Serum Uric Acid Levels Associated with Outcomes of Neurodegenerative Disorders and Brain Health: Findings from the UK Biobank.

BACKGROUND: The relationship between serum uric acid (SUA) levels and brain-related health remains uncertain. OBJECTIVES: This study aimed to investigate the relationship between SUA levels and some neurodegenerative disorders and brain structure. DESIGN: A longitudinal study. SETTING AND PARTICIPANTS: 384,517 participants who did not have stroke, dementia, and Parkinsonism, with complete urate testes and covariates were included. MEASUREMENTS: Cox proportional hazards models, competing risk models, and restricted cubic spine models were applied. RESULTS: During the median follow-up time of 12.7 years (interquartile range [IQR]:12.0, 13.5), 7821 (2.0%) participants developed stroke, 5103 (1.3%) participants developed dementia, and 2341 (0.6%) participants developed Parkinsonism. Nonlinear relationships were identified between SUA levels and stroke (J-shaped), dementia, and Parkinsonism (U-shaped). SUA levels of 4.2 mg/dl, 6.4 mg/dl, and 6.6 mg/dl yielded the lowest risk of stroke, dementia, and Parkinsonism, respectively. Besides, we found high SUA levels reduced the volumes of total brain, grey matter, white matter, grey matter in the hippocampus, and hippocampus, but increased lateral-ventricle volume. Inflammation accounted for 9.1% and 10.0% in the association of SUA with stroke and lateral-ventricle volume. CONCLUSIONS: Lower SUA levels increased the risk of Parkinsonism, while both lower and higher SUA levels were positively associated with increased risk of stroke and dementia. Moreover, high SUA levels reduced brain structure volumes. Our findings suggest the association between SUA levels and brain-related disorders and highlight the importance of SUA management.

Gut microbiome and metabolome alterations in traditional Chinese medicine damp-heat constitution following treatment with a Chinese patent medicine and lifestyle intervention.

BACKGROUND: The gut microbiota is crucial in human health and diseases. Traditional Chinese Medicine Constitution (TCMC) divides people into those with a balanced constitution (Ping-he [PH]) and those with an unbalanced constitution. Dampness-heat constitution (Shi-re [SR]) is a common unbalanced constitution in the Chinese population and is susceptible to diseases. However, unbalanced constitutions can be regulated by Chinese medicine and lifestyle interventions in clinical practice. Ermiao Pill (EMP) is a Chinese medicine known for clearing heat and draining dampness and improving SR. However, the efficacy and mechanism of EMP are unclear. HYPOTHESIS/PURPOSE: To determine alterations in the gut microbiota and metabolome in SR and any changes after EMP treatment combined with lifestyle intervention. STUDY DESIGN: Randomized clinical trial. METHODS: We enrolled 112 healthy SR individuals and evaluated the efficacy of EMP along with lifestyle interventions. We further assessed serum cytokine levels, serum and urinary metabolomes, and the gut microbiota by 16S rRNA gene sequencing analysis before and after the EMP and lifestyle interventions. RESULTS: 107 SR individuals (55 in the intervention group and 52 in the control group) completed the 1-month-intervention and 1-year-follow-up. The intervention group significantly improved their health status within 1 month, with a reduced SR symptom score, and the efficacy lasted to the 1-year follow-up. The control group needed a further 6 months to reduce the SR symptom score. The gut microbiota of PH individuals was more diverse and had significantly higher proportions of many bacterial species than the SR. Microbiota co-occurrence network analysis showed that SR enriches metabolites correlating with microbial community structure, consistent with traits of healthy SR-enriched microbiota. CONCLUSION: EMP combined with lifestyle intervention produced health benefits in SR individuals. Our study indicates a pivotal role of gut microbiota and metabolome alterations in distinguishing between healthy SR and PH. Furthermore, the study reveals structural changes of gut microbiota and metabolites induced by EMP and lifestyle intervention. The treatment enriched the number of beneficial bacteria, such as Akkermansia muciniphila and Lactobacillus in the gut. Our findings provide a strong indication that several metabolite factors are associated with the gut microbiota. Moreover, the gut microbiome and metabolome might be powerful tools for TCMC diagnosis and personalized therapy.

