ALS-linked C9orf72-SMCR8 complex is a negative regulator of primary ciliogenesis.

Massive GGGGCC (G4C2) repeat expansion in C9orf72 and the resulting loss of C9orf72 function are the key features of ~50% of inherited amyotrophic lateral sclerosis and frontotemporal dementia cases. However, the biological function of C9orf72 remains unclear. We previously found that C9orf72 can form a stable GTPase activating protein (GAP) complex with SMCR8 (Smith-Magenis chromosome region 8). Herein, we report that the C9orf72-SMCR8 complex is a major negative regulator of primary ciliogenesis, abnormalities in which lead to ciliopathies. Mechanistically, the C9orf72-SMCR8 complex suppresses the primary cilium as a RAB8A GAP. Moreover, based on biochemical analysis, we found that C9orf72 is the RAB8A binding subunit and that SMCR8 is the GAP subunit in the complex. We further found that the C9orf72-SMCR8 complex suppressed the primary cilium in multiple tissues from mice, including but not limited to the brain, kidney, and spleen. Importantly, cells with C9orf72 or SMCR8 knocked out were more sensitive to hedgehog signaling. These results reveal the unexpected impact of C9orf72 on primary ciliogenesis and elucidate the pathogenesis of diseases caused by the loss of C9orf72 function.

Bioremediation of mercury-polluted soil and water by the plant symbiotic fungus Metarhizium robertsii.

Fungi are central to every terrestrial and many aquatic ecosystems, but the mechanisms underlying fungal tolerance to mercury, a global pollutant, remain unknown. Here, we show that the plant symbiotic fungus Metarhizium robertsii degrades methylmercury and reduces divalent mercury, decreasing mercury accumulation in plants and greatly increasing their growth in contaminated soils. M. robertsii does this by demethylating methylmercury via a methylmercury demethylase (MMD) and using a mercury ion reductase (MIR) to reduce divalent mercury to volatile elemental mercury. M. robertsii can also remove methylmercury and divalent mercury from fresh and sea water even in the absence of added nutrients. Overexpression of MMD and MIR significantly improved the ability of M. robertsii to bioremediate soil and water contaminated with methylmercury and divalent mercury. MIR homologs, and thereby divalent mercury tolerance, are widespread in fungi. In contrast, MMD homologs were patchily distributed among the few plant associates and soil fungi that were also able to demethylate methylmercury. Phylogenetic analysis suggests that fungi could have acquired methylmercury demethylase genes from bacteria via two independent horizontal gene transfer events. Heterologous expression of MMD in fungi that lack MMD homologs enabled them to demethylate methylmercury. Our work reveals the mechanisms underlying mercury tolerance in fungi, and may provide a cheap and environmentally friendly means of cleaning up mercury pollution.

Mechanical and chemical itch regulated by neuropeptide Y-Y1 signaling.

Itch is a somatosensory sensation to remove potential harmful stimulation with a scratching desire, which could be divided into mechanical and chemical itch according to diverse stimuli, such as wool fiber and insect biting. It has been reported that neuropeptide Y (NPY) neurons, a population of spinal inhibitory interneurons, could gate the transmission of mechanical itch, with no effect on chemical itch. In our study, we verified that chemogenetic activation of NPY neurons could inhibit the mechanical itch as well as the chemical itch, which also attenuated the alloknesis phenomenon in the chronic dry skin model. Afterwards, intrathecal administration of NPY1R agonist, [Leu31, Pro34]-NPY (LP-NPY), showed the similar inhibition effect on mechanical itch, chemical itch and alloknesis as chemo-activation of NPY neurons. Whereas, intrathecal administration of NPY1R antagonist BIBO 3304 enhanced mechanical itch and reversed the alloknesis phenomenon inhibited by LP-NPY treatment. Moreover, selectively knocking down NPY1R by intrathecal injection of Npy1r siRNA enhanced mechanical and chemical itch behavior as well. These results indicate that NPY neurons in spinal cord regulate mechanical and chemical itch, and alloknesis in dry skin model through NPY1 receptors.

Agave REVEILLE1 regulates the onset and release of seasonal dormancy in Populus.

