The essential role of glutamine metabolism in diabetic cardiomyopathy: A review.

Diabetic cardiomyopathy (DCM) is a pathophysiological condition caused by diabetes mellitus and is the leading cause of diabetes mellitus-related mortality. The pathophysiology of DCM involves various processes, such as oxidative stress, inflammation, ferroptosis, and abnormal protein modification. New evidence indicates that dysfunction of glutamine (Gln) metabolism contributes to the pathogenesis of DCM by regulating these pathophysiological mechanisms. Gln is a conditionally essential amino acid in the human body, playing a vital role in maintaining cell function. Although the precise molecular mechanisms of Gln in DCM have yet to be fully elucidated, recent studies have shown that supplementing with Gln improves cardiac function in diabetic hearts. However, excessive Gln may worsen myocardial injury in DCM by generating a large amount of glutamates or increasing O-GlcNacylation. To highlight the potential therapeutic method targeting Gln metabolism and its downstream pathophysiological mechanisms, this article aims to review the regulatory function of Gln in the pathophysiological mechanisms of DCM.

Methylmalonic acid, vitamin B12, and mortality risk in patients with preexisting coronary heart disease: a prospective cohort study.

BACKGROUND: The inconsistent relationship between Vitamin B12 (B12), methylmalonic acid (MMA, marker of B12 deficiency) and mortality was poorly understood, especially in patients with coronary heart disease (CHD). This study aims to investigate the association of serum MMA, and B12-related biomarkers (serum level, dietary intake, supplement use, and sensibility to B12) with all-cause and cardiovascular mortality in adults with CHD. METHODS: The data of this study were from a subcohort within the US National Health and Nutrition Examination Survey (NHANES). We included adults with preexisting CHD with serum MMA and B12, and dietary B12 intake measurements at recruitment. All participants were followed up until 31 December 2019. Weighted Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% CI of mortality risk. RESULTS: Overall, 1755 individuals (weighted mean [SE] age, 65.2 [0.5] years; 1047 men [weighted 58.5%]) with CHD were included, with geometric mean levels of serum MMA 182.4 nmol/L, serum B12 494.5 pg/ml, and dietary B12 intake 4.42 mg/day, and percentage of B12 supplements use 39.1%. During a median follow-up of 7.92 years, 980 patients died. Serum B12 concentration, dietary B12 intake and supplements use were not significantly associated with mortality risk (each p ≥ 0.388). In contrast, individuals in the top tertile of MMA had multivariable-adjusted HRs (95% CIs) of 1.70 (1.31-2.20) for all-cause mortality, and 2.00 (1.39-2.89) for cardiovascular mortality (both p trend < 0.001) compared to those in the bottom tertile of MMA. MMA-related mortality risk was particularly higher among participants with sufficient serum B12 (p < 0.001). CHD patients with increased levels of both MMA and B12 had a doubled mortality risk compared to those with lower MMA and B12 (p < 0.001). CONCLUSION: MMA accumulation but not serum or dietary vitamin B12 was associated with increased cardiovascular mortality risk among patients with CHD. This paradox may be related to decreased response to vitamin B12.

Impact of gut microbiota on nonalcoholic fatty liver disease: insights from a leave-one-out cross-validation study.

Introduction: Enteric dysbacteriosis is strongly associated with nonalcoholic fatty liver disease (NAFLD). However, the underlying causal relationship remains unknown. Thus, the present study aimed to investigate the relationship between gut microbiota and NAFLD using Mendelian randomization (MR) and analyze the target genes potentially regulated by specific microbiota. Methods: Bidirectional two-sample MR analysis was performed using inverse variance weighted (IVW) supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Data were pooled from gut microbiota and NAFLD association studies. The least absolute shrinkage, selection operator regression, and the Support Vector Machine algorithm were used to identify genes regulated by these intestinal flora in NAFLD. The liver expression of these genes was verified in methionine choline-deficient (MCD) diet-fed mice. Results: IVW results confirmed a causal relationship between eight specific gut microbes and NAFLD. Notably, the order Actinomycetales, NB1n, the family Actinomycetaceae, Oxalobacteraceae and the genus Ruminococcaceae UCG005 were positively correlated, whereas Lactobacillaceae, the Christensenellaceae R7 group, and Intestinibacter were negatively correlated with NAFLD onset. In NAFLD, these eight bacteria regulated four genes: colony-stimulating factor 2 receptor ß, fucosyltransferase 2, 17-beta-hydroxysteroid dehydrogenase 14, and microtubule affinity regulatory kinase 3 (MAPK3). All genes, except MARK3, were differentially expressed in the liver tissues of MCD diet-fed mice. Discussion: The abundance of eight gut microbiota species and NAFLD progression displayed a causal relationship based on the expression of the four target genes. Our findings contributed to the advancement of intestinal microecology-based diagnostic technologies and targeted therapies for NAFLD.

