Angelicin: A leading culprit involved in fructus Psoraleae liver injury via inhibition of VKORC1.

ETHNOPHARMACOLOGICAL RELEVANCE: The adverse effects of Fructus Psoraleae (FP), especially liver injury, have attracted wide attention in recent years. AIM OF THE STUDY: To establish a system to explore potential hepatotoxic targets and the chief culprit of liver injury based on clinical experience, network pharmacological method, molecular docking, and in vitro and in vivo experiments. MATERIALS AND METHODS: Clinical applications and adverse reactions to FP were obtained from public literatures. Components absorbed in the blood were selected as candidates to search for potential active targets (PATs) of FP. Subsequently, potential pharmacological core targets (PPCTs) were screened through the "drug targets-disease targets" network. Non-drug active targets (NPATs) were obtained by subtracting the PPCTs from the PATs. The potential hepatotoxic targets (PHTs) of FP were the intersection targets obtained from Venn analysis using NPATs, hepatotoxic targets, and adverse drug reaction (ADR) targets provided by the databases. Then, potential hepatotoxic components and targets were obtained using the "NPATS-component" network relationship. Molecular docking and in vitro and in vivo hepatotoxicity experiments were performed to verify the targets and related components. RESULTS: Overall, 234 NPATs were acquired from our analysis, and 6 targets were identified as PHTs. Results from molecular docking and in vitro and in vivo experiments showed that angelicin is the leading cause of liver injury in FP, and VKORC1 plays an important role. CONCLUSION: The results indicate that six targets, especially VKORC1, are associated with the PHTs of FP, and angelicin is the leading culprit involved in FP liver injury via inhibition of VKORC1.

Efficacy comparison of 21 interventions to prevent retinopathy of prematurity: a Bayesian network meta-analysis of randomized controlled trials.

BACKGROUND: The objective of this study was to evaluate the comparative efficacy of current interventions for the prevention of retinopathy of prematurity (ROP) in premature infants. METHODS: A network meta-analysis (NMA) was performed. We searched PubMed, Web of Science, Scopus, Embase, and the Cochrane Library for relevant studies from their inception to May 5, 2022. Publications were eligible for our study if they were randomized controlled trials (RCTs) involving preterm infants at <37 weeks of gestational age and reported the incidence of any-stage ROP treated with the interventions of interest. The overall effect was pooled using the random effects model. RESULTS: We identified 106 RCTs (involving 23894 participants). This NMA showed that vitamin A supplementation markedly reduced the incidence of ROP, in comparison with placebo (odds ratio [OR] = 0.59, 95% credible interval [95% CrI] 0.33, 0.85), fish oil-based lipid emulsion (OR = 0.57, 95% CrI 0.24, 0.90), early erythropoietin (OR = 0.51, 95% CrI 0.34, 0.98), probiotics (OR = 0.48, 95% CrI 0.32, 0.97), and human milk (OR = 0.50, 95% CrI 0.21, 0.78). Vitamin A supplementation has the highest probability of being the best option for reducing the ROP risk compared with the other 20 interventions based on its surface under the cumulative ranking curve (SUCRA) value (SUCRA = 92.50%, 95% CrI 0.71, 1.00). CONCLUSIONS: Our findings suggest that among 21 interventions, vitamin A supplementation might be the best method of preventing ROP. This NMA offers an important resource for further efforts to develop preventive strategies for ROP.

Lysohexaenetides A and B, linear lipopeptides from Lysobacter sp. DSM 3655 identified by heterologous expression in Streptomyces.

Lysobacter harbors a plethora of cryptic biosynthetic gene clusters (BGCs), albeit only a limited number have been analyzed to date. In this study, we described the activation of a cryptic polyketide synthase (PKS)/nonribosomal peptide synthetase (NRPS) gene cluster (lsh) in Lysobacter sp. DSM 3655 through promoter engineering and heterologous expression in Streptomyces sp. S001. As a result of this methodology, we were able to isolate two novel linear lipopeptides, lysohexaenetides A (1) and B (2), from the recombinant strain S001-lsh. Furthermore, we proposed the biosynthetic pathway for lysohexaenetides and identified LshA as another example of entirely iterative bacterial PKSs. This study highlights the potential of heterologous expression systems in uncovering cryptic biosynthetic pathways in Lysobacter genomes, particularly in the absence of genetic manipulation tools.

