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Jin Jin Lu,1,2 Wei Min Yang,1 Fan Li,1 Wei Zhu,1 Zhong Chen1 1Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China; 2Department of Urology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Fan LiDepartment of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jie Fang Avenue, Wuhan 430030, People’s Republic of ChinaTel +86 027 83665207Fax +86 027 83663640Email fanli117@hotmail.comObjective: To investigate differential microRNAs’ expression in heterogeneous bladder cancer cells, as well as to investigate the mechanism of changes in invasive and proliferative capacity induced by tunneling nanotubes (TNTs) mediated transport of microRNA between bladder cancer cells of varying histological grade.Materials and methods: Differences in microRNA expression between bladder cancer cells of different grade were identified from a literature review. The identified heterogeneous microRNAs were analyzed by qPCR in T24 (high grade) and RT4 (low grade) bladder cancer cells. Scanning electron microscopy (SEM) and laser confocal fluorescence microscopy (LCM) were used to observe tunneling nanotubes (TNTs) between RT4 and T24 cells. Differentially expressed microRNA was labeled and traced by Fluorescent In Situ Hybridization (FISH) following co-culture of T24 and RT4 cells. MicroRNA mimic and inhibition technologies were applied to investigate how TNTs-mediated intercellular transport of microRNA affects the invasive and proliferative behavior of bladder cancer cells.Results: MicroRNA-155 (miR-155) levels were highly expressed in T24 cells, whereas the same was not true in RT4 cells. MiR-155 was confirmed to be a crucial factor sustaining T24 bladder cancer cell proliferation, migration and cell cycle progression by CCK8, Matrigel test and cell cycle analysis, respectively. After T24 and RT4 co-culture, TNTs were assessed by SEM and LCM between T24 and RT4 cells. In addition, we observed TNTs mediated transport of miR-155 from T24 cells to RT4 cells, which thereby acquired a higher proliferative rate, an increased frequency of cells in the S phase, and increased invasive ability in Matrigel test. At the same time, Deptor, the target protein of miR-155 in RT4 cells, was downregulated, followed by mTOR/4EBP1/p70S6K- eIF4e/S6RP signaling activation.Conclusion: MiR-155 was differentially expressed between RT4 and T24 bladder cancer cells. Intercellular transport of miR-155 via TNTs can promote bladder cancer cell reprogramming by Deptor-mTOR signal pathway activation.Keywords: tunneling nanotubes, microRNA, bladder cancer, cell invasion, cell proliferation

AIM OF THE STUDY: Cynomorium songaricum Ruprecht has been used in traditional Korean medicine to treat male infertility, including sexual dysfunction, by improving kidney function. Glial cell-derived neurotrophic factor (GDNF) produced by Sertoli cells induces the proliferation of undifferentiated spermatogonia. We investigated the effects of Cynomorium songaricum on sperm parameters and GDNF expression in rat testes. MATERIALS AND METHODS: Sperm analysis, RT-PCR, and Western blotting assays were performed after administration of CS to 8-week-old male Wistar rats for 56 consecutive days (1.0 g/kg/day, p.o.), the period of sperm formation in the rat. RESULTS AND CONCLUSIONS: The CS-treated animals showed significant increases in epididymal sperm count and absolute testes weights compared to the control group. CS also increased the expression of GDNF at both the mRNA and protein levels. These results suggest that CS may improve male fertility by enhancing spermatogenesis and GDNF expression. [ABSTRACT FROM AUTHOR]

Background: Major depressive disorder (MDD) and schizophrenia (SCH) are common and severe mental disorders that are mainly diagnosed depending on the subjective identification by psychiatrists. Finding potential objective biomarkers that can distinguish these two diseases is still meaningful., Methods: In the present study, we investigate the differences in plasma inflammatory cytokines and short-chain fatty acids (SCFAs) among patients with MDD (n = 24) and SCH (n = 24), and gender- and age-matched healthy controls (HC, n = 27) and identify potential plasma biomarkers., Results: We found that the concentrations of pro-inflammatory cytokines were increased, whereas the anti-inflammatory cytokines were decreased in both MDD and SCH. Meanwhile, except for an increase in 4-Methylvaleric acid, other SCFAs with statistical differences were reduced in both MDD and SCH. Moreover, potential biomarker panels were developed that can effectively discriminate MDD from HC (AUC = 0.997), SCH from HC (AUC = 0.999), and from each other (MDD from SCH, AUC = 0.983)., Conclusions: These data suggest that alterations in plasma cytokines and SCFAs might be one of the potential features for distinguishing MDD and SCH., Trial Registration: Chinese Clinical Trial Registry: ChiCTR2100051243, registration date: 2021/09/16., Competing Interests: Declarations. Ethics approval and consent to participate: The research was registered in the Chinese Clinical Trial Registry (number: ChiCTR2100051243, 16th September 2021) and its protocol was approved by the China Registered Clinical Trial Ethics Review Committee (number: ChiECRCT20210335). All subjects voluntarily participated in this research and provided written informed consent. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests. Role of the funding source: We thank our financial sponsors for providing the fees for the analysis of plasma fatty acids and inflammatory cytokines for this study and the page charges for the publication of the article., (© 2024. The Author(s).)

Altered hepatic glucose fluxes are critical during the pathogenesis of type 2 diabetes. G protein-coupled receptors represent important regulators of hepatic glucose production. Recent studies have shown that hepatocytes express GPCRs that can couple to G 12/13 , a subfamily of heterotrimeric G proteins that has attracted relatively little attention in the past. Here we show, by analyzing several mutant mouse strains, that selective activation of hepatocyte G 12/13 signaling leads to pronounced hyperglycemia and that this effect involves the stimulation of the ROCK1-JNK signaling cascade. Using both mouse and human hepatocytes, we also show that activation of endogenous sphingosine-1-phosphate type 1 receptors strongly promotes glucose release in a G 12/13 -dependent fashion. Studies with human liver samples indicate that hepatic GNA12 (encoding Gα 12 ) expression levels positively correlate with indices of insulin resistance and impaired glucose homeostasis, consistent with a potential pathophysiological role of enhanced hepatic G 12/13 signaling., Competing Interests: Competing interests The authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Bilateral repetitive transcranial magnetic stimulation (B-rTMS) has been largely used in the treatment of major depressive disorder (MDD). Nonetheless, information on the acute treatment by B-rTMS combined with antidepressants (ADs) on the plasma fatty acids in MDD is limited. The present study focused on depressive symptoms; Plasma was obtained from 27 adult patients with MDD at baselinephase (MDD), after 2 weeks of treatment (MDD-2w), and 27 healthy controls (HC). Meanwhile, we evaluated the composition of short-chain fatty acids (SCFAs) and medium-and long-chain fatty acids (MLCFAs) in the plasma. Consequently, the levels of Isobutyric acid, Caproic acid, and Propionic acid were low both in the MDD and MDD-2w groups and negatively correlated with the scores of HAMD and HAMA. Besides, minimal changes were observed between the MDD and HC groups, whereas significant MLCFA levels were high in the MDD-2w group. Moreover, we developed combined panels that could effectively differentiate MDD from HCs (AUC=0.99), MDD-2w from HC (AUC=0.983), and MDD from MDD-2w (AUC=0.852). These findings may provide a reference for the use of B-rTMS combined with ADs against the acute phase of depressive episodes and shed light on the relationship between plasma FAs and MDD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Essential oils from herbs, including those from Asarum sieboldii Miq., are readily absorbed through mucous membranes, explaining their widespread use in inhalation formulations. Asarum sieboldii Miq. has a long history of traditional use for various medicinal purposes, attributed to its anti-inflammatory, antiallergic, and antioxidant properties. Despite research on Asarum sieboldii Miq. for allergic inflammation in respiratory diseases, detailed mechanistic studies are still lacking., Aim of the Study: We utilized bioinformatics and network pharmacology to identify the effectiveness of Asarum sieboldii Miq. in treating allergic rhinitis (AR). Our aim is to elucidate the potential therapeutic effects of essential oil derived from Asarum sieboldii Miq. (ASO), which is recognized for its diverse pharmacological properties, on AR., Materials and Methods: Common genes associated with the active compounds of ASO and AR were utilized to construct a related network and predict their mode of action. AR was induced in BALB/c mice by exposing them to ovalbumin (OVA) and particulate matter 10 (PM 10 ; airborne particles <10 μm). With induction, aerosolized ASO (0.0002% and 0.02%) were administered via nebulizer for 5 min per day, three times a week for 7 weeks. Mice were examined for histopathological changes in the nasal tissue, nasal epithelial inflammation, the production of allergen-specific cytokine response in vitro and in vivo., Results: The common genes of ASO and AR were predicted to include 'Tight junction', 'Apoptosis', and 'TGF-beta signaling', which are the main pathways of pathogenesis in AR. Consistent with network prediction, nebulized ASO treatment effectively improved the expression of tight junction-related factors, zonula occludens-1, claudin-1, occludin and junction adhesion molecule A, in OVA + PM 10 induced mice. Additionally, it reduced hyperplasia of nasal epithelial thickness, goblet cell counts, and inflammatory cell infiltration (eosinophils, neutrophils, macrophages, and lymphocytes) in nasal lavage fluid, while also alleviating allergic symptoms such as sneezing, rubbing, and serum IgE level when compared to the AR-induced group. The levels of mRNA and protein expression related to tight junctions were restored to normal levels by ASO, as confirmed in immunofluorescence analysis in nasal epithelial cells RPMI2650. Furthermore, treatment of ASO on PM 10 -treated nasal epithelial cells significantly reduced ROS production, recovered mitochondria membrane potential, and inhibition of the production of proinflammatory cytokines (TNF-α, IL-4, and IL-13) and inflammatory mediators linked to the MAPK/NF-κB signaling pathways., Conclusion: Intranasal nebulization of ASO improves TJs and alleviates allergic nasal inflammation in AR. It supports the potential pharmaceutical application of ASO treatment for AR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Aims/Background To investigate the application value of a machine learning model in predicting mild depression associated with migraine without aura (MwoA). Methods 178 patients with MwoA admitted to the Department of Neurology of the First Affiliated Hospital of Anhui University of Traditional Chinese Medicine from March 2022 to March 2024 were selected as subjects. According to their inpatient medical records, 38 patients were selected as the validation group by random number method, and the remaining 140 patients were included in the modelling group. According to the diagnosis results, the patients in the modelling group and validation group were further divided into a MwoA with mild depression group and a MwoA without mild depression group. Results The results of univariate analysis and Multivariate logistic regression analysis showed that gender, course of disease, attack frequency, headache duration, Migraine Disability Assessment Questionnaire (MIDAS), and Headache Impact Test-6 (HIT-6) score were independent influencing factors for mild depression in MwoA patients ( p < 0.05). The receiver operating characteristic (ROC) analysis results showed that the area under the curve of the established prediction model for MwoA patients with mild depression in the modelling group and the validation group was 0.982 and 0.901, respectively, the sensitivity was 0.978 and 0.857, respectively, and the specificity was 0.892 and 0.929, respectively. Conclusion Gender, course of disease, seizure frequency, headache duration, MIDAS score, and HIT-6 score are independent influencing factors for mild depression in patients with MwoA. The model displays good performance for the prediction of mild depression in patients with MwoA.