Applicability of Zipf's Law in Traditional Chinese Medicine Prescriptions.

Objective Traditional Chinese medicine (TCM) prescriptions have been used to cure diseases in China for thousands of years, in which many TCM herbs have no definite common quantity. Some key TCM herbs are commonly used and thus deserve in-depth investigations based on a more acceptable classification method. This study analyzes whether TCM prescriptions follow Zipf's law and attempts to obtain the thresholds of key TCM herbs based on the application of Zipf's law. Methods A total of 84,418 TCM prescriptions were collected and standardized. We tested whether Zipf's law and Zipf's distribution fit the Chinese herb distributions. A linear fitting experiment was performed to verify the relationship between the frequency distribution and frequency of TCM herbs. Results The distribution of TCM herbs in TCM prescriptions conformed to Zipf's law. Accordingly, the thresholds were obtained for the key TCM herbs. Conclusion The distribution of TCM herbs in TCM prescriptions follows Zipf's law.

[Identification of metabolites of Yiqi Baoyuan Prescription in rat plasma, bile, urine and feces after oral administration].

This study was designed to determine the metabolites of Yiqi Baoyuan Prescription(YQBYP) in rats. The ultra-high performance liquid chromatography coupled to time-of-flight mass spectrometry(UPLC-TOF-MS) and mass defect filter(MDF) were employed to analyze the metabolites of YQBYP in rat plasma, bile, urine and feces. Chromatographic separation was conducted on Acquity UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 µm) under gradient elution with 0.1% formic acid aqueous solution(A)-acetonitrile(B), and the column temperature was 30 ℃. Electrospray ion(ESI) source was used under positive and negative ion modes, with capillary voltage of 3.0 kV and mass scanning range of m/z 100-1 000. In this experiment, 9 prototype components and 36 metabolites were identified in rat plasma, bile, urine and feces samples. The results showed that the main metabolic pathways of YQBYP in rats involved methylation, demethylation, oxidation, and other phase Ⅰ reactions as well as glucuronidation, sulfation, and other phase Ⅱ reactions. This study provided scientific basis for clarifying the therapeutic material basis of YQBYP and product development.

Electroacupuncture attenuates surgical pain-induced delirium-like behavior in mice via remodeling gut microbiota and dendritic spine.

Surgical pain is associated with delirium in patients, and acupuncture can treat pain. However, whether electroacupuncture can attenuate the surgical pain-associated delirium via the gut-brain axis remains unknown. Leveraging a mouse model of foot incision-induced surgical pain and delirium-like behavior, we found that electroacupuncture stimulation at specific acupoints (e.g., DU20+KI1) attenuated both surgical pain and delirium-like behavior in mice. Mechanistically, mice with incision-induced surgical pain and delirium-like behavior showed gut microbiota imbalance, microglia activation in the spinal cord, somatosensory cortex, and hippocampus, as well as an enhanced dendritic spine elimination in cortex revealed by two-photon imaging. The electroacupuncture regimen that alleviated surgical pain and delirium-like behavior in mice also effectively restored the gut microbiota balance, prevented the microglia activation, and reversed the dendritic spine elimination. These data demonstrated a potentially important gut-brain interactive mechanism underlying the surgical pain-induced delirium in mice. Pending further studies, these findings revealed a possible therapeutic approach in preventing and/or treating postoperative delirium by using perioperative electroacupuncture stimulation in patients.

Pharmacokinetics-derived absorbed components responsible for Guizhi-Fuling capsule target PI3K/Akt-Erk to exert an anti-dysmenorrhea effect.