Qingyi granules ameliorate severe acute pancreatitis in rats by modulating the gut microbiota and serum metabolic aberrations.

CONTEXT: Qingyi granules can be used to effectively treat patients with severe acute pancreatitis (SAP). OBJECTIVE: To elucidate the role of gut microbiota-mediated metabolism in the therapeutic effects of Qingyi granules. MATERIALS AND METHODS: Sprague-Dawley rats were grouped into the sham operation, SAP model, Qingyi granule intervention (Q, 1.8 g/kg) and emodin intervention (E, 50 mg/kg) groups and observed for 24 h. H&E staining and ELISA were used for histopathological analysis and serum enzyme and cytokine assays. 16S rDNA sequencing and UHPLC-HRMS were used for gut microbiota analysis and untargeted metabolomics. RESULTS: In SAP rats, Qingyi granules decreased the pancreatic pathological score (Q, 7.4 ± 1.14; SAP, 11.6 ± 1.14, p < 0.01); serum amylase (Q, 121.2 ± 6.7; SAP, 144.3 ± 8.86, p < 0.05), lipase (Q, 566 ± 20.34; SAP, 656.7 ± 29.32, p < 0.01), and diamineoxidase (Q, 492.8 ± 26.08; SAP, 566.1 ± 26.83, p < 0.05) activities; and IL-1ß (Q, 29.48 ± 0.88; SAP, 36.17 ± 1.88, p < 0.01), IL-6 (Q, 112.2 ± 3.57; SAP, 128.9 ± 9.09, p < 0.05) and TNF-α (Q, 215.3 ± 8.67; SAP, 266.4 ± 28.03, p < 0.05) levels. SAP induced Helicobacter and Lactobacillus overgrowth and suppressed Romboutsia and Allobaculum growth and caused aberrations in bacterial metabolites, which were partly reversed by Qingyi granules. DISCUSSION AND CONCLUSIONS: Qingyi granules can modulate the gut microbiota and metabolic abnormalities to ameliorate SAP. Multi-omics approaches allow systematic study of the pharmacological mechanisms of compound prescriptions for critical illnesses.

Ameliorative effect of cheqianzi decoction on hyperuricemia and kidney injury and underlying mechanism in rats.

Cheqianzi Decoction (CQD) is a Traditional Chinese Medicine (TCM) formula comprising four herbs and is recorded in the Ancient Materia Medica "Shengji Zonglu". Individually, these four herbs have been shown to reduce uric acid (UA) levels, to treat hyperuricemia (HUA), and alleviate kidney damage. However, the therapeutic efficacy of the CQD and related mechanism are not yet clear. In this study, high performance liquid chromatography (HPLC) analysis confirmed that the contents of the chemical components of the four herbal medicines were in accordance with the provisions of the Chinese Pharmacopoeia. A total of 99 potential targets were identified in the network pharmacology analysis of CQD, indicating its involvement in the regulation of inflammatory and apoptotic signaling pathways, and potential value for treating HUA and alleviating kidney injury. In vivo pharmacodynamic studies showed that compared with the Model group, significantly decreased levels of serum uric acid (SUA), serum creatinine (SCr), blood urea nitrogen (BUN) (all P < 0.05), and inflammatory factors (P < 0.01) were detected in the CQD group. Quantitative real-time PCR and Western blot analyses showed that compared with the Model group, adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) expression in the CQD group was significantly upregulated (P < 0.01) at both the mRNA and protein levels, while mRNA expression of Caspase3 and NOD-like receptor family member 3 (NLRP3) (P < 0.05) and protein expression of NLRP3 (P < 0.01) were significantly downregulated. In conclusion, CQD promotes UA excretion by activating ABCG2, and induces inflammasome NLRP3-mediated reduction in inflammatory and apoptotic factors to achieve renal protection. Thus, our findings indicate the therapeutic potential of CQD in HUA with kidney injury.

Study on the difference and correlation between the contents and toxicity of aristolochic acid analogues in Aristolochia plants.