Background and Aims: Many children with Wilson's disease are complicated with dyslipidemia. The aim of this study was to investigate the risk factors for the development of fatty liver disease (FLD) in children with Wilson's disease., Methods: We evaluated sex, age, weight, the disease course, treatment course, clinical classification, alanine transaminase (ALT), aspartate transaminase, γ-glutamyl transpeptidase, total biliary acid, triglyceride, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, homocysteine, uric acid, fibrinogen (FBG), creatinine, procollagen III N-terminal propeptide, laminin, hyaluronic acid, type IV collagen, and performed receiver operating characteristic curve analysis to investigate the forecast value of individual biochemical predictors and combined predictive indicators to evaluate FLD in Wilson's disease., Results: The multivariate logistic regression analysis revealed that ALT [odds ratio (OR), 1.011; 95% confidence interval (CI), 1.004-1.02; P  = 0.006], uric acid (OR, 1.01; 95% CI, 1.002-1.018; P  = 0.017), FBG (OR, 3.668; 95% CI, 1.145-13.71; P  = 0.037), creatinine (OR, 0.872; 95% CI, 0.81-0.925; P  < 0.001), and laminin (OR, 1.01; 95% CI, 1.002-1.018; P  = 0.017) acted as independent risk factors in Wilson's disease complicated with FLD. The receiver operating characteristic curves for combined predictive indicators demonstrated an area under the curve values of 0.872, which was found to be a significant predictors for FLD in Wilson's disease., Conclusions: We screened out the most important risk factors, namely ALT, uric acid, creatinine, FBG, and laminin for Wilson's disease complicated with FLD. The joint prediction achieved is crucial for identifying children with Wilson's disease complicated with FLD., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The fermentation process has a significant impact on the aromatic profile of wines, particularly in relation to the difference in fermentation matrix caused by grape varieties. This study investigates the leaching and evolution patterns of aroma compounds in Vitis vinifera L. Marselan and Merlot during an industrial-scale vinification process, including the stages of cold soak, alcohol fermentation, malolactic fermentation, and one-year bottle storage. The emphasis is on the differences between the two varieties. The results indicated that most alcohols were rapidly leached during the cold soak stage. Certain C6 alcohols, terpenes, and norisoprenoids showed faster leaching rates in 'Marselan', compared to 'Merlot'. Some branched chain fatty-acid esters, such as ethyl 3-methylbutyrate, ethyl 2-methylbutyrate, and ethyl lactate, consistently increased during the fermentation and bottling stages, with faster accumulation observed in 'Marselan'. The study combines the Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) model based on odor activity values to elucidate the accumulation of these ethyl esters during bottle storage, compensating for the reduction in fruity aroma resulting from decreased levels of ( E )- β -damascenone. The 'Marselan' wine exhibited a more pronounced floral aroma due to its higher level of linalool, compared to the 'Merlot' wine. The study unveils the distinctive variation patterns of aroma compounds from grapes to wine across grape varieties. This provides a theoretical framework for the precise regulation of wine aroma and flavor, and holds significant production value.

Objective: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood., Methods: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1 loxP/loxP ) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age., Results: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1 loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1 loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1 loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition., Conclusions: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

In this work, shrimp shell-derived magnetic NiFe 2 O 4 /N, O co-doped porous carbon nanozyme with superior oxidase (OXD)-like activity was prepared and used for colorimetric/photothermal/smartphone dual-signal triple-mode detection of antioxidants in fruits and beverages. The magnetic NiFe 2 O 4 /N, O co-doped porous carbon (MNPC) material was triumphantly fabricated using a combined in-situ surface chelation and pyrolysis method. The resultant MNPC composite exhibits a superior OXD-like activity, which can effectively oxidize 3,3',5,5'-tetramethylbenzidine (TMB) for yielding colorimetric/temperature dual-signal (CTDS) in absence of H 2 O 2 . This CTDS output sensor was successfully used for the determination of ascorbic acid and tannic acid. The proposed CTDS sensor with good specificity and high sensitivity can satisfy different on-site analysis requirements. Interestingly, the MNPC as a sustainable filler was further used for improving packaging properties of polyvinyl alcohol film. In short, this work offers a large-scale and cheap method to fabricate magnetic carbon-based nanozyme for monitoring antioxidants and ameliorating packaging properties., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Intestinal dysbacteriosis has frequently been involved in the context of depression. Nonetheless, only scant information is available about the features and functional changes of gut microbiota in female middle-aged depression (MAD)., Objective: This study aims to explore whether there are characteristic changes in the gut microbes of female MAD and whether these changes are associated with depressive-like behaviors. Meanwhile, this study observed alterations in the lipid metabolism function of gut microbes and further examined changes in plasma medium- and long-chain fatty acids (MLCFAs) in mice that underwent fecal microbiota transplantation (FMT)., Methods: Stool samples obtained from 31 MAD, along with 24 healthy individuals (HC) were analyzed by 16 S rRNA gene sequencing. Meanwhile, 14-month-old female C57BL/6J mice received antibiotic cocktails and then oral gavage of the microbiota suspension of MAD or HC for 3 weeks to reconstruct gut microbiota. The subsequent depressive-like behaviors, the composition of gut microbiota, as well as MLCFAs in the plasma were evaluated., Results: A noteworthy disruption in gut microbial composition in MAD individuals compared to HC was observed. Several distinct bacterial taxa, including Dorea, Butyricicoccus, and Blautia, demonstrated associations with the demographic variables. A particular microbial panel encompassing 49 genera effectively differentiated MAD patients from HC (AUC = 0.82). Fecal microbiome transplantation from MAD subjects led to depressive-like behaviors and dysfunction of plasma MLCFAs in mice., Conclusions: These findings suggest that microbial dysbiosis is linked to the pathogenesis of MAD, and its role may be associated with the regulation of MLCFAs metabolism., Competing Interests: Declaration of competing interest none, (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: There is growing evidence of associations between the gut microbiota and anxiety disorders, where changes in gut microbiotas may affect brain function and behavior via the microbiota-gut-brain axis. However, population-level studies offering a higher level of evidence for causality are lacking. Our aim was to investigate the specific gut microbiota and associated metabolites that are closely related to anxiety disorders to provide mechanistic insights and novel management perspectives for anxiety disorders., Method: This study used summary-level data from publicly available Genome-Wide Association Studies (GWAS) for 119 bacterial genera and the phenotype "All anxiety disorders" to reveal the causal effects of gut microbiota on anxiety disorders and identify specific bacterial genera associated with anxiety disorders. A two-sample, bidirectional Mendelian randomization (MR) design was deployed, followed by comprehensive sensitivity analyses to validate the robustness of results. We further conducted multivariable MR (MVMR) analysis to investigate the potential impact of neurotransmitter-associated metabolites, bacteria-associated dietary patterns, drug use or alcohol consumption, and lifestyle factors such as smoking and physical activity on the observed associations., Results: Bidirectional MR analysis identified three bacterial genera causally related to anxiety disorders: the genus Eubacterium nodatum group and genus Ruminococcaceae UCG011 were protective, while the genus Ruminococcaceae UCG011 was associated with an increased risk of anxiety disorders. Further MVMR suggested that a metabolite-dependent mechanism, primarily driven by tryptophan, tyrosine, phenylalanine, glycine and cortisol, which is consistent with previous research findings, probably played a significant role in mediating the effects of these bacterial genera to anxiety disorders. Furthermore, modifying dietary pattern such as salt, sugar and processed meat intake, and adjusting smoking state and physical activity levels, appears to be the effective approaches for targeting specific gut microbiota to manage anxiety disorders., Conclusion: Our findings offer potential avenues for developing precise and effective management approaches for anxiety disorders by targeting specific gut microbiota and associated metabolites., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Qiu, Ma, Yu, Yang, Hu, Guo and Chen.)