Deciduous woody plants like poplar (Populus spp.) have seasonal bud dormancy. It has been challenging to simultaneously delay the onset of bud dormancy in the fall and advance bud break in the spring, as bud dormancy, and bud break were thought to be controlled by different genetic factors. Here, we demonstrate that heterologous expression of the REVEILLE1 gene (named AaRVE1) from Agave (Agave americana) not only delays the onset of bud dormancy but also accelerates bud break in poplar in field trials. AaRVE1 heterologous expression increases poplar biomass yield by 166% in the greenhouse. Furthermore, we reveal that heterologous expression of AaRVE1 increases cytokinin contents, represses multiple dormancy-related genes, and up-regulates bud break-related genes, and that AaRVE1 functions as a transcriptional repressor and regulates the activity of the DORMANCY-ASSOCIATED PROTEIN 1 (DRM1) promoter. Our findings demonstrate that AaRVE1 appears to function as a regulator of bud dormancy and bud break, which has important implications for extending the growing season of deciduous trees in frost-free temperate and subtropical regions to increase crop yield.

Long Noncoding RNA PSMB8-AS1 Mediates the Tobacco-Carcinogen-Induced Transformation of a Human Bronchial Epithelial Cell Line by Regulating Cell Cycle.

Lung cancer is the main cause of cancer deaths around the world. Nitrosamine 4-(methyl nitrosamine)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific carcinogen of lung cancer. Abundant evidence implicates long noncoding RNAs (lncRNAs) in tumorigenesis. Yet, the effects and mechanisms of lncRNAs in NNK-induced carcinogenesis are still unclear. In this study, we discovered that NNK-induced transformed Beas-2B cells (Beas-2B-NNK) showed increased cell migration and proliferation while decreasing rates of apoptosis. RNA sequencing and differentially expressed lncRNAs analyses showed that lncRNA PSMB8-AS1 was obviously upregulated. Interestingly, silencing the lncRNA PSMB8-AS1 in Beas-2B-NNK cells reduced cell proliferation and migration and produced cell cycle arrest in the G2/M phase along with a decrease in CDK1 expression. Conclusively, our results demonstrate that lncRNA PSMB8-AS1 could promote the malignant characteristics of Beas-2B-NNK cells by regulating CDK1 and affecting the cell cycle, suggesting that it may supply a new prospective epigenetic mechanism for lung cancer.

Change analysis for intermediate disease markers in nutritional epidemiology: a causal inference perspective.

BACKGROUND: Several approaches are commonly used to estimate the effect of diet on changes of various intermediate disease markers in prospective studies, including "change-score analysis", "concurrent change-change analysis" and "lagged change-change analysis". Although empirical evidence suggests that concurrent change-change analysis is most robust, consistent, and biologically plausible, in-depth dissection and comparison of these approaches from a causal inference perspective is lacking. We intend to explicitly elucidate and compare the underlying causal model, causal estimand and interpretation of these approaches, intuitively illustrate it with directed acyclic graph (DAG), and further clarify strengths and limitations of the recommended concurrent change-change analysis through simulations. METHODS: Causal model and DAG are deployed to clarify the causal estimand and interpretation of each approach theoretically. Monte Carlo simulation is used to explore the performance of distinct approaches under different extents of time-invariant heterogeneity and the performance of concurrent change-change analysis when its causal identification assumptions are violated. RESULTS: Concurrent change-change analysis targets the contemporaneous effect of exposure on outcome (measured at the same survey wave), which is more relevant and plausible in studying the associations of diet and intermediate biomarkers in prospective studies, while change-score analysis and lagged change-change analysis target the effect of exposure on outcome after one-period timespan (typically several years). Concurrent change-change analysis always yields unbiased estimates even with severe unobserved time-invariant confounding, while the other two approaches are always biased even without time-invariant heterogeneity. However, concurrent change-change analysis produces almost linearly increasing estimation bias with violation of its causal identification assumptions becoming more serious. CONCLUSIONS: Concurrent change-change analysis might be the most superior method in studying the diet and intermediate biomarkers in prospective studies, which targets the most plausible estimand and circumvents the bias from unobserved individual heterogeneity. Importantly, careful examination of the vital identification assumptions behind it should be underscored before applying this promising method.

Rapid screening and evaluation of natural antioxidants from leaf, stem, and root of Artemisia argyi by online liquid microextraction combined with HPLC-based antioxidant assay system coupled with calibration quantitative analysis.