ETHNOPHARMACOLOGICAL RELEVANCE: The nephrotoxicity and carcinogenicity induced by traditional Chinese medicines (TCMs) containing aristolochic acids (AAs) and related compound preparations have greatly limited their clinical application. While the toxicity of AA-I and AA-II is relatively clear, there are marked differences in the toxic effects of different types of aristolochic acid analogues (AAAs). Thus, the toxicity of TCMs containing AAAs cannot be evaluated based on the toxicity of a single compound. AIM OF THE STUDY: To systematically investigate the toxicity induced by Zhushalian (ZSL), Madouling (MDL) and Tianxianteng (TXT) as representative TCMs derived from Aristolochia. MATERIALS AND METHODS: AAA contents in ZSL, MDL and TXT were determined using HPLC. Subsequently, mice were treated for 2 weeks with high (H) and low (L) dosages of TCMs containing total AAA contents of 3 mg/kg and 1.5 mg/kg, respectively. Toxicity was evaluated using biochemical and pathological examination and was based on organ indices. Correlations between AAA contents and induced toxicity were analysed using multiple methods. RESULTS: Of the total AAA content, ZSL contained mainly AA-I and AA-II (>90%, of which AA-I accounted for 49.55%). AA-I accounted for 35.45% in MDL. TXT mainly contained AA-IVa (76.84%) and other AAAs accounted for <10%. Short-term toxicity tests indicated that ZSL and high-dose MDL induced obvious renal interstitial fibrosis and gastric injury, whereas TXT (high and low dosages) caused only slight toxicity. Correlation analysis suggested that AA-I might be the critical hazard factor for toxicity. CONCLUSIONS: The toxicity of TCMs containing AAAs cannot be generalised. The toxicity of TXT is relatively low compared with those of ZSL and MDL. The toxicity of Aristolochia depends mainly on the AA-I content; therefore, control of AA-I levels in TCMs and related compound preparations is required to reduce the risk of toxicity associated with the use of Aristolochia herbs in clinical settings.

Differences in p38-STAT3-S100A11 signaling after the administration of aristolochic acid I and IVa may account for the disparity in their nephrotoxicity.

BACKGROUND: The safety of herbs containing aristolochic acids (AAs) has become a widespread concern. Previous reports indicate that AAs are highly nephrotoxic and carcinogenic, although there are more than 170 analogues of aristolochic acid. Not all AAs have the same degree of nephrotoxicity or carcinogenicity. Previous studies have found that aristolochic acid IVa (AA-IVa), the principal component of AAs within members of the Aristolochiaceae family, especially Asarum, a commonly used herb in China, has essentially no significant nephrotoxicity. However, several studies, including ours, have shown that aristolochic acid I (AA-I) is clearly nephrotoxic. PURPOSE: The focus of the study was to elucidate the molecular mechanism responsible for the difference in nephrotoxicity between the AA-I and AA-IVa. STUDY DESIGN/METHOD: Mice were administered with AA-I or AA-IVa for 22 weeks through the oral route, followed by a 50-week recovery time. The kidney tissues of mice were extracted at the end of 22 weeks. Pathological examination and proteomic detection (tandem mass tagging (TMT) and phosphorylated proteomics) were performed on the kidney tissue to investigate the key signaling pathways and targets of AAs-induced renal interstitial fibrosis (RIF). The key signaling pathways and targets were verified by Western blot (WB), siRNA transfection, and luciferase assays. RESULTS: AA-I caused severe nephrotoxicity, high mortality, and extensive RIF. However, the same AA-IVa dosage exhibited almost no nephrotoxicity and does not trigger RIF. The activation of the p38-STAT3-S100A11 signaling pathway and upregulated expression of α smooth muscle actin (α-SMA) and Bcl2-associated agonist of cell death (Bad) proteins could be the molecular mechanism underlying AA-I-induced nephrotoxicity. On the other hand, AA-IVa did not regulate the activation of the p38-STAT3-S100A11 signaling pathway and had relatively little effect on the expression of α-SMA and Bad. Consequently, the difference in the regulation of p38-STAT3-S100A11 pathway, α-SMA, and Bad proteins between AA-I and AA-IVa may be responsible for the divergence in their level of nephrotoxicity. CONCLUSION: This is the first study to reveal the molecular mechanism underlying the difference in nephrotoxicity between AA-I and AA-IVa. Whether STAT3 is activated or not may be the key factor leading to the difference in nephrotoxicity between AA-I and AA-IVa.

Involvement of p38 MAPK/cPLA2 and arachidonic acid metabolic pathway in Shengmai injection-induced pseudo-allergic reactions.