This study explores the leaching and evolution of anthocyanins and aroma compounds during wine-making, using an industrial-scale vinification of Cabernet Sauvignon with whole-process skin-seed contact. The results indicated that compounds within the same class displayed similar evolutionary patterns during fermentation. The extraction of anthocyanins, C6 aldehydes, and β-damascenes occurred continuously during cold soak, accompanied by the conversion of C6 aldehydes into alcohols and hydrolytic release of glycosidic β-damascenone. During alcoholic fermentation, pyranoanthocyanins, polymeric pigments, esters, benzene compounds, higher alcohols, and acids were generated. The concurrent occurrence of malolactic fermentation and prolonged maceration led to aromas associated with lactic acid bacteria metabolism. Finally, a comparison between free-run wine and pressed wine revealed high concentrations of C6 compounds and polymeric pigments with flavanol dimers in the pressed wine. These results can be used as a reference to optimize the vinification process to enhance the red due and fruity aromas of the wine., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Qiu-Hong Pan reports financial support was provided by Ningxia Hui Autonomous Region Key R&D projects., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Hypertension is a prevalent cardiovascular disease characterized by elevated blood pressure and increased vascular resistance. HDAC inhibitors have emerged as potential therapeutic agents due to their ability to modulate gene expression and cellular processes. YPX-C-05, a novel hydroxamic acid-based HDAC inhibitor, shows promise in its vasodilatory effects and potential targets for hypertension treatment. In this study, we aimed to elucidate the mechanisms underlying YPX-C-05's vasodilatory effects and explore its therapeutic potential in hypertension., Methods: To determine the ex vivo vasodilatory effects of YPX-C-05, isolated aortic rings precontracted with phenylephrine were used. We assessed YPX-C-05's inhibitory effects on HDACs and its impact on histone H4 deacetylation levels in endothelial cells. Network pharmacology analysis was employed to predict putative targets of YPX-C-05 for hypertension treatment. To investigate the involvement of the PI3K/Akt/eNOS pathway, we employed enzyme-linked immunosorbent assay and to assess the levels of NO, ET-1, BH2, and BH4 in human umbilical vein endothelial cells. And we also analyzed the mRNA expression of eNOS and ET-1. Furthermore, Western blotting was conducted to quantify the phosphorylated and total Akt and eNOS levels in human umbilical vein endothelial cell lysates following treatment with YPX-C-05. In order to elucidate the vasodilatory mechanism of YPX-C-05, we employed pharmacological inhibitors for evaluation purposes. Furthermore, we evaluated the chronic antihypertensive effects of YPX-C-05 on N-omega-nitro-L-arginine-induced hypertensive mice in an in vivo model. Vascular remodeling was assessed through histological analysis., Results: Our findings demonstrated that YPX-C-05 exerts significant vasodilatory effects in isolated aortic rings precontracted with phenylephrine. Furthermore, YPX-C-05 exhibited inhibitory effects on HDACs and increased histone H4 acetylation in endothelial cells. Network pharmacology analysis predicted YPX-C-05 might activate endothelial eNOS via PI3K/Akt signaling pathway. Inhibition of the PI3K/Akt/eNOS pathway attenuated the vasodilatory effects of YPX-C-05, as evidenced by reduced levels of phosphorylated Akt and eNOS in human umbilical vein endothelial cell lysates. The chronic administration of YPX-C-05 in N-omega-nitro-L-arginine-induced hypertensive mice resulted in significant antihypertensive effects. Histological analysis demonstrated a reduction in vascular remodeling, further supporting the therapeutic potential of YPX-C-05 in hypertension., Conclusion: This study demonstrates for the first time that the novel hydroxamic acid-based HDAC inhibitor YPX-C-05 produces significant antihypertensive and vasodilatory effects through the PI3K/Akt/eNOS pathway. Our findings support the developing prospect of YPX-C-05 as a novel antihypertensive drug., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

It is widely accepted that prevéraison application of naphthaleneacetic acid (NAA) can delay the ripening of grapes and improve their quality. However, how NAA impacts grape aroma compound concentrations remains unclear. This study incorporated the analyses of aroma metabolome, phytohormones, and transcriptome of Vitis vinifera L. cv. Cabernet Sauvignon grapes cultivated in continental arid/semiarid regions of western China. The analyses demonstrated that NAA application increased β-damascenone and 1,1,6-trimethyl-1,2-dihydronaphthalene (TDN) in the harvested grapes by delaying véraison and upregulating VvPSY1 and VvCCD4b expressions. Additionally, NAA treatment decreased 2-isobutyl-3-methoxypyrazine (IBMP) at the same phenological stage. Notably, abscisic acid (ABA) levels increased in NAA-treated grapes during véraison, which triggered further changes in norisoprenoid metabolisms. The ABA-responsive factor VvABF2 was potentially involved in VvPSY1 positive modulation, while the auxin response factor VvARF10 may play a role in VvCCD4b upregulation and VvOMT2 downregulation during NAA induction. VvARF10 possibly acts as a crosstalk node between the ABA and auxin signaling pathways following NAA treatment in regulating aroma biosynthesis.

The present study examined potential association between the daily intake and serum levels of copper (Cu), selenium (Se), and zinc (Zn) and the risk of osteoarthritis (OA) and rheumatoid arthritis (RA) using data from the National Health and Nutrition Examination Survey (NHANES). Daily intake and serum concentrations of Cu, Zn, and Se in 4200 adults from the 2011-2016 NHANES were examined and divided into normal, OA patients, and RA patients. The level of serum Cu was higher in OA and RA than in non-arthritis, while the levels of serum Se and Zn were no different in the three groups. Serum Se and Zn, but not Cu, concentrations were highly correlated with daily intake. Cu, Se, and Zn intake was independently associated with increased risk of OA, but not with RA. And there was a trend for higher odds of OA among participants in the higher Cu, Se, and Zn intake. Future large longitudinal studies are warranted to confirm these findings., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Competing Interests: Declaration of competing interest No conflict of interest exists in the submission of this manuscript, and all authors approve the manuscript for publication. I want to declare on behalf of my co-authors that the work described was an original article that has not been published previously and is not under consideration for publication elsewhere. All the authors listed have approved the manuscript that is enclosed.