To reveal the utilization value of leaf, stem, and root of Artemisia argyi, a rapid online liquid microextraction combined with a high-performance liquid chromatography coupled with 2,2-nitrogen-di (3-ethyl-benzothiazole-6-sulfonic acid) diammonium salt antioxidant assay system was established for analysis of antioxidants in the leaf, stem, and root of A. argyi, and a calibration quantitative method of antioxidant activity with equivalent chlorogenic acid was proposed. Thirty-three positive peaks were identified; among them, 12 compounds were found that possess good antioxidant activity including eleven organic acids (components 2-4, 8, 11-14, 17, 19, and 21) and one flavonoids (component 22). The proposed calibration quantitative method avoided the influence of content of compound and compared the extent of radical scavenging capacity of five antioxidant compounds, which were ranked as follow: 3,5-dicaffeoylquinic acid > 3,4-dicaffeoylquinic acid ≈ 4,5-dicaffeoylquinic acid > 1,4-dicaffeoylquinic acid > chlorogenic acid. In conclusion, this study provided composition and biological potential for the future development of the leaf, stem, and root of A. argyi. It is believed that the online liquid microextraction combined with high-performance liquid chromatography based antioxidant assay system can be widely used for the rapid screening of natural antioxidant components in the different parts of natural products.

Scramblases and virus infection.

The asymmetric distribution of lipids, maintained by flippases/floppases and scramblases, plays a pivotal role in various physiologic processes. Scramblases are proteins that move phospholipids between the leaflets of the lipid bilayer of the cellular membrane in an energy-independent manner. Recent studies have indicated that viral infection is closely related to cellular lipid distribution. The level and distribution of phosphatidylserine (PtdSer) in cells have been demonstrated to be critical regulators of viral infections. Previous studies have supported that the infection of human immunodeficiency virus (HIV), Zika virus, Ebola virus (EBOV), influenza virus, and dengue fever virus require the externalization of phospholipids mediated by scramblases, which are also involved in the pathogenicity of the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, we review the relationship of scramblases with viruses and the potential viral effector proteins that might utilize host scramblases.

Single-nucleus transcriptome inventory of giant panda reveals cellular basis for fitness optimization under low metabolism.

BACKGROUND: Energy homeostasis is essential for the adaptation of animals to their environment and some wild animals keep low metabolism adaptive to their low-nutrient dietary supply. Giant panda is such a typical low-metabolic mammal exhibiting species specialization of extremely low daily energy expenditure. It has low levels of basal metabolic rate, thyroid hormone, and physical activities, whereas the cellular bases of its low metabolic adaptation remain rarely explored. RESULTS: In this study, we generate a single-nucleus transcriptome atlas of 21 organs/tissues from a female giant panda. We focused on the central metabolic organ (liver) and dissected cellular metabolic status by cross-species comparison. Adaptive expression mode (i.e., AMPK related) was prominently displayed in the hepatocyte of giant panda. In the highest energy-consuming organ, the heart, we found a possibly optimized utilization of fatty acid. Detailed cell subtype annotation of endothelial cells showed the uterine-specific deficiency of blood vascular subclasses, indicating a potential adaptation for a low reproductive energy expenditure. CONCLUSIONS: Our findings shed light on the possible cellular basis and transcriptomic regulatory clues for the low metabolism in giant pandas and helped to understand physiological adaptation response to nutrient stress.

Anti-inflammatory and analgesic properties of Polyphyllin VI revealed by network pharmacology and RNA sequencing.

Inflammatory pain, sustained by a complex network of inflammatory mediators, is a severe and persistent illness affecting many of the general population. We explore possible anti-inflammatory pathways of Polyphyllin VI (PPVI) based on our prior study, which showed that PPVI reduces inflammation in mice to reduce pain. Network pharmacology and RNA-Seq identified the contribution of the MAPK signaling pathway to inflammatory pain. In the LPS/ATP-induced RAW264.7 cell model, pretreatment with PPVI for 1 h inhibited the release of IL-6 and IL-8, down-regulated expression of the P2X7 receptor(P2X7R), and decreased phosphorylation of p38 and ERK1/2 components of the MAPK pathway. Moreover, PPVI decreased expression of IL-6 and IL-8 was observed in the serum of the inflammatory pain mice model and reduced phosphorylation of p38 and ERK1/2 in the dorsal root ganglia while the reductions of expression of IL-6 and phosphorylation of ERK1/2 were not observed after the pre-treatment with A740003 (an antagonist of the P2X7R). These results suggest that PPVI may inhibit the release of IL-8 by regulating P2X7R to reduce the phosphorylation of p38. However, the modulation of PPVI on the release of IL-6 and phosphorylation of ERK1/2 may mediated by other P2X7R-independent signals.