ETHNOPHARMACOLOGICAL RELEVANCE: Guizhi-Fuling capsule (GZFL), a well-known herbal remedy, has been widely used to treat primary dysmenorrhea (PD). Hence, systematic identifying multiple active ingredients and the involved mechanism is essential and urgently needed for GZFL. AIM OF THE STUDY: This study was planned to assess the pharmacokinetics of GZFL in rats, and identify whether these GZFL-derived absorbed components (ACs) contribute to the efficacy of source herbs and relevant mechanism. MATERIALS AND METHODS: The in vivo pharmacokinetic profile of 11 phytochemicals and 13 metabolites in healthy and PD rats were evaluated using liquid chromatography with mass spectrometry (LC-MS/MS). Whereafter, the introduced contribution strategy assessed ACs' effect (doses = their contents in GZFL) in PD rats with the mechanism. RESULT: The pharmacokinetic profiles of prototypes and metabolites differed in healthy and PD rats. As a main proxy of GZFL, 11ACs exerted an anti-PD effect (improvement of indexes for writhing latency, writhing time, PGF2α/PGE2, TXB2/6-keto-PGF1α and ß-EP) by regulating PI3K-Akt/ERK pathway. CONCLUSION: As a paradigmatic example, 11ACs contributed an average of 113.55% to GZFL in terms of anti-PD efficacy, providing an approach to rapidly, accurately and consistently identify the bioactive components and their pathway from herbs.

[Determination of eight active components of Bufei Huoxue Capsules in rat plasma and their pharmacokinetics by UHPLC-MS/MS].

An ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS) method was established to investigate the pharmacokinetic behaviors of psoralenoside, isopsoralenoside, calycosin-7-glucoside, ononin, psoralen, isopsoralen, methylnissolin, and neobavaisoflavone in rat plasma after oral administration of Bufei Huoxue Capsules. After SD rats were administered with Bufei Huoxue Capsules suspension by gavage, blood samples were collected from the inner canthus at different time points. After protein precipitation, plasma samples were separated on ACQUITY UPLC BEH C_(18) column(2.1 mm×100 mm, 1.7 µm). The mobile phase consisted of acetonitrile(A) and water(B) containing 0.1% formic acid in gradient elution. The positive and negative ions were measured simultaneously in the multi-reaction monitoring(MRM) mode. The pharmacokinetic parameters were calculated and fitted by DAS 3.2.8. Psoralenoside, isopsoralenoside, calycosin-7-glucoside, ononin, psoralen, isopsoralen, methylnissolin, and neobavaisoflavone were detected in the rat plasma after drug administration, with AUC_(0-t) of(3 357±1 348),(3 555±1 696),(3.03±0.88),(2.21±0.33),(1 787±522),(2 295±539),(5.69±1.41) and(3.40±0.75) µg·L~(-1)·h, and T_(max) of(1.56±0.62),(1.40±0.70),(0.21±0.05),(0.25±0.12),(0.26±0.11),(0.34±0.29),(0.74±0.59), and 0.25 h. The method is proved specific and repeatable and is suitable for the determination of psoralenoside, isopsoralenoside, calycosin-7-glucoside, ononin, pso-ralen, isopsoralen, methylnissolin, and neobavaisoflavone in the rat plasma, which can be applied to pharmacokinetic study.

The influence of essential oils from ZhaLi NuSi Prescription on the pharmacokinetics of its non-volatile components in normal rats.

Hui Medicine ZhaLi NuSi Prescription (ZLNS) is described in "Hui Hui Prescription," and it has been used to treat cerebral infarction in Hui Region, China. In this study, a rapid and reliable ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS/MS) method was established and applied to simultaneously determine geniposidic acid, oxypaeoniflorin, hydroxysafflor yellow A, caffeic acid, magnoflorine, paeoniflorin, ferulic acid, ß-ecdysterone, icariin, rhein, and baohuoside I in rat plasma. The pharmacokinetic parameters of these components and the influence of essential oils (EOs) on them were investigated in normal rats. The results showed that the pharmacokinetic parameters (AUC0 - t , AUC0 - ∞ , t1/2 , tmax , cmax ) of the aforementioned compounds were significantly changed after co-administering with ZLNS EO. The AUC values of oxypaeoniflorin, paeoniflorin, ferulic acid, and baohuoside I with EOs were decreased significantly. This is the first report for the comparative pharmacokinetic study of ZLNS bioactive components in normal rats, which may provide the basis for drug interaction study in vivo and insight into their clinical applications.