Astragalus membranaceus and Cinnamomum cassia are used as spices and flavorful ingredients, or medicinal herbs with pharmacological effects. In this study, the hair-growth-promoting effects of the YH complex, a newly developed formula consisting of membranaceus and C . cassia , are investigated with the prediction of its molecular mechanism. The target gene of the YH complex was about 74.8% overlapped with the gene set of 'Hair growth' on the GO Biological Process database. The oral administration of the YH complex promoted hair regrowth and increased hair-shaft thickness in depilated hair loss mice. In addition, the anagen/telogen hair follicle ratio was significantly increased by the YH complex. The growth factors affecting the growth of hair follicles were dose-dependently increased by treatment with the YH complex. The Wnt/β-catenin signaling pathway expressions in skin tissues were apparently increased by the administration of the YH complex. In conclusion, the YH complex consisting of A . membranaceus and C . cassia induced hair follicle differentiation and preserved the growing-anagen phase by increasing growth factors and the Wnt/β-catenin signaling pathway, leading to the restoration of hair loss. The YH complex can be a remedy for hair loss diseases, such as alopecia areata, androgenetic alopecia, telogen effluvium, and chemotherapy-induced alopecia.

It is known that animal-origin medicine could be one of effective treatment to remedy atopic dermatitis (AD) by controlling the cytokines. Cicadidae Periostracum (CP), the slough of Cryptotympana pustulata , has been frequently used for treating AD and skin affliction in traditional Korean Medicine. This study is aimed at investigating the ameliorating effects of CP on AD and its potential mechanism. The dinitrochlorobenzene sensitized mice were treated with CP for 2 weeks. The various biomarkers and the dermatitis scores presented that CP treatment can induce the visual and biological improvements of AD model. Pruritus, the most serious symptom of AD, which can cause repeated scratching behaviors and finally lead to lichenification, was reduced with CP treatment by regulating the inflammatory reactions. In addition, CP treatment diminished the number of mast cells that are known for causing inflammatory reactions. Moreover, it is proven that CP can decline secretion of interleukin-22, which means CP treatment has anti-inflammatory effects. CP treatment can correct the imbalance of helper T (Th)1 and Th2, downregulating thymic stromal lymphopoietin that leads to decrease of mRNA level of inflammatory cytokines. The crucial role of CP treatment is controlling of the Janus kinase 1/signal transducer and activator of transcription 3 pathway. In addition, CP treatment has the inhibitory effects on kallikrein related peptidase (KLK) 5 and KLK7. Taken together, CP treatment can ameliorate most symptoms and problems caused by AD disease, improving the AD patients' life quality., Competing Interests: The authors declare no potential conflicts of interest., (© Korean Society for Food Science of Animal Resources.)

Background: Recurrent aphthous stomatitis (RAS) is the most common ulcerative disease that affects oral mucosa. The coating agents, topical analgesics, and topical steroids are usually used as treatment methods. Glycyrrhiza glabra has been used for RAS treatment based on its anti-inflammatory, antioxidant, and immunomodulatory properties. In this study, a systemic review on the therapeutic effect of topical licorice on RAS management was performed., Methods: Science Direct, Scopus, Cochrane databases, PubMed Google Scholar, and ResearchGate were searched up to September 2021 to find all English randomized clinical trials studying the effect of G. glabra , or its compositions on RAS. Meta-analysis was not conducted because of data heterogeneity. Articles were reviewed qualitatively, and only those with a Jadad score ≥3 were included. Animal studies, in vitro , review papers, non-English papers, and case reports were excluded., Results: Six studies with 314 subjects were included after screening. The result showed licorice has significant effects on RAS pain reduction, ulcer size, and healing time. Its effectiveness is related to its dose-dependent anti-inflammatory and antioxidant effects through several mechanisms. It also has antibacterial effects against Streptococci mutans and Porphyromonas gingivalis as another mechanism of action in RAS treatment. In addition, licorice can elevate the epidermal growth factor (EGF) level compared to the control group, which has an essential role in oral mucosal tissue integrity., Conclusion: Licorice extract has been used in different dosage forms, including paste, patch, and mouthwash with concentrations of 1% or 5%. The healing time after licorice therapy is expected to be within 4-8 days. Licorice did not show any adverse effect in the intervention groups, indicating its effectiveness and safety in RAS treatment., Competing Interests: None declared., (Copyright: © Iranian Journal of Medical Sciences.)

The inhibition of bone loss remains a challenge for postmenopausal women, considering the fact that only three anabolic treatments for osteoporosis have been approved by the FDA. This study aimed to investigate the osteogenic capacities of Osteo-F, a newly developed herbal formula, upon integrating network analysis and pre-clinical studies into clinical trials. The network pharmacology analysis showed that a potential mechanism of Osteo-F is closely related to osteoblast differentiation. Consistent with the predicted mechanism, Osteo-F treatment significantly enhanced bone matrix formation and mineralization with collagen expression in osteoblasts. Simultaneously, secreted bone-forming molecules were upregulated by Osteo-F. After the administration of Osteo-F to osteoporotic mice, the femoral BMD and osteocalcin in the serum and bone tissues were significantly improved. Subsequently, a randomized, double-blinded, placebo-controlled clinical trial showed that 253 mg of Osteo-F supplementation for 24 weeks resulted in significant improvements in the Z-score and serum osteocalcin levels of postmenopausal women compared to the placebo, thus indicating bone anabolic efficacy. In the current study, the bone anabolic effect of Osteo-F was determined by activating the differentiation and mineralization of osteoblasts through integrating experiments based on network analysis into clinical trials, with synchronized, reliable evidence, demonstrating that Osteo-F is a novel bone anabolic treatment in postmenopausal women.

This two-consecutive-year study aimed to evaluate the effects of ground management methods on the volatomics of 'Cabernet Sauvignon' grapes and wines in Northwest China, in which inner-row crop covering with purslane (GRASS) and mulching with black plastic film (FILM) treatments were carried out, respectively. Compared with clean tillage (CK), the GRASS and FILM treatments changed the microclimates of grapevine fruit zones and rhizospheres, which delayed the ripening of grape berries and affected the accumulation of aroma substances in the mature grapes effectively. GRASS increased the concentration of terpenes and C 13 -norisoprenoids in berries and gave more floral, fruity, and caramel fragrances to wines, while FILM had the opposite effect of significantly increasing the synthesis of C 6 /C 9 compounds and brought more green leaf flavors, showing that inner-row purslane covering is a potential and stable viticultural practice to improve the wine quality in this booming wine region.

Background: Recently, for various reasons, the need for non-invasive treatment for localized fat has emerged. This study confirmed whether Magnolia officinalis (MO) pharmacopuncture reduces localized fat by promoting lipolysis and inhibiting adipogenesis., Methods: The network was built using genes related to the active compound of MO and the mode of action of MO was predicted by the functional enrichment analysis. Based on the result from network analysis, 100 µL of 2 mg/mL MO pharmacopuncture was injected into the inguinal fat pad for 6 weeks in obese C57BL/6J mice. Normal saline was injected into the right-side inguinal fat pad as a self-control., Results: It was expected that the 'AMP-activated protein kinase (AMPK) signaling pathway' would be affected by the MO Network. MO pharmacopuncture reduced the weight and size of inguinal fat in HFD-induced obese mice. The phosphorylation of AMPK along with the increases of lipases was significantly increased by MO injection. Also, the expression levels of fatty acid synthesize-related mediators were suppressed by MO injection., Conclusion: Our results demonstrated that MO pharmacopuncture promoted the expression of AMPK, which has beneficial effects on activation of lipolysis and inhibition of lipogenesis. Pharmacopuncture of MO can be a non-surgical alternative therapy in the treatment of local fat tissue., Competing Interests: The authors declare no conflict of interest., (© 2023 Korea Institute of Oriental Medicine. Published by Elsevier B.V.)

Abies holophylla is an evergreen coniferous species that has been widely used for treating pulmonary diseases and colds. Previous research has demonstrated the anti-inflammatory effect of Abies species and the anti-asthmatic activities of Abies holophylla leaf essential oil (AEO). As asthma and allergic rhinitis (AR) share pathophysiology and pharmacotherapeutic interventions, AEO inhalation can also ameliorate upper respiratory allergic diseases. This study explored the protective effects of AEO on AR with network pharmacological pathway prediction. The potential target pathways of AEO were analyzed by a network pharmacological approach. The BALB/c mice were sensitized by ovalbumin (OVA) and 10 μm particular matter (PM 10 ) to induce allergic rhinitis. Aerosolized AEO 0.0003% and 0.03% were delivered by nebulizer for 5 min a day, 3 times a week for 7 weeks. Nasal symptoms (sneezing and rubbing), histopathological changes in nasal tissues, serum IgE, and zonula occludens-1 (ZO-1) expressions on nasal tissues were analyzed. After AR induction with OVA+PM 10 and inhalation of AEO 0.0003% and 0.03% treatment, AEO significantly decreased allergic symptoms (sneezing and rubbing), hyperplasia of nasal epithelial thickness, goblet cell counts, and serum IgE level. The network analysis demonstrated that the possible molecular mechanism of AEO is highly associated with the IL-17 signaling pathway and tight junction. The target pathway of AEO was investigated in RPMI 2650 nasal epithelial cells. Treatment of AEO on PM 10 -treated nasal epithelial cells significantly reduced the production of inflammatory mediators related to the IL-17 signaling pathway, NF-κB, and the MAPK signaling pathway and prevented the reduction in TJ-related factors. When taken together, AEO inhalation may be considered as a potential treatment for AR by alleviating nasal inflammation and recovering the tight junction.