Association of major dietary patterns and different obesity phenotypes in Southwest China: the China Multi-Ethnic Cohort (CMEC) Study.

PURPOSE: Dietary behavior is an important part of lifestyle interventions for obesity and its cardiovascular comorbidities. However, little is known about associations between dietary patterns and obesity phenotypes in Southwest China, a region with unique dietary patterns and significant heterogeneity in obesity. METHODS: Data from the baseline survey of the China Multi-Ethnic Cohort in Southwest China were analyzed (n = 64,448). Dietary intakes during the past year were measured with the semi-quantitative Food Frequency Questionnaire (s-FFQ). Principal component factor analysis (PCFA) was used to identify dietary patterns. Multinomial logistic regressions were used to examine the associations between dietary patterns and obesity phenotypes and stratified analyses were performed to assess whether the associations differed across demographic variables. RESULTS: Three dietary patterns were identified and then named according to their apparent regional gathering characteristics: the Sichuan Basin dietary pattern (characterized by high intakes of various foods), the Yunnan-Guizhou Plateau dietary pattern (characterized by agricultural lifestyles), and the Qinghai-Tibet Plateau dietary pattern (characterized by animal husbandry lifestyles), respectively. Higher adherence to the Sichuan Basin dietary pattern was positively associated with metabolically healthy overweight/obesity (MHO, OR 1.13, 95% CI 1.05-1.21) but negatively associated with metabolically unhealthy normal weight (MUNW, OR 0.78, 95% CI 0.65-0.95). Higher adherence to the other two dietary patterns was positively associated with MHO and metabolically unhealthy overweight/obesity (MUO). Besides, differences in socioeconomic status also affected the relationship between dietary patterns and obesity phenotypes. CONCLUSIONS: Adherence to the more diverse Sichuan basin dietary pattern performed a mixed picture, while the other two may increase the risk of obesity phenotypes, which indicates nutritional interventions are urgently needed.

Associations between major dietary patterns and blood pressure among Southwest Chinese: A cross-sectional analysis based on the China Multi-Ethnic Cohort (CMEC) study.

BACKGROUND AND AIMS: In the less developed multi-ethnic regions (LEMRs) of Southwest China, the associations between dietary patterns and blood pressure (BP) values remain unclear. We aimed to investigate such associations and related effect modifiers. METHODS AND RESULTS: This study included 81,433 participants from the China Multi-Ethnic Cohort Study. Dietary intakes during the year before the interview were measured with the Quantitative Food Frequency Questionnaire. Three major dietary patterns that were highly in line with geographical and ethnic distributions of the study population, i.e., "Sichuan Basin," "Yunnan-Guizhou Plateau," and "Qinghai-Tibet Plateau," were derived using principal component factor analysis. The multilinear regression model combined with inverse probability of exposure weighting was used to estimate the associations between dietary patterns and BP values. Comparing the highest with the lowest quintiles, the Sichuan Basin dietary pattern (characterized by urban lifestyles) was associated with 2.67 mmHg lower systolic blood pressure (SBP) (95% CI: -3.07 to -2.27) and 0.89 mmHg lower diastolic blood pressure (95% CI: -1.12 to -0.65). In contrast, both the Yunnan-Guizhou Plateau (characterized by agricultural lifestyles) and the Qinghai-Tibet Plateau dietary patterns (characterized by nomadic lifestyles) showed positive associations with BP. In the stratified analysis, the associations between dietary patterns and SBP were significantly stronger in women than in men for all three kinds of dietary patterns. CONCLUSION: Both major dietary patterns and their associations with BP showed a substantial disparity in LEMRs of Southwest China. Dietary patterns in regions of higher socioeconomic status are more conducive to reducing the rising of BP, especially for women and urban residents, which might provide insights into the BP control in LEMRs of Southwest China.

Matrix Metalloproteinase-7 Associated with Congestive Heart Failure in Peritoneal Dialysis Patients: A Prospective Cohort Study.