ETHNOPHARMACOLOGICAL RELEVANCE: Adverse reactions to traditional Chinese medicine injections involve pseudo-allergic reactions (PARs). However, in clinical practice, "immediate allergic reactions" and PARs in response to these injections are not often differentiated. AIM OF THE STUDY: This study aimed to clarify the type of reactions produced by Shengmai injections (SMI) and elucidate the possible mechanism. MATERIALS AND METHODS: A mouse model was used to evaluate vascular permeability. Metabolomic and arachidonic acid metabolite (AAM) analyses were performed using UPLC-MS/MS, and the p38 MAPK/cPLA2 pathway was detected by western blotting. RESULTS: The first exposure to intravenous SMI rapidly and dose-dependently induced edema and exudative reactions in the ears and lungs. These reactions were not IgE-dependent and were likely to be PARs. Metabolomic analysis showed that endogenous substances were perturbed in SMI-treated mice, in which the arachidonic acid (AA) metabolic pathway was the most affected. SMI substantially increased the levels of AAMs in lung, including prostaglandins (PGs), leukotrienes (LTs), and hydroxy-eicosatetraenoic acids (HETEs). The p38 MAPK/cPLA2 signaling pathway was activated after a single SMI dose. Inhibitors of cyclooxygenase-2 and 5-lipoxygenase enzymes reduced exudation and inflammation in the ears and lungs of mice. CONCLUSION: Production of inflammatory factors that increase vascular permeability may result in SMI-induced PARs, and p38 MAPK/cPLA2 signaling pathway and downstream AA metabolic pathway are involved in the reactions.

Long-term oral administration of Asarum heterotropoides f. mandshuricum (Maxim.) Kitag. decoction and its aristolochic acid analogs do not cause renal toxicity in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Asarum heterotropoides f. mandshuricum (Maxim.) Kitag. (AH) is widely used to treat influenza, COVID-19, allergic rhinitis, headache, toothache, rheumatoid arthritis, and peptic ulcer. However, its clinical use is controversial due to the concern of aristolochic acid nephropathy (AAN) caused by its component aristolochic acid analogs (AAs). AIM OF THE STUDY: The chronic toxicity of AH decoction and its main components AA IVa (AA-IVa) and aristolactam I (AL-I) was evaluated in mice. MATERIALS AND METHODS: AAs contents in AH were quantitated by liquid chromatography-mass spectrometry. A parallel design was employed to examine the potential chronic toxicity of AH decoction at doses equivalent to 0.5, 1.6, and 5.0 g/kg AH (approximately 10-100 times the clinical doses for humans) and its major AA components at doses equivalent to that in 5.0 g/kg AH to mice after consecutive daily oral administration for 12 and 24 weeks, and at 32 weeks after withdrawal for 8 weeks. RESULTS: AH crude herb contained 2.18 µg/g of AA-I, 48.49 µg/g of AA-IVa, and 14.0 µg/g of AL-I. AH decoction contained 5.45 µg/g of AA-IVa and 2.71 µg/g of AL-I. None of AA-II and AA-IIIa were detected in AH. After long-term administration of AH decoction and its major components AA-IVa and AL-I, mice showed no signs of illness or body weight changes. In addition, biochemical and pathohistological examinations showed that long-term administration of AH decoction and its major components AA-IVa and AL-I did not alter 1) serum levels of glutamic-pyruvic transaminase, glutamic oxalacetic transaminase, alkaline phosphatase, creatinine, and urea nitrogen, 2) renal tissue mRNA expression of kidney injury molecule 1 and neutrophil gelatinase-associated lipocalin, and 3) pathological morphology in the mouse liver, kidney, stomach, and bladder. CONCLUSIONS: AH has no obvious toxicity to mice and is relatively safe when it is used in the form of decoction. AA-IVa and AL-I, the two major AAs in AH, are not toxic to mice at the dose equivalent to that in the high dose of AH decoction. Considering the limited toxicological data on AH, we recommend that AH decoction medication should not overdose and the duration should not be too long.