Background: Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is associated with high mortality rates. Viral and bacterial coinfection is the primary cause of AECOPD. How coinfection with these microbes influences host inflammatory response and the gut microbiota composition is not entirely understood., Methods: We developed a mouse model of AECOPD by cigarette smoke exposure and sequential infection with influenza H1N1 virus and non-typeable Haemophilus influenzae (NTHi). Viral and bacterial titer was determined using MDCK cells and chocolate agar plates, respectively. The levels of cytokines, adhesion molecules, and inflammatory cells in the lungs were measured using Bio-Plex and flow cytometry assays. Gut microbiota was analyzed using 16S rRNA gene sequencing. Correlations between cytokines and gut microbiota were determined using Spearman's rank correlation coefficient test., Results: Coinfection with H1N1 and NTHi resulted in more severe lung injury, higher mortality, declined lung function in COPD mice. H1N1 enhanced NTHi growth in the lungs, but NTHi had no effect on H1N1. In addition, coinfection increased the levels of cytokines and adhesion molecules, as well as immune cells including total and M1 macrophages, neutrophils, monocytes, NK cells, and CD4 + T cells. In contrast, alveolar macrophages were depleted. Furthermore, coinfection caused a decline in the diversity of gut bacteria. Muribaculaceae , Lactobacillus , Akkermansia , Lachnospiraceae , and Rikenella were further found to be negatively correlated with cytokine levels, whereas Bacteroides was positively correlated., Conclusion: Coinfection with H1N1 and NTHi causes a deterioration in COPD mice due to increased lung inflammation, which is correlated with dysbiosis of the gut microbiota., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Li, Lin, Xiao, Liu, Mai, Zhou, Zeng, Cheng, Weng, Zhao, Chen, Jiang, Chen, Deng, Xie, Yang, Xia and Yang.)

Objective: To observe the effects of electroacupuncture(EA) at "Fengchi"(GB20) on the ethology, microglia activation and P2X7 receptor(P2X7R) expression in the periaqueductal gray(PAG) in recurrent migraine rat model, so as to explore the underlying mechanism of EA reducing central sensitization of migraine., Methods: Thirty-six male SD rats were randomly divided into control, model and EA groups, with 12 rats in each group. Recurrent migraine model was induced using repea-ted dural electrical stimulation once another day(the 1 st , 3 rd , 5 th , 7 th and 9 th days), for a total of 5 times; rats in the EA group received EA treatment(2 Hz/15 Hz, 0.8-1 mA) at GB20 after dural electrical stimulation, for 10 min every time, once a day for 9 days; rats in the control group only received electrode placement. The facial and hindpaw mechanical withdrawal threshold was detected by using an electronic von-Frey on the 0 th (baseline), 2 nd , 4 th , 6 th , and 8 th days. Microglia activation in the PAG was evaluated by using immunofluorescence staining to detect the number of ionized calcium binding adaptor molecule-1(Iba-1)-labeled microglia. Expression levels of microglia marker Iba-1, inflammatory factor interleukin(IL)-1β and P2X7R were detected by Western blot., Results: Compared with the control group, the facial and hindpaw mechanical withdrawal threshold of rats were significantly reduced on the 2 nd , 4 th , 6 th , and 8 th days( P <0.01， P <0.001); the microglia in the PAG area were significantly activated, with the number of Iba-1-positive microglia, and the expression levels of Iba-1, IL-1β and P2X7R proteins significant increased( P <0.001, P <0.05) in the model group. Compared with the model group, the facial and hindpaw mechanical withdrawal threshold of rats were significantly increased on the 4 th , 6 th , and 8 th days( P <0.05， P <0.001， P <0.01), and the above indicators were significantly reversed ( P <0.05) in the EA group., Conclusion: EA at GB20 can significantly improve facial and hindpaw mechanical withdrawal threshold of migraine rats, and its possible mechanism may be related to inhibiting microglia activation mediated by P2X7R in the PAG.

Allergic rhinitis is one of the most common diseases, which is caused by IgE-mediated reactions to inhaled allergens. Essential oils from the Mentha piperita leaf (EOM) are known to be effective for various diseases, such as respiratory diseases. However, the effect of inhalation of EOM on tight junctions and inflammation related to allergic rhinitis is not yet known. The purpose of this research was to explain the effects of the inhalation of EOM on tight junctions and inflammation of allergic rhinitis through network pharmacology and an experimental study. For that purpose, a pharmacology network analysis was conducted comprising major components of EOM. Based on the network pharmacology prediction results, we evaluated the effect of EOM on histological changes in mice with ovalbumin and PM10-induced allergic rhinitis. Allergic symptoms, infiltration of inflammatory cells, and regulation of ZO-1 were investigated in mice with allergic rhinitis. Other allergic parameters were also analyzed by reverse transcription polymerase chain reaction and western blot in nasal epithelial cells. In the network analysis, the effects of EOM were closely related to tight junctions and inflammation in allergic rhinitis. Consistent with the results from the network analysis, EOM significantly decreased epithelial thickness, mast cell degranulation, goblet cell secretion, and the infiltration of inflammatory cells in nasal tissue. EOM also regulated the MAPK-NF-κB signaling pathway, which was related to tight junctions in nasal epithelial cells. This research confirmed that inhalation of EOM effectively restores tight junctions and suppresses inflammation in the allergic rhinitis model. These results reveal that EOM has a therapeutic mechanism to treat allergic rhinitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Park, Yoon Chung, Kim and Yang.)

Objective: The endocrine pancreatic β-cells play a pivotal role in maintaining whole-body glucose homeostasis and its dysregulation is a consistent feature in all forms of diabetes. However, knowledge of intracellular regulators that modulate β-cell function remains incomplete. We investigated the physiological role of ROCK1 in the regulation of insulin secretion and glucose homeostasis., Methods: Mice lacking ROCK1 in pancreatic β-cells (RIP-Cre; ROCK1 loxP/loxP , β-ROCK1 -/- ) were studied. Glucose and insulin tolerance tests as well as glucose-stimulated insulin secretion (GSIS) were measured. An insulin secretion response to a direct glucose or pyruvate or pyruvate kinase (PK) activator stimulation in isolated islets from β-ROCK1 -/- mice or β-cell lines with knockdown of ROCK1 was also evaluated. A proximity ligation assay was performed to determine the physical interactions between PK and ROCK1., Results: Mice with a deficiency of ROCK1 in pancreatic β-cells exhibited significantly increased blood glucose levels and reduced serum insulin without changes in body weight. Interestingly, β-ROCK1 -/- mice displayed a progressive impairment of glucose tolerance while maintaining insulin sensitivity mostly due to impaired GSIS. Consistently, GSIS markedly decreased in ROCK1-deficient islets and ROCK1 knockdown INS-1 cells. Concurrently, ROCK1 blockade led to a significant decrease in intracellular calcium and ATP levels and oxygen consumption rates in isolated islets and INS-1 cells. Treatment of ROCK1-deficient islets or ROCK1 knockdown β-cells either with pyruvate or a PK activator rescued the impaired GSIS. Mechanistically, we observed that glucose stimulation in β-cells greatly enhanced ROCK1 binding to PK., Conclusions: Our findings demonstrate that β-cell ROCK1 is essential for glucose-stimulated insulin secretion and for glucose homeostasis and that ROCK1 acts as an upstream regulator of glycolytic pyruvate kinase signaling., (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Lipidomics has been established as a potential tool for the investigation of mental diseases. However, the composition analysis and the comparison of the peripheral lipids regarding adult women with major depressive depression (MDD) or bipolar depression (BPD) has been poorly addressed. In the present study, age-matched female individuals with MDD ( n = 28), BPD ( n = 22) and healthy controls (HC, n = 25) were enrolled. Clinical symptoms were assessed and the plasma samples were analyzed by comprehensive lipid profiling based on liquid chromatography-mass spectrometry (LC/MS). We found that the composition of lipids was remarkably changed in the patients with MDD and BPD when compared to HC or compared to each other. Moreover, we identified diagnostic potential biomarkers comprising 20 lipids that can distinguish MDD from HC (area under the curve, AUC = 0.897) and 8 lipids that can distinguish BPD from HC (AUC = 0.784), as well as 13 lipids were identified to distinguish MDD from BPD with moderate reliability (AUC = 0.860). This study provides further understanding of abnormal lipid metabolism in adult women with MDD and BPD and may develop lipid classifiers able to effectively discriminate MDD from BPD and HC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Guo, Li, Wang, Yang, Yang, Cui, Zhou, Chen, Yu, Peng and Tan.)