Background: Matrix metalloproteinase-7 (MMP7) is markedly expressed in patients with chronic kidney disease; its expression in dialysate and role in patients undergoing peritoneal dialysis (PD) have not been well established. Methods: Participants undergoing PD from June 1st, 2015, to June 30th, 2020, were involved and were followed up every 3 months for the first year and every 6 months thereafter until death, PD withdrawal, or the end of the study. Data at each follow-up point were collected and analyzed for the association with congestive heart failure (CHF), PD withdrawal, and combined endpoint. Results: A total of 283 participants were included in this study. During a median follow-up of 21 months, 20 (7%) participants died, 93 (33%) withdrew from PD, and 105 (37%) developed CHF. A significantly increased level of serum and dialysate MMP7 was observed at baseline. Dialysate MMP7 presented a good linearity with serum MMP7. Baseline serum and dialysate MMP7 levels were associated with CHF in multivariable Cox proportional hazards regression models. After categorization, participants with high baseline MMP7 levels had a higher incidence of CHF (42%), and the hazard ratios (95% confidence intervals) were 1.595 (1.023-2.488). Interestingly, participants with higher serum MMP7 levels were trended to use dialysate with higher glucose concentration. However, the ultrafiltration volumes were not significantly increased. Higher MMP7 levels were also positively associated with PD withdrawal and combined endpoint. Conclusions: The expression of MMP7 in serum and dialysate was markedly increased and was tightly associated with the risk of CHF in PD patients. This finding suggests that the measurement of MMP7 may inform strategies for managing CHF at an earlier stage.

A noncanonical role of NOD-like receptor NLRP14 in PGCLC differentiation and spermatogenesis.

NOD-like receptors (NLRs) are traditionally recognized as major inflammasome components. The role of NLRs in germ cell differentiation and reproduction is not known. Here, we identified the gonad-specific Nlrp14 as a pivotal regulator in primordial germ cell-like cell (PGCLC) differentiation in vitro. Physiologically, knock out of Nlrp14 resulted in reproductive failure in both female and male mice. In adult male mice, Nlrp14 knockout (KO) inhibited differentiation of spermatogonial stem cells (SSCs) and meiosis, resulting in trapped SSCs in early stages, severe oligozoospermia, and sperm abnormality. Mechanistically, NLRP14 promoted spermatogenesis by recruiting a chaperone cofactor, BAG2, to bind with HSPA2 and form the NLRP14-HSPA2-BAG2 complex, which strongly inhibited ChIP-mediated HSPA2 polyubiquitination and promoted its nuclear translocation. Finally, loss of HSPA2 protection and BAG2 recruitment by NLRP14 was confirmed in a human nonsense germline variant associated with male sterility. Together, our data highlight a unique proteasome-mediated, noncanonical function of NLRP14 in PGCLC differentiation and spermatogenesis, providing mechanistic insights of gonad-specific NLRs in mammalian germline development.

Cryo-EM structure of C9ORF72-SMCR8-WDR41 reveals the role as a GAP for Rab8a and Rab11a.

A massive intronic hexanucleotide repeat (GGGGCC) expansion in C9ORF72 is a genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recently, C9ORF72, together with SMCR8 and WDR41, has been shown to regulate autophagy and function as Rab GEF. However, the precise function of C9ORF72 remains unclear. Here, we report the cryogenic electron microscopy (cryo-EM) structure of the human C9ORF72-SMCR8-WDR41 complex at a resolution of 3.2 Å. The structure reveals the dimeric assembly of a heterotrimer of C9ORF72-SMCR8-WDR41. Notably, the C-terminal tail of C9ORF72 and the DENN domain of SMCR8 play critical roles in the dimerization of the two protomers of the C9ORF72-SMCR8-WDR41 complex. In the protomer, C9ORF72 and WDR41 are joined by SMCR8 without direct interaction. WDR41 binds to the DENN domain of SMCR8 by the C-terminal helix. Interestingly, the prominent structural feature of C9ORF72-SMCR8 resembles that of the FLNC-FNIP2 complex, the GTPase activating protein (GAP) of RagC/D. Structural comparison and sequence alignment revealed that Arg147 of SMCR8 is conserved and corresponds to the arginine finger of FLCN, and biochemical analysis indicated that the Arg147 of SMCR8 is critical to the stimulatory effect of the C9ORF72-SMCR8 complex on Rab8a and Rab11a. Our study not only illustrates the basis of C9ORF72-SMCR8-WDR41 complex assembly but also reveals the GAP activity of the C9ORF72-SMCR8 complex.

