, protein S activity, protein C activity), the positive rate of autoantibodies [including antiphospholipid antibodies (anticardiolipin antibody and anti-β2 glycoprotein Ⅰ antibody), antinuclear antibody] and the mode of conception of the two groups were analyzed. Results: Compared to the control group, the SCH group had higher levels of platelet [(240±45)×109/L vs (227±37)×109/L], fibrinogen [(4.0±0.8) vs (3.6±0.7) g/L], D-dimer [(0.42±0.18) vs (0.31±0.15) mg/L], blood homocysteine [(8.9±4.2) vs (6.9±2.3) μmol/L], and lower level of protein S activity [(55±14)% vs (68±20)%], and there were significant differences between the two groups (all P<0.05). The SCH group had higher positive rates of autoantibodies [24.0% (24/100) vs 8.0% (8/100)], antiphospholipid antibodies [15.0% (15/100) vs 6.0% (6/100)], anti-β2 glycoprotein Ⅰ antibody [10.0% (10/100) vs 3.0% (3/100)], antinuclear antibody [11.0% (11/100) vs 2.0% (2/100)] and assisted reproduction rate [10.0% (10/100) vs 2.0% (2/100)] than those of the control group (all P<0.05). Conclusion: The occurrence of SCH is related to blood hypercoagulability, positive autoantibodies, and assisted reproduction.

Comprehensive evaluation and analysis of laboratory resource allocation in 14 blood stations based on entropy weight -TOPSIS method / 中国输血杂志

【Objective】 To investigate the resource allocation status of blood testing laboratories in 14 blood stations in Gansu Province, explore the impact of differences in basic conditions on the comprehensive testing ability of laboratories, so as to promote the homogenization and standardization of blood screening capacity in blood stations in Gansu and improve blood safety and effectivenes. 【Methods】 An evaluation index system of laboratory resource allocation was constructed and a question-naire was designed. The data of human resources, infrastructure and key equipment of 14 blood stations were collected. The entropy weight -TOPSIS method was used to evaluate and rank the resource allocation of 14 blood stations. 【Results】 In the comprehensive evaluation of blood testing laboratory resource allocation in 14 blood stations in Gansu, the top three were laboratories A, B and I, and the last three were laboratories G, M and J. On the whole, the main issue was unreasonable structure of human resources: most laboratories had unreasonable age structure; except for Laboratory A, there was no personnel with bachelor's degree or above in laboratories; most laboratories had not established a team with intermediate professional titles. In terms of infrastructure, the size of seven laboratories could not meet the needs of modern laboratory testing, and all eight blood stations had no spare nucleic acid laboratories nor a mutual spare laboratory with other blood stations As for the key equipment, 5 laboratories had no automatic blood grouping diagnostic instrument, 5 laboratories only had one set of enzyme immunoassay detection system, 3 laboratories had no spare equipment for the key equipment, which means if the equipment failure could not be repaired in time, the release of results would be affected. 【Conclusion】 There were significant differences in human resources, infrastructure and key equipment of blood testing laboratories in 14 blood stations in Gansu, which had a great impact on laboratory testing capacity and subsequent development. It is suggested that governments at all levels and health administrative departments optimize the input of laboratory resource allocation according to the blood collection volume of blood stations to gradually narrow the differences in resource distribution between different regions, improve the degree of laboratory automation and optimize the personnel structure, so as to build high-quality and efficient blood testing laboratories and ensure the safety of clinical blood use.