Hexavalent chromium (Cr(VI)) pollution is a global problem, and the reduction of highly toxic Cr(VI) to less toxic Cr(III) is considered to be an effective method to address Cr(VI) pollution. In this study, low-toxicity carbon quantum dots (CQDs) were used to reduce Cr(VI) in wastewater. The results show that CQDs can directly reduce Cr(VI) at pH 2 and can achieve a reduction efficiency of 94% within 120 min. It is observed that under pH higher than 2, CQDs can activate peroxymonosulfate (PMS) to produce reactive oxygen species (ROS) for the reduction of Cr(VI) and the reduction efficiency can reach 99% within 120 min even under neutral conditions. The investigation of the mechanism shows that the hydroxyl groups on the surface of CQDs can be directly oxidized by Cr(VI) because of the higher redox potential of Cr(VI) at pH 2. As the pH increases, the carbonyl groups on the surface of CQDs can activate PMS to generate ROS, O 2 •- , and 1 O 2 , which result in Cr(VI) being reduced. To facilitate the practical application of CQDs, the treatment of Cr(VI) in real water samples by CQDs was simulated and the method reduced Cr(VI) from an initial concentration of 5 mg/L to only 8 μg/L in 150 min, which is below the California water quality standard of 10 μg/L. The study provides a new method for the removal of Cr(VI) from wastewater and a theoretical basis for practical application., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Background: Hypertension is a public health problem globally. Understanding the perceived challenges of low-income older people populations with chronic disease is an obstacle the world is facing today., Aim: To explore perceived challenges of self-management in low-income older people with hypertension., Methods: Data were collected in three communities from September 2019 to October 2019 by semi-structured interviews. Interviews were audio-taped by digital voice recorder and analysed according to Colaizzi's seven steps., Results: Participants demonstrated perceived challenges concerning hypertension self-management. Six themes were identified: hypertension belief bias, family dysfunction, deep-rooted habit, elder self-neglect, medical informatization and supportive health policy. Each theme was identified with several subthemes., Conclusions: Findings implied that most of the low-income older people lacked self-management behaviours. Future research is needed to address perceived challenges related to self-management behaviour for patients with hypertension worldwide., (© 2022 John Wiley & Sons Australia, Ltd.)

Accumulated genetic mutations are an important cause for the development of acute myeloid leukemia (AML), but abnormal changes in the inflammatory microenvironment also have regulatory effects on AML. Exploring the relationship between inflammatory response and pathological features of AML has implications for clinical diagnosis, treatment and prognosis evaluation. We analyzed the expression variation landscape of inflammatory response-related genes (IRRGs) and calculated an inflammatory response score for each sample using the gene set variation analysis (GSVA) algorithm. The differences in clinical- and immune-related characteristics between high- and low-inflammatory response groups were further analyzed. We found that most IRRGs were highly expressed in AML samples, and patients with high inflammatory response had poor prognosis and were accompanied with highly activated chemokine-, cytokine- and adhesion molecule-related signaling pathways, higher infiltration ratios of monocytes, neutrophils and M2 macrophages, high activity of type I/II interferon (IFN) response, and higher expression of immune checkpoints. We also used the Genomics of Drug Sensitivity in Cancer (GDSC) database to predict the sensitivity of AML samples with different inflammatory responses to common drugs, and found that AML samples with low inflammatory response were more sensitive to cytarabine, doxorubicin and midostaurin. SubMap algorithm also demonstrated that high-inflammatory response patients are more suitable for anti-PD-1 immunotherapy. Finally, we constructed a prognostic risk score model to predict the overall survival (OS) of AML patients. Patients with higher risk score had significantly shorter OS, which was confirmed in two validation cohorts. The analysis of inflammatory response patterns can help us better understand the differences in tumor microenvironment (TME) of AML patients, and guide clinical medication and prognosis prediction., (© 2022 The Author(s).)

Aims: The association of auraptene (AUR), a 7-geranyloxycoumarin, on osteoporosis and its potential pathway was predicted by network pharmacology and confirmed in experimental osteoporotic mice., Methods: The network of AUR was constructed and a potential pathway predicted by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) terms enrichment. Female ovariectomized (OVX) Institute of Cancer Research mice were intraperitoneally injected with 0.01, 0.1, and 1 mM AUR for four weeks. The bone mineral density (BMD) level was measured by dual-energy X-ray absorptiometry. The bone microstructure was determined by histomorphological changes in the femora. In addition, biochemical analysis of the serum and assessment of the messenger RNA (mRNA) levels of osteoclastic markers were performed., Results: In total, 65.93% of the genes of the AUR network matched with osteoporosis-related genes. Osteoclast differentiation was predicted to be a potential pathway of AUR in osteoporosis. Based on the network pharmacology, the BMD and bone mineral content levels were significantly (p < 0.05) increased in the whole body, femur, tibia, and lumbar spine by AUR. AUR normalized the bone microstructure and the serum alkaline phosphatase (ALP), bone-specific alkaline phosphatase (bALP), osteocalcin, and calcium in comparison with the OVX group. In addition, AUR treatment reduced TRAP-positive osteoclasts and receptor activator of nuclear factor kappa-B ligand (RANKL) + nuclear factor of activated T cells 1 (NFATc1) + expression in the femoral body. Moreover, the expressions of initiators for osteoclastic resorption and bone matrix degradation were significantly (p < 0.05) regulated by AUR in the lumbar spine of the osteoporotic mice., Conclusion: AUR ameliorated bone loss by downregulating the RANKL/NFATc1 pathway, resulting in improvement of osteoporosis. In conclusion, AUR might be an ameliorative cure that alleviates bone loss in osteoporosis via inhibition of osteoclastic activity. Cite this article: Bone Joint Res  2022;11(5):304-316.

Objective: To analyze the clinical features and spinal lesions related to micturitionin of chronic prostatitis/chronic pelvic pain syndrome(CP/CPPS) patients. Methods: Patients with CP/CPPS were enrolled to this study at the outpatient department of Tongji Hospital between January and June 2019. The data of clinical features was collected and analyzed, including lower urinary tract symptoms(LUTS), bowel syndrome and pain over different parts of body, as well as lower urinary tract dysfunction, spinal lesions and pelvic organ morphological changes demonstrated by MRI. The potential role of spinal lesions in the development of CP/CPPS syndrome was investigated. Results: A total of 126 CP/CPPS patients were included, with an age［ M （ Q 1 ， Q 3 ）］of 41(31,53) years and a course of disease of 2(1,20) years. Among them, 126 (100.0%) were complicated with LUTS, 72(57.1%) with bowel dysfunction and 88(69.8%) with pain. MRI showed the cervical central disc herniation(126 cases, 100.0%), the ischemic changing in the cervical area of visceral efferant pathway(82 cases, 65.1%), the lumbar central disc herniation(65 cases, 51.6%), and the sacral nerve cysts(97 cases, 77.0%) are commonly seen. In addition, the morphological changes in the visceral organs containing smooth muscle were demonstrated, including thickened bladder wall(91 cases, 72.2%), distended seminal vesicles(70 cases, 55.6%) and distended sigmoid colon/rectum(59 cases, 46.8%). Conclusions: CP/CPPS patients were characterized by the co-existence of LUTS, bowel dysfunction and somatic pain in one individual. The presence of multi-organ symptoms, combined with the high prevalence of spinal lesions associated with micturition reflex, suggesting the potential role of the spinal lesions in the development of CP/CPPS.

Asthma, a common chronic pulmonary disorder characterized by airway remodeling, hyperresponsiveness and obstruction, can be aggravated by repeated exposure to particulate matter (PM). The potential effect and mechanisms of Asarum sieboldii Radix essential oil (AEO) against asthma were explored based on network pharmacology. AEO was pre-treated using a nebulizer for 3 weeks and the mice were sensitized to ovalbumin (OVA) and PM 10 with the co-treatment of AEO for 4 weeks. In addition, A549 lung epithelial cells were sensitized with PM 10 to investigate the underlying mechanisms of AEO regarding the lung-fibrosis-related mediators. The target genes of methyl eugenol, a main compound of AEO, were highly matched by 48% with the gene set of asthma. AEO markedly inhibited the increase in epithelial thickness through the accumulation of goblet cells in the airways. Collagen deposition in the lung tissues of OVA+PM 10 -challenged asthmatic mice was significantly decreased by AEO. AEO also inhibited the influx of inflammatory cells in the bronchoalveolar lavage fluid, as well as the increases in serum IgE and IgG 2a and cytokines in the lung tissues. Furthermore, AEO regulated the expressions of fibrotic mediators, especially POSTN and TGF-β. In conclusion, we expect that AEO can be one of the effective alternative therapeutics to relieve asthma.