Costunolide covalently targets NACHT domain of NLRP3 to inhibit inflammasome activation and alleviate NLRP3-driven inflammatory diseases

The NLRP3 inflammasome's core and most specific protein, NLRP3, has a variety of functions in inflammation-driven diseases. Costunolide (COS) is the major active ingredient of the traditional Chinese medicinal herb Saussurea lappa and has anti-inflammatory activity, but the principal mechanism and molecular target of COS remain unclear. Here, we show that COS covalently binds to cysteine 598 in NACHT domain of NLRP3, altering the ATPase activity and assembly of NLRP3 inflammasome. We declare COS's great anti-inflammasome efficacy in macrophages and disease models of gouty arthritis and ulcerative colitis via inhibiting NLRP3 inflammasome activation. We also reveal that the α-methylene-γ-butyrolactone motif in sesquiterpene lactone is the certain active group in inhibiting NLRP3 activation. Taken together, NLRP3 is identified as a direct target of COS for its anti-inflammasome activity. COS, especially the α-methylene-γ-butyrolactone motif in COS structure, might be used to design and produce novel NLRP3 inhibitors as a lead compound.

Mindfulness-based online intervention on mental health among undergraduate nursing students during coronavirus disease 2019 pandemic in Beijing, China: A randomized controlled trial.

Objective: To evaluate the effect of mindfulness intervention on improving mental health among undergraduate nursing students during the coronavirus disease 2019 (COVID-19) pandemic in China. Methods: An online mindfulness intervention course named Mindfulness Living With Challenge (MLWC) was developed by the research team, and a randomized controlled trial using MLWC among Chinese undergraduate nursing students was carried out. A total of 120 undergraduate nursing students were randomized into control (60 students) and intervention groups (60 students) via a WeChat mini program. Self-administered questionnaire surveys were conducted at pre- and post-intervention, measuring depression, anxiety, stress, mindfulness, and perceived social support. After intervention, the acceptance of the online mindfulness course among participants was assessed by employing the theory of technology acceptance model (TAM). Results: Among the enrolled 120 participants, 86.67% (52/60) and 93.33% (56/60) of the intervention and control groups remained completed the trial and the questionnaire surveys. Compared with the control group, the reduction of anxiety and stress symptoms, as well as the improvement of mindfulness level and perceived social support in the MLWC intervention group were statistically significant (P < 0.05), while the change in depression was not statistically significant. The scores of the four dimensions in TAM ranged from (5.88 ± 0.94) to (5.91 ± 0.97). Conclusion: Online mindfulness intervention implemented in this study is effective in improving mental health among undergraduate nursing students, and they were interested in this intervention. Clinical trial registration: [www.ClinicalTrials.gov], identifier [ChiCTR2 200058103].

Role and molecular mechanism of traditional Chinese medicine in preventing cardiotoxicity associated with chemoradiotherapy.

Cardiotoxicity is a serious complication of cancer therapy. It is the second leading cause of morbidity and mortality in cancer survivors and is associated with a variety of factors, including oxidative stress, inflammation, apoptosis, autophagy, endoplasmic reticulum stress, and abnormal myocardial energy metabolism. A number of studies have shown that traditional Chinese medicine (TCM) can mitigate chemoradiotherapy-associated cardiotoxicity via these pathways. Therefore, this study reviews the effects and molecular mechanisms of TCM on chemoradiotherapy-related cardiotoxicity. In this study, we searched PubMed for basic studies on the anti-cardiotoxicity of TCM in the past 5 years and summarized their results. Angelica Sinensis, Astragalus membranaceus Bunge, Danshinone IIA sulfonate sodium (STS), Astragaloside (AS), Resveratrol, Ginsenoside, Quercetin, Danggui Buxue Decoction (DBD), Shengxian decoction (SXT), Compound Danshen Dripping Pill (CDDP), Qishen Huanwu Capsule (QSHWC), Angelica Sinensis and Astragalus membranaceus Bunge Ultrafiltration Extract (AS-AM),Shenmai injection (SMI), Xinmailong (XML), and nearly 60 other herbs, herbal monomers, herbal soups and herbal compound preparations were found to be effective as complementary or alternative treatments. These preparations reduced chemoradiotherapy-induced cardiotoxicity through various pathways such as anti-oxidative stress, anti-inflammation, alleviating endoplasmic reticulum stress, regulation of apoptosis and autophagy, and improvement of myocardial energy metabolism. However, few clinical trials have been conducted on these therapies, and these trials can provide stronger evidence-based support for TCM.

Effectiveness of a Brief Mindfulness-Based Intervention of "STOP touching your face" During the COVID-19 Pandemic: a Randomized Controlled Trial.