Scientific basis of acupuncture on mesenchymal stem cells for treating ischemic stroke / 中国针灸

The scientific basis of acupuncture on mesenchymal stem cells (MSCs) for treating ischemic stroke (IS) is discussed. MSCs transplantation has great potential for the treatment of tissue damage caused by early stage inflammatory cascade reactions of IS, but its actual transformation is limited by various factors. How to improve the homing efficiency of MSCs is the primary issue to enhance its efficacy. As such, the possible mechanisms of acupuncture and MSCs transplantation in inhibiting inflammatory cascade reactions induced by IS are explored by reviewing literature, and a hypothesis that acupuncture could promote the secretion of stromal cell-derived factor-1α (SDF-1α) from ischemic foci to regulate SDF-1α/CXC chemokine receptor 4 (CXCR4) axis, thereby improving the homing efficiency of MSCs transplantation, exerting its neuroprotective function, and improving the bed transformation ability, is proposed.

Comparative study of medical common data models for FAIR data sharing / 中华流行病学杂志

The common data model (CDM) is an important tool to facilitate the standardized integration of multi-source heterogeneous healthcare big data, enhance the consistency of data semantic understanding, and promote multi-party collaborative analysis. The data collections standardized by CDM can provide powerful support for observational studies, such as large-scale population cohort study. This paper provides an in-depth comparative analysis of the data storage structure, term mapping pattern, and auxiliary tools development of the three international typical CDMs, then analyzes the advantages and limitations of each CDM and summarizes the challenges and opportunities faced in the CDM application in China. It is expected that exploring the advanced technical concepts and practical patterns of foreign countries in data management and sharing will provide references for promoting FAIR (findable, accessible, interoperable, reusable) construction of healthcare big data in China and solving the current practical problems, such as the poor quality of data resources, the low degree of semantization, and the inabilities of data sharing and reuse.

Chemical constituents from stems and leaves of Cratoxylum cochinchinense and their inhibitory effects on proliferation of synoviocytes in vitro / 中国中药杂志

The chemical constituents from the stems and leaves of Cratoxylum cochinchinense were isolated and purified using silica gel, ODS gel, and Sephadex LH-20 gel column chromatography, as well as preparative HPLC. The chemical structures of all isolated compounds were identified on the basis of their physicochemical properties, spectroscopic analyses, and the comparison of their physicochemical and spectroscopic data with the reported data in literature. As a result, 21 compounds were isolated from the 90% ethanol extract of the stems and leaves of C. cochinchinense, which were identified as cratocochine(1), 1-hydroxy-3,7-dimethoxyxanthone(2), 1-hydroxy-5,6,7-trimethoxyxanthone(3), ferrxanthone(4), 3,6-dihydroxy-1,5-dimethoxyxanthone(5), 3,6-dihydroxy-1,7-dimethoxyxanthone(6), 1,2,5-trihydroxy-6,8-dimethoxyxanthone(7), securixanthone G(8), gentisein(9), 3,7-dihydroxy-1-methoxyxanthone(10), pancixanthone B(11), garcimangosxanthone A(12), pruniflorone L(13), 9-hydroxy alabaxanthone(14), cochinchinone A(15), luteolin(16), 3,5'-dimethoxy-4',7-epoxy-8,3'-neolignane-5,9,9'-triol(17), N-benzyl-9-oxo-10E,12E-octadecadienamide(18), 15-hydroxy-7,13E-labdadiene(19), stigmasta-4,22-dien-3-one(20), and stigmast-5-en-3β-ol(21). Among these isolates, compound 1 was a new xanthone, compounds 2-5, 7, 8, 12, and 16-21 were isolated from the Cratoxylum plant for the first time, and compounds 11 and 13 were obtained from C. cochinchinense for the first time. Furthermore, all isolated compounds 1-21 were appraised for their anti-rheumatoid arthritis activities by MTS method through measuring their anti-proliferative effect on synoviocytes in vitro. As a result, xanthones 1-15 displayed notable anti-rheumatoid arthritis activities, which showed inhibitory effects on the proliferation of MH7A synoviocytes with the IC_(50) values ranging from(8.98±0.12) to(228.68±0.32) μmol·L~(-1).