Nanoplatform based on carbon nanoparticles loaded with doxorubicin enhances apoptosis by generating reactive oxygen species for effective cancer therapy.

At present, due to its wide application and relatively low cost, chemotherapy remains a clinically important cancer treatment option; however, a number of chemotherapeutic drugs have important limitations, such as lack of specificity, high toxicity and side effects, and multi-drug resistance. The emergence of nanocarriers has removed numerous clinical application limitations of certain antitumor chemotherapy drugs and has been widely used in the treatment of tumors with nanodrugs. The present study used carbon nanoparticles (CNPs) as a nanocarrier for doxorubicin (DOX) to form the novel nanomedicine delivery system (CNPs@DOX)was demonstrated by UV-vis and fluorescence spectrophotometry, ζ potential and TEM characterization experiments. The results confirmed the successful preparation of CNPs@DOX nanoparticles with a particle size of 96±17 nm, a wide range of absorption and a negatively charged surface. Furthermore, CNPs@DOX produced more reactive oxygen species and induced apoptosis, and thus exhibited higher cytotoxicity than DOX, which is a small molecule anticancer drug without a nanocarrier delivery system.. The present study provides a strategy for the treatment of tumors with nanomedicine.

ß-Sitosterol Suppresses LPS-Induced Cytokine Production in Human Umbilical Vein Endothelial Cells via MAPKs and NF-κB Signaling Pathway.

Atherosclerosis (AS) is an inflammatory disease, whose occurrence and development mechanism is related to a great number of inflammatory cytokines. ß-sitosterol (BS), a natural compound extracted from numerous vegetables and plant medicines, has been suggested to improve AS, but the underlying mechanism remains vague. This work focused on investigating how BS affected the lipopolysaccharide (LPS)-treated human umbilical vein endothelial cells (HUVECs) and further exploring the potential targets and mechanisms through network pharmacology (NP) and molecular docking (MD). According to in vitro experiments, LPS resulted in an increase in the expression of inflammatory cytokines like tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (Cox-2), and interleukin-6 (IL-6). Besides, secretion of IL-6, interleukin-1ß (IL-1ß), and TNF-α also increased in HUVECs, whereas BS decreased the expression and secretion of these cytokines. NP analysis revealed that the improvement effect of BS on AS was the result of its comprehensive actions targeting 99 targets and 42 pathways. In this network, MAPKs signaling pathway was the core pathway, whereas MAPK1, MAPK8, MAPK14, and NFKB1 were the hub targets. MD analysis also successfully validated the interactions between BS and these targets. Moreover, verification test results indicated that BS downregulated the abnormal expression and activation of MAPKs and NF-κB signaling pathways in LPS-treated cells, including p38, JNK, ERK, NF-κB, and IκB-α phosphorylation expressions. Furthermore, p65 nuclear translocation was also regulated by BS treatment. In conclusion, the BS-related mechanisms in treating AS are possibly associated with inflammatory response inhibition by regulating MAPKs and NF-κB signaling pathways.

Association of stress management skills and stressful life events with allergy risk: a case-control study in southern China.