Separated kin: location of multiple children and mental health trajectories of older parents in rural China.

OBJECTIVE: This study examines the longitudinal association between the location of multiple children and depressive symptoms of older parents in rural China, where massive rural-to-urban migration has profoundly altered the family life of the aging population. METHODS: Using seven waves of panel data from the Longitudinal Study of Older Adults in Anhui Province (2001-2018, N = 8,253) and multilevel growth curve models, this study compares mental health trajectories of old parents across different compositions of local and migrant children over an 18-year time period. RESULTS: The results show that older parents with a greater share of adult children who had migrated away not only scored worse mental health on average, but also experienced a more rapid increase in depressive symptoms across ages, after accounting for other covariates. Further, older adults who had their most children migrated away for a longer period of time suffered from the steeper rate of increase in depressive symptoms as they got older. CONCLUSIONS: We suggest that it is not the geographic locality of a single child but the location of multiple children that matters for parental mental health in later life.

Pterostilbene could alleviate diabetic cognitive impairment by suppressing TLR4/NF-кB pathway through microbiota-gut-brain axis.

Diabetic cognitive impairment (DCI) is a serious neurodegenerative disorder caused by diabetes, with chronic inflammation being a crucial factor in its pathogenesis. Pterostilbene is a well-known natural stilbene derivative that has excellent anti-inflammatory activity, suggesting its potential medicinal advantages for treating DCI. Therefore, this study is to explore the beneficial effects of pterostilbene for improving cognitive dysfunction in DCI mice. A diabetic model was induced by a high-fat diet plus streptozotocin (40 mg·kg-1 ) for consecutive 5 days. After the animals were confirmed to be in a diabetic state, they were treated with pterostilbene (20 or 60 mg·kg-1 , i.g.) for 10 weeks. Pharmacological evaluation showed pterostilbene could ameliorate cognitive dysfunction, regulate glycolipid metabolism disorders, improve neuronal damage, and reduce the accumulation of ß-amyloid in DCI mice. Pterostilbene alleviated neuroinflammation by suppressing oxidative stress and carbonyl stress damage, astrocyte and microglia activation, and dopaminergic neuronal loss. Further investigations showed that pterostilbene reduced the level of lipopolysaccharide, modulated colon and brain TLR4/NF-κB signaling pathways, and decreased the release of inflammatory factors, which in turn inhibited intestinal inflammation and neuroinflammation. Furthermore, pterostilbene could also improve the homeostasis of intestinal microbiota, increase the levels of short-chain fatty acids and their receptors, and suppress the loss of intestinal tight junction proteins. In addition, the results of plasma non-targeted metabolomics revealed that pterostilbene could modulate differential metabolites and metabolic pathways associated with inflammation, thereby suppressing systemic inflammation in DCI mice. Collectively, our study found for the first time that pterostilbene could alleviate diabetic cognitive dysfunction by inhibiting the TLR4/NF-κB pathway through the microbiota-gut-brain axis, which may be one of the potential mechanisms for its neuroprotective effects.

Combination of UHPLC-Q Exactive-Orbitrap MS, Bioinformatics and Molecular Docking to Reveal the Mechanism of Huan-Lian-Jie-Du Decoction in the Treatment of Diabetic Encephalopathy.

Diabetic encephalopathy (DE) is a serious complication of diabetes, which affects patients' quality of life. We aimed to explore HLJDD in the treatment of DE by LC/MS and bioinformatics. UPLC-Q Exactive-Orbitrap MS was employed to clarify the compounds. The modules and hub targets of DE were gained from WGCNA. Subsequently, an Herb-Compound-Target network was constructed and enrichment analysis was used. In addition, a protein-protein interaction (PPI) network was constructed and molecular docking was used to verify the above analysis. As result, 138 compounds and 10 prototypes in brain were identified. In network pharmacology, 8 modules and 5692 hub targets were obtained from WGCNA. An Herb-Compound-Target network was constructed by 4 herbs, 10 compounds and 56 targets. The enrichment analysis showed that the treatment of DE with HLJDD involve oxidative stress and neuroprotection. Beside, SRC, JUN, STAT3, MAPK1 and PIK3R1 were identified and as hub targets of HLJDD in treating DE. Moreover, Molecular docking showed that five hub targets had strong affinity with the corresponding alkaloids. Therefore, we explored the underlying mechanisms of HLJDD in the treatment of DE and to provide the theoretical and scientific basis for subsequent experimental studies and clinical applications.