The preventive effect and mechanism of Dayuanyin in hypoxic pulmonary hypertension through NF-κB signaling pathway / 药学学报

Dayuanyin (DYY) has been shown to reduce lung inflammation in both coronavirus disease 2019 (COVID-19) and lung injury. This experiment was designed to investigate the efficacy and mechanism of action of DYY against hypoxic pulmonary hypertension (HPH) and to evaluate the effect of DYY on the protection of lung function. Animal welfare and experimental procedures are approved and in accordance with the provision of the Animal Ethics Committee of the Institute of Materia Medica, Chinese Academy of Medical Science. Male C57/BL6J mice were randomly divided into 4 groups: control group, model group, DYY group (800 mg·kg-1), and positive control sildenafil group (100 mg·kg-1). The animals were given control solvents or drugs by gavage three days in advance. On day 4, the animals in the model group, DYY group and sildenafil group were kept in a hypoxic chamber containing 10% ± 0.5% oxygen, and the animals in the control group were kept in a normal environment, and the control solvent or drugs continued to be given continuously for 14 days. The right ventricular systolic pressure, right ventricular hypertrophy index, organ indices and other metrics were measured in the experimental endpoints. Meantime, the expression levels of the inflammatory factors in mice lung tissues were measured. The potential therapeutic targets of DYY on pulmonary hypertension were predicted using network pharmacology, the expression of nuclear factor kappa B (NF-κB) signaling pathway-related proteins were measured by Western blot assay. It was found that DYY significantly reduced the right ventricular systolic pressure, attenuated lung injury and decreased the expression of inflammatory factors in mice. It can also inhibit hypoxia-induced activation of NF-κB signaling pathway. DYY has a protective effect on lung function, as demonstrated by DYY has good efficacy in HPH, and preventive administration can slow down the disease progression, and its mechanism may be related to inhibit the activation of NF-κB and signal transducer and activator of transcription 3 (STAT3) by DYY.

Impaired peri-olfactory cerebrospinal fluid clearance is associated with ageing, cognitive decline and dyssomnia.

BACKGROUND: Animal experiments have demonstrated the dependency of cerebrospinal fluid clearance function on age and sleep, which partially underlay the cognitive decline in the elderly. However, human evidence is lacking, which could be mainly attributed to the limited methods of cerebrospinal fluid clearance function assessment. METHOD: Serial T1-weighted and T2-fluid attenuated inversion recovery imaging were performed in 92 patients before and at multiple time points including 4.5 h, 15 h and 39 h after intrathecal injection of contrast agent to visualize the putative meningeal lymphatic pathway, peri-olfactory nerve pathway, and peri-optic nerve pathway. We defined the clearance function as the percentage change in signal unit ratio of critical locations in these pathways from baseline to 39 h after intrathecal injection, and further analysed their relationships with age, sleep, and cognitive function. FINDINGS: Cerebrospinal fluid clearance through the putative meningeal lymphatic and perineural pathways were clearly visualized. The clearance function of putative meningeal lymphatic and perineural pathways were impaired with ageing (all P < 0.05). The clearance function through peri-olfactory nerve pathway in inferior turbinate was positively correlated with sleep quality and cognitive function (both P < 0.05), and mediated the association of sleep quality with cognitive function (percent change in ß [bootstrap 95% CI]: 33% [-0.220, -0.007]). INTERPRETATION: The impaired clearance through putative peri-olfactory nerve pathway may explain the cognitive decline in patients with sleep disturbance. The study shows a promising method to assess cerebrospinal fluid clearance function of putative peri-neural pathways via dynamic magnetic resonance imaging with intrathecal injection of contrast agent. FUNDING: This work was supported by the National Natural Science Foundation of China (81971101, 82171276 and 82101365).

Effects of resilience on impulsivity, cognition and depression during protracted withdrawal among Chinese male methamphetamine users.