Cobalamin Intake and Related Biomarkers: Examining Associations With Mortality Risk Among Adults With Type 2 Diabetes in NHANES.

OBJECTIVE: Despite that periodical monitoring of cobalamin (vitamin B12) in metformin-treated patients with diabetes is recommended, cobalamin-associated mortality benefits or risks remain unclear. We investigated the association between cobalamin intake and related biomarkers and mortality risk in adults with diabetes using metformin or not. RESEARCH DESIGN AND METHODS: This study included 3,277 adults with type 2 diabetes from the National Health and Nutrition Examination Survey (NHANES) and followed up until 31 December 2015. Weighted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for mortality risk. RESULTS: Among 3,277 participants, 865 all-cause deaths occurred during a median follow-up of 7.02 years. There was no robust relationship between all-cause mortality and serum cobalamin or intake of foods or cobalamin supplements, regardless of metformin treatment (each P ≥ 0.120). The doubling of methylmalonic acid (MMA), a cobalamin-deficiency marker, was significantly associated with higher all-cause (HR 1.31 [95% CI 1.18-1.45], P < 0.001) and cardiac (HR 1.38 [95% CI 1.14-1.67], P = 0.001) mortality. Cobalamin sensitivity was assessed by the combination of binary B12low/high and MMAlow/high (cutoff values: cobalamin 400 pg/mL, MMA 250 nmol/L). Patients with decreased cobalamin sensitivity (MMAhighB12high) had the highest mortality risk. The multivariable-adjusted HRs (95% CIs) of all-cause mortality in MMAlowB12low, MMAlowB12high, MMAhighB12low, and MMAhighB12high groups were 1.00 (reference), 0.98 (0.75-1.28), 1.49 (1.16-1.92), and 1.96 (1.38-2.78), respectively. That association was especially significant in metformin nonusers. CONCLUSIONS: Serum and dietary cobalamin were not associated with reduced mortality. Decreased cobalamin sensitivity was significantly associated with all-cause and cardiac mortality, particularly among metformin nonusers.

Association of habitually low intake of dietary selenium with new-onset stroke: A retrospective cohort study (2004-2015 China Health and Nutrition Survey).

Background: As an essential trace element in the body, selenium is associated with the development of many diseases. The purpose of this study was to explore the association between dietary selenium intake and new-onset stroke risk in Chinese adults. Methods: Adults aged ≥18 years in the China Health and Nutrition Survey (CHNS) from 2004 to 2015 were enrolled. Participants were divided into five groups according to the quintile of dietary selenium intake: Q1 (≤ 29.80 µg/day), Q2 (29.80-38.53 µg/day), Q3 (38.53-47.23 µg/day), Q4 (47.23-60.38 µg/day), Q 5(>60.38 µg/day). Cox proportional-hazards model was used to explore the effect of dietary selenium on new-onset stroke. Restricted cubic spline (RCS) was used to visualize the dose-response relationship between dietary selenium and the risk of morbidity. Results: A total of 11,532 subjects were included, and 271 (2.35%) of them developed stroke during a mean follow-up of 6.78 person-years. Compared with the lowest selenium intake group, the HR and 95%CI of stroke in the participants with selenium intake of Q2, Q3, Q4 and Q5 were: 0.85 (0.59, 1.21), 0.62 (0.42, 0.92), 0.43 (0.28, 0.68), 0.49 (0.30, 0.82), respectively. There was an L-shaped relationship between dietary selenium and stroke (nonlinear P-value = 0.0420). The HR and 95%CI of developing stroke was 0.75 (0.65, 0.87) in participants with selenium intake ≤ 60 µg/day. Conclusions: The L-shaped negative association between dietary selenium and stroke in Chinese adults which indicated that dietary selenium should be improved to a certain level to prevent stroke.

Rapid screening of lipase inhibitors in licorice extract by using porcine pancreatic lipase immobilized on Fe3O4 magnetic nanoparticles.