Background: Asthma is one of the most common chronic inflammatory diseases of the airways. Essential oil from Abies holophylla leaf (EOA) has been reported to have anti-inflammatory property. This study aimed to predict the inhibitory effect of EOA against asthma by network analysis and to confirm the underlying mechanism of EOA on airway inflammation., Purpose and Study Design: The effects and underlying mechanisms of EOA on asthma were investigated by in silico network pharmacology and an experimental in vivo study., Methods: To define the effectiveness of EOA on asthma, the network pharmacology was constructed using major components of EOA. EOA (0.0003 and, 0.03 v/v%) was aerosolized by nebulizer 3 times a week for 5 min for 7 weeks. After 3 weeks of treating the mice with EOA, asthma was induced by sensitizing them with ovalbumin (OVA) and PM10. The effects of EOA on the IL-17 related signaling pathway was confirmed using an asthmatic model., Results: The network analysis showed that EOA is highly associated with the IL-17-related signaling pathway. EOA inhibited respiratory epithelium hyperplasia, collagen deposition and goblet cell activation in the lung and trachea tissues. In addition, EOA reduced the number of eosinophils, lymphocytes and macrophages in BALF. Furthermore, in the asthmatic model of mice, we showed that EOA inhibited IL-17-related cytokines, increased Treg-related cytokines and decreased the TRAF6 and MAPK and, suppressed the nuclear transcriptional activities of NF-kB., Conclusions: The network pharmacology and in vivo study indicated that EOA may have an inhibitory effect on airway inflammation in asthma exposure through the IL-17-related signaling pathway., (Copyright © 2021 Elsevier GmbH. All rights reserved.)

Plasmonic metals under photoexcitation can generate energetic hot electrons to directly induce chemical reactions. However, the capability and fundamental insights of the transportation of these hot electrons at plasmonic metal-2D material interfaces remain unclear. Herein, hot-electron transfer at Au-graphene interfaces has been in situ studied using surface-enhanced Raman spectroscopy (SERS) with atomic layer accuracy. Combining in situ SERS studies with density functional theory calculations, it is proved that hot electrons can be injected from plasmonic Au nanoparticles to graphene and directly penetrate graphene to trigger photocatalytic reactions. With increasing graphene layers, the transportation of hot electrons decays rapidly and would be completely blocked after five layers of graphene. Moreover, the transfer of hot electrons can be modulated by applying an external electric field, and the hot-electron transfer efficiency under electrochemical conditions is improved by over three times in the presence of a monolayer of graphene., (© 2021 Wiley-VCH GmbH.)

Ginkgo biloba Extract( GBE50) Dispersible Tablets is a new standardized prescription,which is widely used in the treatment of ischemic cardiovascular and cerebrovascular diseases. However,there are still many problems in its clinical application.Rational and safe use of GBE50 Dispersible Tablets is pivotal to the medication safety and clinical prognosis of patients. This consensus has been jointly formulated by clinical experts of traditional Chinese medicine and western medicine in cardiovascular and cerebrovascular diseases and followed the Manual for the Clinical Experts Consensus of Chinese Patent Medicine published by the China Association of Chinese Medicine. The present study identified clinical problems based on clinical investigation,searched the research papers according to PICO clinical problems,carried out evidence evaluation,classification,and recommendation by GRADE system,and reached the expert consensus with nominal group technique. The consensus combines evidence with expert experience. Sufficient evidence of clinical problems corresponds to &quot; recommendations&quot;,while insufficient evidence to &quot; suggestions&quot;. Safety issues of GBE50 Dispersible Tablets,such as indications,usage and dosage,and medication for special populations,are defined to improve clinical efficacy,promote rational medication,and reduce drug risks. This consensus needs to be revised based on emerging clinical issues and evidencebased updates in practical applications in the future.

Banhasasim-tang (BST), a herbal medicine, has been used for nausea and fever from cold damage. This study aimed to investigate the protective effects of BST in cold restraint stress-induced gastric ulcers. Male Sprague Dawley rats were orally treated with various doses of BST including 0.25, 0.5, 1, 3, 6, 9, 12 and 18g/kg based on the human daily intake dose. After treatment once per day for 3 days, rats were restrained into the cold stress chamber for 12h at 4°C to induce gastric ulcers. Gastric hemorrhagic ulcer area was evaluated and serum adrenocorticotropic hormone (ACTH), corticosterone, epinephrine and dopamine levels were determined. Compared to cold stress-induced gastric ulcer rats, hemorrhage ulcer areas were reduced in BST-treated stomach tissues at all concentrations. Increased serum ACTH, corticosterone and epinephrine levels were significantly decreased by BST treatment in cold stress-induced gastric ulcer rats. Moreover, there were increments of serum dopamine levels in 3 and 6g/kg of BST-treated groups. Taken together, BST positively ameliorated cold restraint stress-induced gastric hemorrhage with decrease in serum stress-related biomarkers such as ACTH, corticosterone, epinephrine and dopamine. The 3-6-fold of human daily intake dose of BST exhibited protective effects as a herbal medicine for gastric ulcers.

Flavonoid glycoside scutellarin (SCU) has been widely applied in the treatment of cerebral ischemic diseases in China. In this article, we conducted research on the working mechanisms of SCU in hypoxia reoxygenation (HR) injury of isolated cerebral basilar artery (BA) and erebral ischemia reperfusion (CIR) injury in rat models. In isolated rat BA rings, HR causes endothelial dysfunction (ED) and acetylcholine (ACh) induces endothelium-dependent vasodilation. The myography result showed that SCU (100 µM) was able to significantly improve the endothelium-dependent vasodilation induced by Ach. However, SCU did not affect the ACh-induced relaxation in normal BA. Further studies suggested that SCU (10-1000 µM) dose-dependently induced relaxation in isolated BA rings which were significantly blocked by the cGMP dependent protein kinase (PKG) inhibitor Rp-8-Br-cGMPs (PKGI-rp, 4 µM). Pre-incubation with SCU (500 µM) reversed the impairment of endothelium-dependent vasodilation induced by HR, but the reversing effect was blocked if PKGI-rp (4 µM) was added. The brain slice staining test in rats' model of middle cerebral artery occlusion (MCAO) induced CIR proved that the administration of SCU (45, 90 mg/kg, iv) significantly reduced the area of cerebral infarction. The Western blot assay result showed that SCU (45 mg/kg, iv) increased brain PKG activity and PKG protein level after CIR surgery. In conclusion, our findings suggested that SCU possesses the ability of protecting brain cells against CIR injury through vascular endothelium protection and PKG signal., (© 2021. The Author(s).)

Understanding the structure and dynamic process of water at the solid-liquid interface is an extremely important topic in surface science, energy science and catalysis 1-3 . As model catalysts, atomically flat single-crystal electrodes exhibit well-defined surface and electric field properties, and therefore may be used to elucidate the relationship between structure and electrocatalytic activity at the atomic level 4,5 . Hence, studying interfacial water behaviour on single-crystal surfaces provides a framework for understanding electrocatalysis 6,7 . However, interfacial water is notoriously difficult to probe owing to interference from bulk water and the complexity of interfacial environments 8 . Here, we use electrochemical, in situ Raman spectroscopic and computational techniques to investigate the interfacial water on atomically flat Pd single-crystal surfaces. Direct spectral evidence reveals that interfacial water consists of hydrogen-bonded and hydrated Na + ion water. At hydrogen evolution reaction (HER) potentials, dynamic changes in the structure of interfacial water were observed from a random distribution to an ordered structure due to bias potential and Na + ion cooperation. Structurally ordered interfacial water facilitated high-efficiency electron transfer across the interface, resulting in higher HER rates. The electrolytes and electrode surface effects on interfacial water were also probed and found to affect water structure. Therefore, through local cation tuning strategies, we anticipate that these results may be generalized to enable ordered interfacial water to improve electrocatalytic reaction rates., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Phlomis umbrosa has been traditionally used for bone diseases in traditional Korean Medicine. Sweroside (SOS), marker compounds of P. umbrosa, has been known to promote osteoblast differentiation. In this study, ameliorative effects of SOS on osteoporosis and potential target pathway were investigated. Ovariectomized mice were administered three doses of SOS three times a week for 4 weeks after inducing osteoporosis. Bone mineral content (BMC) and bone mineral density (BMD) were analyzed by dual energy X-ray absorptiometry. A human osteosarcoma cell line (SaOS-2) was differentiated to clarify the promoting effects of SOS on osteoblast differentiation and bone formation. Osteoblastic bone-forming markers were evaluated in lumbar vertebrae (LV) and mineralized SaOS-2 cells. SOS markedly elevated BMC and BMD levels and attenuated the bone marrow adipocytes in the femoral shaft. SOS increased the formation of bone matrix in SaOS-2 cells. Bone morphogenetic protein-2 (BMP2) and runt-related transcription factor 2 (CBFA1) in LV and SaOS-2 cells were up-regulated by SOS. SOS increased alkaline phosphatase (ALPL), osteopontin (SPP1), and bone sialoprotein-1 (BSPH1). In conclusion, SOS induced the formation of mineralized bone matrix by regulating BMP2/CBFA1-mediated molecules. Therefore, SOS could be a therapeutic compound of treatment for osteoporosis by producing the new bone matrix., (© 2021 John Wiley & Sons Ltd.)