BACKGROUND: Psychosocial stress and stressful life events are known to aggravate allergic diseases. Less is known about the impact of stress management skills on allergies. Here we sought to determine whether stress management skills are associated with the allergies and to assess the combined effects of stress management skills and stressful events on allergy risk. METHODS: A survey on risk factors for self-reported allergic diseases was carried out among 28,144 southern Chinese people; 14 stressful life events and 8 stress management skills were retrospectively recorded in a case-control setting with multivariate logistic regression analysis. Multiplicative and additive interactions between stressful events and stress management skills were evaluated. RESULTS: Stressful events significantly increased allergy risk. The odds ratio (OR) for allergies was 1.65 (95% confidence interval CI, 1.41-1.93) for those reporting one or two stressful events and 3.10 (95% CI, 2.55-3.79) for those reporting more than three stressful events compared to participants without stressful events. Stress management skills were adversely associated with allergic risk for people experiencing stressful events (OR, 0.71; 95% CI, 0.53-0.97) when adjusted demographically, particularly "concentrate on pleasant thoughts at bedtime" (OR, 0.67; 95% CI, 0.51-0.89), "pace myself to prevent tiredness" (OR, 0.67; 95% CI, 0.54-0.83), "get enough sleep" (OR, 0.48; 95% CI, 0.32-0.72) and "take some time for relaxation each day" (OR, 0.55; 95% CI, 0.37-0.80). But in people without stressful events, no association was observed. There was a significant linear trend for allergy risk from good stress management skills with no stressful events to poor stress management skills with stressful events (P < 0.001), with significant interaction in additive models (P = 0.006). CONCLUSIONS: There are independent and antagonistic combined associations of stressful life events and stress management skills with allergy risk. The data supports the use of stress management skills in managing allergic disease among people with stressful life events.

Gut Microbiota and Urine Metabonomics Alterations in Constitution after Chinese Medicine and Lifestyle Intervention.

Traditional Chinese Medicine Constitution (TCMC) divides human beings into balanced (ping-he) constitution (PH) and unbalanced constitution. Yang-deficiency (yang-xu) constitution (YAX) is one of the most common unbalanced constitutions in Chinese general population, and it causes susceptibility to particular diseases. However, unbalanced constitutions can be regulated by Chinese medicine and lifestyle intervention in clinical practice. Gui-fu-di-huang-wan (GFDHW) is a well-known Chinese medicine with yang-invigorating activity and is regarded as improving YAX. In this study, 60 healthy YAX students selected from a prospective population of 5185 were enrolled in a randomized clinical trial and completed the study. We compared the gut microbiota and urinary metabolome between individuals with PH and those with YAX before and after one-month-intervention. Compared with the control group, the health status of the intervention group improved significantly, the YAX symptom score was reduced, and the efficacy remained high at the one-year follow-up. The gut microbiota of the healthy PH exhibited greater diversity, and significantly higher species were identified. Compared to PH group, YAX individuals showed increased abundance of Bacteroidetes and Bacteroides, also had higher levels of gut microbial-derived urinary metabolites. After one-month-intervention, both GFDHW treatment and lifestyle intervention enriched the diversity and modulated the structure in YAX. The intervention group also partially restored the microbiome and metabolome to healthy PH-like levels. Further, a microbiota co-occurrence network analysis showed that the metabolites enriched in YAX were correlated with microbial community structure. Taken together, our results suggest that Chinese medicine combined with lifestyle intervention benefits YAX individuals. Gut microbiota/metabolite crosstalk might be involved in the Chinese medicine-mediated effects.

Systems pharmacological study based on UHPLC-Q-Orbitrap-HRMS, network pharmacology and experimental validation to explore the potential mechanisms of Danggui-Shaoyao-San against atherosclerosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS) plays an important role in the pathogenesis of cardiovascular and cerebrovascular diseases. Danggui-Shaoyao-San (DSS) is not only a representative Chinese formula to treat gynecological disorder, but also found its use in AS-related diseases. However, the active ingredients and the anti-AS effects are vague yet. AIM OF THE STUDY: An integrated strategy combined ultrahigh-performance liquid chromatography quadrupole-Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-HRMS), network pharmacology and experiments was carried out to investigate the potential materials and pharmacological mechanisms of DSS for AS. MATERIALS AND METHODS: First, UHPLC-Q-Orbitrap-HRMS was applied to identify the active compositions of DSS. Then, the putative targets of DSS relevant to AS were predicted from TCMSP and BATMAN, which were further determined through bioinformatic analyses, including protein-protein interactions (PPI), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). Finally, Western blot, qPCR and ELISA were carried out for target validation in human umbilical vein endothelial cells (HUVECs). RESULTS: A total of 37 active ingredients of DSS, connecting 47 key targets were identified. The functional enrichment showed that DSS may treat AS through regulating a series of signaling pathways which involving inflammatory responses, immune systems and metabolism. The in vitro experiment revealed that DSS ameliorated AS mainly through anti-inflammatory effects, by reducing the levels of vascular cell adhesion molecule-1 (VCAM1), intercellular adhesion molecule-1 (ICAM1), IL-6, TNF-α, cyclooxygenase-2 (Cox-2) and IL-1ß. DSS also inhibited the phosphorylation of IκB-α, NF-κB (p65), p38 and JNK in lipopolysaccharide (LPS)-induced HUVEC injury model. Moreover, as the main bioactive compounds of DSS, paeoniflorin (PF), ferulic acid (FA) and pachymic acid (PA) inhibited IL-6 and TNF-α secretion as well as IκB-α, NF-κB (p65), p38 and JNK activation. All these findings were consistent with the predicted targets and pathways. CONCLUSION: Collectively, the basic pharmacological effects and relevant mechanisms of DSS in the treatment of AS were revealed. The results suggest that DSS is a potential drug for AS treatment, and PF, FA, PA may be the core compositions contributing to the pharmacological function of this formula.