Objectives: Avoiding touching the eyes, nose, and mouth (T-zone) is a strategy to reduce the spread of COVID-19. This study evaluated the effectiveness of a brief mindfulness-based intervention (MBI) named "STOP (Stop, Take a Breath, Observe, Proceed) touching your face" for reducing face-touching behavior. Methods: In this online-based, two-arm, wait-list, randomized controlled trial, eligible participants were randomly assigned to the intervention (n = 545) or control group (n = 545). The results of 60-min self-monitoring of face-touching behavior were reported before and after the intervention. Reduction of the percentage of T-zone touching was the primary outcome, and reduction of face-touching frequency was a key secondary outcome. Outcomes were analyzed on an intention-to-treat (ITT) basis with a complete case analysis (CCA). Results: ITT analysis revealed that the percentage of T-zone touching was significantly reduced by 8.1% in the intervention group (from 81.1 to 73.0%, RR = 0.901, OR = 0.631, RD = - 0.081, p = 0.002), and insignificantly reduced by 0.6% in the control group (from 80.0 to 79.4%, p = 0.821). Fewer participants performed T-zone touching in the intervention group than in the control group (73.0% vs. 79.4%, RR = 0.919, OR = 0.700, RD = - 0.064, p = 0.015) after the intervention, and there was a greater reduction of T-zone touching frequency in the intervention group than in the control group [mean ± SD: 1.7 ± 5.13 vs. 0.7 ± 3.98, mean difference (95% CI): 1.03 (0.48 to 1.58), p < 0.001, Cohen's d = - 0.218]. The above results were further confirmed by CCA. Conclusions: This brief mindfulness-based intervention was potentially effective at reducing the spread of COVID-19 and could be further investigated as an intervention for preventing other infectious diseases spread by hand-to-face touching. Trial Registration: ClinicalTrials.gov NCT04330352. Supplementary Information: The online version contains supplementary material available at 10.1007/s12671-022-02019-x.

The Definitions of Health Apps and Medical Apps From the Perspective of Public Health and Law: Qualitative Analysis of an Interdisciplinary Literature Overview.

BACKGROUND: The terms health app and medical app are often used interchangeably but do not necessarily mean the same thing. To better understand these terms and better regulate such technologies, we need distinct definitions of health and medical apps. OBJECTIVE: This study aimed to provide an overview of the definitions of health and medical apps from an interdisciplinary perspective. We summarized the core elements of the identified definitions for their holistic understanding in the context of digital public health. METHODS: The legal frameworks for medical device regulation in the United States, the European Union, and Germany formed the basis of this study. We then searched 6 databases for articles defining health or medical apps from an interdisciplinary perspective. The narrative literature review was supported by a forward and backward snowball search for more original definitions of health and medical apps. A qualitative analysis was conducted on the identified relevant aspects and core elements of each definition. On the basis of these findings, we developed a holistic definition of health and medical apps and created a decision flowchart to highlight the differences between the 2 types. RESULTS: The legal framework showed that medical apps could be regulated as mobile medical devices, whereas there is no legal term for health apps. Our narrative literature review identified 204 peer-reviewed publications that offered a definition of health and medical apps. After screening for original definitions and applying the snowball method, 11.8% (24/204) of the publications were included in the qualitative analysis. Of these 24 publications, 22 (88%) provided an original definition of health apps and 11 (44%) described medical apps. The literature suggests that medical apps are a part of health apps. To describe health or medical apps, most definitions used the user group, a description of health, the device, the legal regulation, collected data, or technological functions. However, the regulation should not be a distinction criterion as it requires legal knowledge, which is neither suitable nor practical. An app's intended medical or health use enables a clear differentiation between health and medical apps. Ultimately, the health aim of an app and its main target group are the only distinction criteria. CONCLUSIONS: Health apps are software programs on mobile devices that process health-related data on or for their users. They can be used by every health-conscious person to maintain, improve, or manage the health of an individual or the community. As an umbrella term, health apps include medical apps. Medical apps share the same technological functions and devices. Health professionals, patients, and family caregivers are the main user groups. Medical apps are intended for clinical and medical purposes and can be legally regulated as mobile medical devices.

Gut Microbiota-Derived Diaminopimelic Acid Promotes the NOD1/RIP2 Signaling Pathway and Plays a Key Role in the Progression of Severe Acute Pancreatitis.