BACKGROUND: Methamphetamine (METH) dependence is a complex and dynamic public health problem. Long-term abuse of METH can increase numerous risks of mental and physical problems. Currently, the methods to reduce METH dependence and improve the withdrawal symptoms are limited and ineffective. Resilience is seen as a multidimensional and dynamic capability to recover or bounce back from stressful events and is also generally considered as a protective factor against mental dysfunction. METHODS: One hundred thirty-four males with METH dependence were consecutively recruited from Huanglong Compulsory Isolated Detoxification Center between 2019 and 2021, of whom 112 were into the group. The Connor-Davidson Resilience Scale (CD-RISC), Self-rating depression scale (SDS), Self-rating anxiety scale (SAS), Barratt Impulsiveness Scale-11(BIS-11), and the Repeatable Battery for the Assessment of Neuropsychological Status (Rbans) were used to evaluate resilience, depression, anxiety, impulsivity, and cognition respectively. RESULTS: The results mainly indicated that high resilience group showed lower SDS, SAS and BIS-11 scores than low resilience group (all p < 0.05). Besides, the total scores of Rbans were higher in high resilience groups than low resilience group (both p < 0.05). Moreover, linear regression results showed that resilience may be influenced by the scores of SDS and SAS. CONCLUSIONS: Resilience is negatively correlated with impulsivity and depression. Besides, it is also positively associated with cognitive function. Drug users with higher resilience may have a strong ability to mobilize psychological resources to create a good psychological environment, which may have a positive effect on the relief or improvement of symptoms.

Oxysterols drive inflammation via GPR183 during influenza virus and SARS-CoV-2 infection

RationaleSevere viral respiratory infections are often characterized by extensive myeloid cell infiltration and activation and persistent lung tissue injury. However, the immunological mechanisms driving excessive inflammation in the lung remain elusive. ObjectivesTo identify the mechanisms that drive immune cell recruitment in the lung during viral respiratory infections and identify novel drug targets to reduce inflammation and disease severity. MethodsPreclinical murine models of influenza virus and SARS-CoV-2 infection. ResultsOxidized cholesterols and the oxysterol-sensing receptor GPR183 were identified as drivers of monocyte-macrophage infiltration to the lung during influenza virus (IAV) and SARS-CoV-2 infections. Both IAV and SARS-CoV-2 infections upregulated the enzymes cholesterol 25-hydroxylase (CH25H) and cytochrome P450 family 7 subfamily member B1 (CYP7B1) in the lung, resulting in local production of the oxidized cholesterols 25-hydroxycholesterol and 7,25-dihydroxycholesterol (7,25-OHC). Loss-of-function mutation of GPR183, or treatment with a GPR183 antagonist, reduced macrophage infiltration and inflammatory cytokine production in the lungs of IAV- or SARS-CoV-2-infected mice. The GPR183 antagonist also significantly attenuated the severity of SARS-CoV-2 infection by reducing weight loss and viral loads. ConclusionThis study demonstrates that oxysterols drive inflammation in the lung and provides the first preclinical evidence for therapeutic benefit of targeting GPR183 during severe viral respiratory infections. Author SummaryViral infections trigger oxysterol production in the lung, attracting macrophages via GPR183. Blocking GPR183 reduced inflammation and disease severity in SARS-CoV-2 infection, making GPR183 a putative target for therapeutic intervention.

Discovery of exogenous ligands for orphan receptor BRS-3 from Chinese herbs / 中国中药杂志