[Comparison of Functional Status Between Diabetic Patients With and Without Nephropathy Based on the International Classification of Functioning,Disability and Health Rehabilitation Set].

Objective To compare the functional status of diabetic patients with and without nephropathy and identify the items that diabetic patients with nephropathy are more likely to develop dysfunction than diabetic patients without nephropathy based on the international classification of functioning,disability and health rehabilitation set(ICF-RS).Methods A cross-sectional study was conducted.A total of 320 diabetic patients hospitalized in Guangdong Provincial Hospital of Chinese Medicine from August 2021 to February 2022 were selected and assigned into a group with nephropathy and a group without nephropathy.The general characteristics,clinical examination,and laboratory findings were compared by the t test,rank sum test,and Chi-squared test.The functional status of the patients was compared between the two groups by the t test based on the ICF-RS.Logistic regression was employed to control interferential factors between the two groups and identify the association between nephropathy and ICF-RS problematic items among diabetic patients.Results The diabetic patients with nephropathy had more problematic items in ICF-RS(P<0.001),the body function dimension(P=0.003),the activity dimension(P<0.001),and the participation dimension(P<0.001)than those without nephropathy.Moreover,the diabetic patients with nephropathy experienced severer problems in 5 body function items(energy and drive functions,sleep functions,sexual functions,exercise tolerance functions,and muscle power functions),10 activity items(transferring oneself,walking,moving around using equipment,moving around,washing oneself,caring for body parts,toileting,dressing,doing housework,and looking after one's health),and 4 participation items(using transportation,assisting others,basic interpersonal interactions,and recreation and leisure)(all P<0.05).The Logistic regression results showed that compared with the diabetic patients without nephropathy,the diabetic patients with nephropathy were more likely to develop problems in energy and drive functions(aOR=4.35,95%CI=1.28-14.79,P=0.019),emotional functions(aOR=1.88,95%CI=1.06-3.34,P=0.031),sexual functions(aOR=3.39,95%CI=1.82-6.34,P<0.001),moving around(aOR=3.11,95%CI=1.76-5.52,P<0.001),doing housework(aOR=17.48,95%CI=3.57-85.60,P<0.001),looking after one's health(aOR=1.97,95%CI=1.13-3.43,P=0.017),using transportation(aOR=2.59,95%CI=1.38-4.88,P=0.003),and recreation and leisure(aOR=2.52,95%CI=1.46-4.35,P<0.001).Conclusion Compared with the diabetic patients without nephropathy,the patients with nephropathy suffer more ICF-RS problematic items and are more likely to develop dysfunction in certain items in all the three dimensions.

[Role of lymphatic system in coronary heart disease based on theory of combined phlegm and stasis].

According to the traditional Chinese medicine(TCM) theory, coronary heart disease(CHD) is mainly caused by heart vessel obstruction due to Qi stagnation, blood stasis, and phlegm turbidity. Chest impediment with combined phlegm and stasis is a common syndrome of CHD, with the manifestations of chest tightness, chest pain, and asthma. Lymphatic system is one of the important immune systems in the human body and has a close relationship with the Qi and blood movement in TCM. The dysfunction of the lymphatic system may lead to metabolism disorders, the generation of dampness pathogen which turns into sticky and difficult-to-dissolve phlegm turbidity. Moreover, it can affect blood circulation and coagulation, causing slow blood flow, increased blood viscosity, and microcirculation disorders. Alterations in lymphatic hydrodynamics may affect the interaction between blood circulation and the lymphatic system. A variety of small molecule drugs and TCM can treat cardiovascular diseases by targeting the lymphatic system. This review discusses the role of the lymphatic system in CHD based on the theory of combined phlegm and stasis, involving the influences of mechanical factors on lymphatic function and the effects and pharmacological mechanisms of TCM and chemicals that target lymphocyte function and lymphatic circulation. By expounding the development process of combined phlegm and stasis in CHD from the lymphatic system, this paper aims to provide new ideas for deciphering pharmacological mechanisms of TCM for resolving phlegm and stasis.