Impaired intestinal barrier function and gut microbiota dysbiosis are believed to be related to exacerbation of acute pancreatitis (AP). As a bacterial cell wall peptidoglycan component, diaminopimelic acid (DAP) is a specific ligand of NOD1 that regulates the NOD1/RIP2/NF-kB signaling pathway. Here, we investigated the role of DAP in the crosstalk between the gut microbiota and pancreas during the occurrence of AP. Upregulation of NOD1/RIP2/NF-kB and elevated serum DAP levels were found in severe AP (SAP) model rats. The accumulation of DAP in SAP patients corroborated its ability to serve as an indicator of disease severity. Subsequently, SAP rats were treated with oral administration of the traditional Chinese medicine Qingyi Keli (QYKL) as well as neomycin, which can widely eliminate DAP-containing bacteria. Both QYKL and neomycin intervention ameliorated intestinal and pancreatic damage and systemic inflammation in SAP rats. Through 16S rDNA sequencing, we found that QYKL could rehabilitate the gut microbiota structure and selectively inhibit the overgrowth of enteric bacteria, such as Helicobacter and Lactobacillus, in SAP rats without affecting some protective strains, including Romboutsia and Allobaculum. Interestingly, we demonstrated that the decrease in serum DAP was accompanied by suppression of the NOD1/RIP2/NF-kB signaling pathway in both the intestine and pancreas of the two intervention groups. Taken together, these results suggested that the gut microbiota-DAP-NOD1/RIP2 signaling pathway might play a critical role in the progression of AP and that SAP could be alleviated via intervention in the signaling pathway. Our work provides new potential early warning indicators of SAP and targets for intervention.

Prediction of clinical efficacy of subcutaneous immunotherapy for Artemisia sieversiana pollen allergic rhinitis by serum metabolomics.

BACKGROUND/PURPOSE: Specific immunotherapy is the only effective etiological treatment for allergic rhinitis, but subcutaneous immunotherapy has a slow onset and poor compliance. Predicting the clinical efficacy of subcutaneous immunotherapy in advance can reduce unnecessary medical costs and resource waste. This study aimed to identify metabolites that could predict the efficacy of subcutaneous immunotherapy on seasonal allergic rhinitis by serum metabolomics. METHODS: Patients (n = 43) with Artemisia sieversiana pollen allergic rhinitis were enrolled and treated with subcutaneous immunotherapy for one year. Patients were divided into the ineffective group (n = 10) and effective group (n = 33) according to the therapeutic index. Serum samples were collected before treatment. Metabolomics was determined by liquid chromatography-mass spectrometry combined with gas chromatography-mass spectrometry and analyzed differential compounds and related metabolic pathways. RESULTS: A total of 129 differential metabolites (P < 0.05) were identified and 4 metabolic pathways, namely taurine and hypotaurine metabolism, pentose and glucuronate interconversions, pentose phosphate pathway, and alanine, aspartate, and glutamate metabolism, were involved. CONCLUSION: Some metabolites, such as hypotaurine, taurine, and l-alanine, have the potential to become predictive biomarkers for effective subcutaneous immunotherapy.

Cornuside ameliorates cognitive impairments in scopolamine induced AD mice: Involvement of neurotransmitter and oxidative stress.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornus officinalis Sieb. et Zucc., traditional Chinese medicine, has been widely used in the treatment of dementia. Cornel iridoid glycosides of Cornus officinalis is therapeutic to Alzheimer's disease (AD), while its pharmacodynamic material basis is not clear. Cornuside, an iridoid glycoside extracted from of Cornus officinalis Sieb. et Zucc, might be a potential anti-AD candidate. AIM OF THE STUDY: Cornuside was evaluated for its effect on scopolamine induced AD mice, and its action mechanisms were explored. MATERIALS AND METHODS: ICR mice were administered with 1 mg/kg scopolamine intraperitoneally to induce amnesia. The therapeutic effect of cornuside of cognitive function was evaluated via series of behavioral tests, including Morris water maze test, step-through test and step-down test. In addition, specific enzyme reaction tests were used to detect the content of acetylcholine (ACh) and malondialdehyde (MDA), as well as the activities of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), choline acetyltransferase (ChAT), superoxide dismutase (SOD), catalase (CAT), monoamine oxidase (MAO) in the brain. The levels of monoamine neurotransmitters were detected by high performance liquid chromatography-electrochemical detection (HPLC-ECD). RESULTS: Cornuside ameliorated the spatial memory impairment in Morris water maze test and cognitive disruption in step-through and step-down test. Furthermore, cornuside improved the level of ACh by reducing the activities of AChE and BuChE, and increasing the activity of ChAT in hippocampus. Cornuside also increased the levels of monoamine neurotransmitters by inhibiting MAO activity in hippocampus and cortex. In addition, cornuside attenuated MDA by enhancing the activities of SOD and CAT in hippocampus and cortex. CONCLUSION: Cornuside improved cognitive dysfunction induced by scopolamine in behavioral tests. The mechanisms of cornuside were further investigated from the aspects of neurotransmitters and oxidative stress. Cornuside could inhibit oxidative stress and neurotransmitter hydrolases, increase ACh and monoamine neurotransmitters, which finally contributed to its therapeutic effect on scopolamine induced amnesia.