Bombesin receptor subtype-3(BRS-3) is an orphan receptor in the bombesin receptor family. Its signal transduction mechanism and biological function have attracted much attention. Seeking the ligand for BRS-3 is of great significance for exploring its function. Considering the fact that the activation of BRS-3 receptor can induce the change in intracellular Ca~(2+) concentration, the fluo-rometric imaging plate reader(FLIPR) was utilized for ligand screening at the cellular level. Among more than 400 monomeric compounds isolated from Chinese herbs, yuanhunine from Corydalis Rhizoma and sophoraisoflavanone A and licoriphenone from Glycyrrhizae Radix et Rhizoma antagonized BRS-3 to varying degrees. It was confirmed in HEK293 cells expressing BRS-3 that yuanhunine, sophoraisoflavanone A, and licoriphenone inhibited the calcium current response after the activation of BRS-3 by [D-Phe~6,β-Ala~(11),Phe~(13),Nle~(14)]bombesin-(6-14) in a dose-dependent manner with the IC_(50) values being 8.58, 4.10, and 2.04 μmol·L~(-1), respectively. Further study indicated that yuanhunine and sophoraisoflavanone A exhibited good selectivity for BRS-3. In this study, it was found for the first time that monomers derived from Chinese herbs had antagonistic activity against orphan receptor BRS-3, which has provided a tool for further study of BRS-3 and also the potential lead compounds for new drug discovery. At the same time, it provides reference for the research and development of innovative drugs based on the active ingredients of Chinese herbs.

A Network Pharmacology-Based Study on Antidepressant Effect of Salicornia europaea L. Extract with Experimental Support in Chronic Unpredictable Mild Stress Model Mice / 中国结合医学杂志

OBJECTIVE@#To investigate the pharmacodynamic material basis, mechanism of actions and targeted diseases of Salicornia europaea L. (SE) based on the network pharmacology method, and to verify the antidepressant-like effect of the SE extract by pharmacological experiments.@*METHODS@#Retrieval tools including Chinese medicine (CM), PubMed, PharmMapper, MAS 3.0 and Cytoscape were used to search the components of SE, predict its targets and related therapeutic diseases, and construct the "Component-Target-Pathway" network of SE for central nervous system (CNS) diseases. Further, protein-protein interaction (PPI) network, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) function annotation of depression-related targets were analyzed to predict the antidepressant mechanism of SE. Chronic unpredictable mild stress (CUMS) model was used to construct a mouse model with depression-like symptoms. And the animals were randomly divided into 6 groups (n=10) including the normal group (nonstressed mice administered with distilled water), the CUMS group (CUMS mice administered with distilled water), the venlafaxine group (CUMS mice administered with venlafaxine 9.38 mg/kg), SE high-, medium-, and low-dose groups (CUMS mice administered with SE 1.8, 1.35 and 0.9 g/kg, respectively). Then some relevant indicators were determined for experimental verification by the forced swim test (FST), the tail suspension test (TST) and open-field test (OFT). Dopamine (DA) concentration in hippocampus and cerebral cortex, IL-2 and corticosterone (CORT) levels in blood, and nuclear factor E2 related factor 2 (Nrf2), kelch-like epichlorohydrin related protein 1 (Keap1), NAD(P) H dehydrogenase [quinone] 1 (NQO1) and heme oxygenase-1 (HO-1) levels in mice were measured by enzyme linked immunosorbent assay (ELISA) and Western blot respectively to explore the possible mechanisms.@*RESULTS@#The "target-disease" network diagram predicted by network pharmacology, showed that the potential target of SE involves a variety of CNS diseases, among which depression accounts for the majority. The experimental results showed that SE (1.8, 1.35 g/kg) significantly decreased the immobility period, compared with the CUMS group in FST and TST in mice after 3-week treatment, while SE exhibited no significant effect on exploratory behavior in OFT in mice. Compared with CUMS group, the SE group (0.9 g/kg) showed significant differences (P<0.05) in DA levels in the hippocampus and cerebral cortex. In addition, compared with CUMS control group, SE (1.8 g/kg) group showed a significant effect on decreasing the activities of CORT (P<0.05), and serum IL-2 level with no statistical significance. Finally, Western blot results showed that compared with the model group, Nrf2, Keap1, NQO1 and HO-1 protein expressions in SE group (1.8 g/kg) were up-regulated (all P<0.01).@*CONCLUSION@#The SE extract may have an antidepressant effect, which appeared to regulate Nrf2-ARE pathway and increased levels of DA and CORT in the hippocampus and cortex.