Effects and mechanism of action of Huang-Lian-Jie-Du-Tang in atopic dermatitis-like skin dysfunction in vivo and in vitro.

ETHNOPHARMACOLOGICAL RELEVANCE: Atopic dermatitis (AD), a disorder prevalent during childhood and adulthood, seriously affects the patient's quality of life. Although Huang-Lian-Jie-Du-Tang (HLJDT) has shown anti-inflammatory effects in previous studies, its effects and mechanism of action underlying AD disorder are still largely unknown. OBJECTIVE: This study explored the anti-inflammatory and immunomodulatory effects of HLJDT on the AD-like dermal disorder, induced in vitro by lipopolysaccharide (LPS)-triggered inflammation, and in vivo by 2,4-dinitrochlorobenzene (DNCB). MATERIALS AND METHODS: In vivo HLJDT effects were investigated by determining the severity of dermatitis, which consisted of observing signs of skin lesions, visually and through haematoxylin and eosin (HE) staining, in mouse ears and dorsal skin, measuring serum levels of interleukin (IL)-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, interferon (IFN)-γ, the tumour necrosis factor (TNF)-α, and determining the splenic index, number of splenic CD4+/CD8+ T-lymphocytes, as well as the phosphorylation levels of mitogen-activated protein kinases (including MAPKs-p38, ERK, and JNK), IκB-α, and nuclear factor kappa B (NF-κB) (p65) within dermal lesions. Morphological changes in LPS-induced inflammation were observed under a microscope, and ELISA and qPCR assays were used to measure IL-1α, IL-1ß, IL-6, and TNF-α expression levels. The protein expression levels of P-ERK/ERK, P-p38/p38, P-JNK/JNK, P-IKß-α, and P-p65 were measured through western blotting. Additionally, p65 expression was assessed by immunofluorescence, and LPS binding to RAW264.7 cell membrane was studied with laser confocal microscopy. RESULTS: HLJDT could remarkably mitigate DNCB-induced AD-like lesion symptoms, alleviating inflammatory mediator infiltration in mouse ears and dorsal skin tissue, down-regulating serum expression levels of IL-1α, IL-1ß, IL-2, IL-4, IL-5, IL-6, IFN-γ, and TNF-α, normalising the splenic CD4+/CD8+ T-lymphocyte ratio, and inactivating MAPKs (including p38, ERK, and JNK), IκB-α, and NF-κB (p65) in dorsal skin. Furthermore, HLJDT inhibited LPS-induced differentiation of RAW264.7 cells, as evidenced by the decreased protein and mRNA expression of IL-1α, IL-1ß, IL-6, and TNF-α. Additionally, it decreased ERK, p38, JNK, IKß-α, and p65 phosphorylation levels in the MAPKs/NF-κB pathway, inhibited p65 nuclear translocation, and reduced LPS binding to the RAW264.7 cell membrane. CONCLUSIONS: HLJDT significantly improved AD-like symptoms via inhibition of the MAPKs/NF-κB pathway. Therefore, administration of HLJDT might be a potential treatment for AD in the clinical setting.