Decursin, a pyranocoumarin compound from the root of Angelica gigas Nakai as a main constituent, has been reported to have various biological activities, including anti-inflammatory, anticancer, and antioxidant effects. This study aimed to predict and confirm the pharmacological relevance of Decursin on chemotherapy-induced alopecia (CIA) with the underlying molecular mechanisms. Decursin-targeted genes were compared with the gene set of alopecia and investigated through functional enrichment analysis. CIA was induced in C57BL/6J mice by injection of cyclophosphamide, and 1, 10, and 100 μM of Decursin were topically treated to depilated dorsal skin. KGF + expression was detected in the dorsal skin tissues. Based on the predicted results, caspase, PIK3/AKT, and MAPKs protein expressions by Decursin were analyzed in the TNF-α-induced keratinocytes. The Decursin network had 60.20% overlapped genes with the network of alopecia. Biological processes, such as cellular response to chemical stimulus, apoptosis, PI3K-AKT signaling pathway, and MAPK signaling pathway, were derived from the Decursin network. In the Decursin-treated skin, there was morphological hair growth and histological restoration of hair follicles in the CIA mice. The KGF + fluorescence and protein expressions were significantly increased by Decursin treatment. In addition, caspase-3, -7, and -8 expressions, induced by TNF-α, were dose-dependently decreased along with the inhibition of PI3K, AKT, ERK, and p38 expressions in Decursin-treated keratinocytes. These findings indicated that Decursin would be a potent therapeutic option for hair loss, in response to chemotherapy.

Transcription factors play a key role in maintaining cell identity. One mechanism of such cell memory after multiple rounds of cell division cycles is through persistent mitotic chromosome binding, although how individual transcription factors achieve mitotic chromosome retention is not completely understood. Here we show that PAX6, a lineage-determining transcription factor, coats mitotic chromosomes. Using deletion and point mutants associated with human ocular diseases in live-cell imaging analysis, we identified two regions, MCR-D1 and MCR-D2, that were responsible for mitotic chromosome retention of PAX6. We also identified three nuclear localization signals (NLSs) that contributed to mitotic chromosome retention independent of their nuclear import functions. Full mitotic chromosome retention required the presence of DNA-binding domains as well as NLSs within MCR-Ds. Furthermore, disease-associated mutations and NLS mutations changed the distribution of intrinsically disordered regions (IDRs) in PAX6. Our findings not only identify PAX6 as a novel mitotic chromosome retention factor but also demonstrate that the mechanism of mitotic chromosome retention involves sequence-specific DNA binding, NLSs, and molecular conformation determined by IDRs. These findings link mitotic chromosome retention with PAX6-related pathogenesis and imply similar mechanisms for other lineage-determining factors in the PAX family., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Localized adiposity is a serious aesthetic problem and a well-known health risk factor. There is a growing interest in minimally invasive treatment options for excessive fat accumulation, such as pharmacopuncture. LIPOSA is a newly developed pharmacopuncture formula from three natural herbs: The tuber of Pinellia ternata (Thunb.) Breitenb., the whole plant of Taraxacum platycarpum Dahlst. and the root of Astragalus membranaceus Bunge. The present study investigated the effects of pharmacopuncture treatment with LIPOSA on localized adiposity. Male C57BL/6J mice were fed high fat diet for 8 weeks to induce obesity. Then, 100 µl LIPOSA was injected into the left-side inguinal fat pad at various concentrations, including 13.35, 26.7 and 53.4 mg/ml. Normal saline was injected into the right-side inguinal fat pad of each mouse as a control. The treatment was performed three times per week for 2 weeks. The weight and histological changes were analyzed in the inguinal fat pad of the obese mice. The expression levels of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), autophagy-related gene (ATG)5, ATG7 and LC3-II, as lipophagy-related factors, were evaluated to confirm the lipid-catabolic effects of LIPOSA. LIPOSA pharmacopuncture markedly decreased the weight of the fat tissue and the size of the adipocytes in the inguinal region of the mouse models of obesity in a dose-dependent manner. The expression levels of ATGL, HSL, ATG5, ATG7 and LC3-II were significantly increased by the LIPOSA treatments. In addition, LIPOSA pharmacopuncture was found to decrease the expression levels of ACC, PPAR-γ and PEPCK. The results indicated that subcutaneous injection of LIPOSA can degrade local fat and induce lipophagic and lipase activation effects. In addition, lipid metabolism related to fat accumulation was regulated by the LIPOSA treatment. The present study suggests that LIPOSA pharmacopuncture can be a non-surgical alternative in the treatment of localized adiposity., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Lee et al.)

Heterochromatin, a type of condensed DNA in eukaryotic cells, has two main categories: Constitutive heterochromatin, which contains H3K9 methylation, and facultative heterochromatin, which contains H3K27 methylation. Methylated H3K9 and H3K27 serve as docking sites for chromodomain-containing proteins that compact chromatin. M33 (also known as CBX2) is a chromodomain-containing protein that binds H3K27me3 and compacts chromatin in vitro. However, whether M33 mediates chromatin compaction in cellulo remains unknown. Here we show that M33 compacts chromatin into DAPI-intense heterochromatin domains in cells. The formation of these heterochromatin domains requires H3K27me3, which recruits M33 to form nuclear bodies. G9a and SUV39H1 are sequentially recruited into M33 nuclear bodies to create H3K9 methylated chromatin in a process that is independent of HP1α. Finally, M33 decreases progerin-induced nuclear envelope disruption caused by loss of heterochromatin. Our findings demonstrate that M33 mediates the formation of condensed chromatin by forming nuclear bodies containing both H3K27me3 and H3K9me3. Our model of M33-dependent chromatin condensation suggests H3K27 methylation corroborates with H3K9 methylation during the formation of facultative heterochromatin and provides the theoretical basis for developing novel therapies to treat heterochromatin-related diseases., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Localized fat deposits are associated with health and aesthetic problems that mainly affect a large proportion of individuals. Recently, bioactive constituents of TP have been reported to affect lipid metabolism. In this study, we performed a network pharmacological analysis to assume potential lipolytic effects of TP and investigated the actual lipolytic effects of TP extract injection on local body fat and its underlying mechanism. Using the genes related to active compounds of TP, the network was constructed. Through the Functional Enrichment Analysis, Lipid Metabolism and Fatty Acid Metabolism were expected to be affiliated with the network, which implied possible lipolytic effects of TP. On the comparison between TP network and Obesity-related Gene Sets, about three-fourths of elements were in common with the gene sets, which indicated a high relevance between TP and obesity. Based on the genes in lipolysis-related pathways, Perilipin, CGI-58, ATGL, HSL and MGL were selected to identify the actual lipolytic effects of TP. TP injection reduced the inguinal fat weight. Also, the diameter of the adipocytes was decreased by the TP treatment in HFD-induced obese mice. In addition, TP suppressed lipid accumulation in differentiated 3T3-L1 adipocytes. Moreover, because the expression of Perilipin was increased, CGI-58, ATGL, HSL and MGL were markedly decreased. Furthermore, glycerol release was down-regulated by the TP treatment. TP exerted its lipolytic effects by regulating the lipolysis machinery through stimulation of lipases. Based on the present findings, TP is expected to be a potent component of injection lipolysis for removing localized body fat., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)