'Mindfulness Living with Insomnia': an mHealth intervention for individuals with insomnia in China: a study protocol of a randomised controlled trial.

INTRODUCTION: Insomnia has a remarkably negative effect on the work, quality of life and psychosomatic health of individuals, and imposes a substantial economic burden on society. Mindfulness-based interventions (MBIs) have proven beneficial in the treatment of insomnia. However, the effect of mobile or online-based (mHealth) MBIs requires further verification. This study will evaluate the effectiveness of an mHealth MBI, 'Mindful Living with Insomnia' (MLWI), relative to that of mHealth cognitive behavioural therapy for insomnia (CBT-I). METHODS AND ANALYSIS: The study is an mHealth, randomised controlled trial. Two hundred and fifty participants will be allocated randomly and equally to either the MLWI or CBT-I group. The intervention will involve 12 sessions over a 6-week course, with 2, 30 min sessions per week. The primary outcomes are sleep quality, severity of insomnia symptoms and sleep activity, according to the Pittsburgh Sleep Quality Index, Insomnia Severity Index and sleep tracker Mi Smart Band, respectively. The secondary outcomes are perceived stress, anxiety, depression and mindfulness. Outcomes will be evaluated at the baseline, end of the intervention period and at the 3-month follow-up. Data analyses will include covariance, regression analysis, χ2, t-test and Pearson's correlations. Participants will be recruited from January to June 2022, or until the recruitment process is complete. The follow-up will be completed in December 2022. All trial results should be available by the end of December 2022. ETHICS AND DISSEMINATION: Full approval for this study has been obtained from the Ethics Committee at The Third Xiangya Hospital, Central South University, Changsha, China (21010). Study results will be disseminated via social media and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04806009.

Pharmacological effects and safety of Andrographis paniculata (Burm.f.) Nees.

Andrographis paniculata (Burm.f.) Nees (AP) is widely used in most Asian and some Western countries. However, its main effects and underlying pharmacological mechanism have not been thoroughly characterized, and its safety has not been sufficiently investigated. The present study aimed to predict and visualize the potential targets and pathways, clarify the main pharmacological effects, and investigate the toxicological properties of AP extract (APE). First, ingenuity pathway analysis (IPA) was performed to directly predict AP's therapeutic targets and pathways; main pharmacological effects of AP were speculated based on IPA results and confirmed by pharmacodynamics experiments. Rodent toxicity studies were then performed through administration of a single dose of 10 g/kg or daily doses of 2, 1, or 0.5 g/kg for 8 weeks to evaluate the safety of APE, and a similar repeated-dose study was performed using dogs with doses equal to half of the above-mentioned doses. Thus, repeated-dose toxicity studies were performed with both rodents and nonrodents. The IPA analysis and confirmatory pharmacodynamics experiments revealed that the main pharmacological effect of APE was anti-inflammation, which might be achieved by influencing various targets (e.g., AR, AKT, and BAX) and pathways (IL-8). In the single-dose toxicity test, no death or abnormal consequences were observed, and maximum tolerated dose of APE was 10 g/kg. Results from the repeated-dose toxicity tests did not reveal any obvious toxic effects from the repeated daily intragastric administration of APE at 1 g/kg for 8 weeks. In conclusion, APE at a dose of 1 g/kg did not exert any adverse effects, and administration of APE could be beneficial for the inflammatory diseases' treatment. PRACTICAL APPLICATION: Andrographis paniculata (Burm.f.) Nees is a plant that exerts clearing and detoxification effects and is widely used around the world, but a comprehensive analysis of its efficacy and safety is needed.