Chalcones, a class of natural lipase inhibitors, have received substantial attention from researchers in recent years. Although many kinds of chalcones are typically distributed in G. inflata, there is little literature about the anti-lipase activity of G. inflata extracts (GIEs). In the present study, a ligand fishing strategy for fast screening of lipase inhibitors from GIEs was thus proposed. Porcine pancreatic lipase (PPL) was firstly immobilized on carboxyl modified Fe3O4 magnetic nanoparticles (MNPs) to obtain PPL functionalized MNPs (PPL@MNPs), and then the PPL@MNPs were incubated with a bioactive fraction to fish out the ligands. Eight ligands were obtained and identified as one flavone together with seven chalcones. Licochalcone A, licochalcone D and licochalcone E inhibited pancreatic lipase (PL) with IC50 of 4.9, 3.2 and 5.8 µM, respectively. Meanwhile, investigation of the structure-activity relationship also revealed that isopentenyl and hydroxyl substituents at ring A were essential for the noncovalent inhibitory potency of the chalcones.

Bardet-Biedl syndrome proteins regulate intracellular signaling and neuronal function in patient-specific iPSC-derived neurons.

Bardet-Biedl syndrome (BBS) is a rare autosomal recessive disorder caused by mutations in genes encoding components of the primary cilium and is characterized by hyperphagic obesity. To investigate the molecular basis of obesity in human BBS, we developed a cellular model of BBS using induced pluripotent stem cell-derived (iPSC-derived) hypothalamic arcuate-like neurons. BBS mutations BBS1M390R and BBS10C91fsX95 did not affect neuronal differentiation efficiency but caused morphological defects, including impaired neurite outgrowth and longer primary cilia. Single-cell RNA sequencing of BBS1M390R hypothalamic neurons identified several downregulated pathways, including insulin and cAMP signaling and axon guidance. Additional studies demonstrated that BBS1M390R and BBS10C91fsX95 mutations impaired insulin signaling in both human fibroblasts and iPSC-derived neurons. Overexpression of intact BBS10 fully restored insulin signaling by restoring insulin receptor tyrosine phosphorylation in BBS10C91fsX95 neurons. Moreover, mutations in BBS1 and BBS10 impaired leptin-mediated p-STAT3 activation in iPSC-derived hypothalamic neurons. Correction of the BBS mutation by CRISPR rescued leptin signaling. POMC expression and neuropeptide production were decreased in BBS1M390R and BBS10C91fsX95 iPSC-derived hypothalamic neurons. In the aggregate, these data provide insights into the anatomic and functional mechanisms by which components of the BBSome in CNS primary cilia mediate effects on energy homeostasis.

Association Between Vitamin D and Hyperuricemia Among Adults in the United States.

Background: Serum uric acid can act as a risk factor for cardiovascular disease (CVD) and as antioxidant defense. Vitamin D deficiency can activate the parathyroid to induce the release of parathyroid hormone, which was thought to increase serum uric acid level, and low vitamin D status may also be associated with risk of CVD. No known studies have explored the association between serum 25(OH) D, vitamin D intake, and HU for the American population. Methods: We extracted 15,723 US adults aged 20-85 years from the National Health and Nutrition Examination Survey (NHANES) in 2007-2014. All dietary intakes were evaluated through 24-h dietary recalls. Multivariable logistic regression analysis was performed to examine the associations after adjustment for confounders. Results: Compared to the lowest quintile (Q1), for males, adjusted odds ratios (ORs) of HU in Q2 to Q4 of serum 25(OH) D levels were 0.78 (95% CI, 0.65-0.93), 0.97 (0.81-1.16), and 0.72 (0.60-0.88); ORs in Q2-Q5 of total vitamin D intake were 0.83 (0.69-0.98), 0.69 (0.58-0.83), 0.66 (0.55-0.79), and 0.59 (0.48-0.71), respectively. In females, OR was 0.80 (0.66-0.97) of serum 25(OH) D for Q3, and ORs in Q5 of total vitamin D intake were 0.80 (0.65-0.98). Conclusions: Our findings indicated that the serum 25(OH) D intakes of dietary vitamin D, supplemental vitamin D, and total vitamin D were inversely associated with HU in males. In females, a lower risk of HU with higher serum 25(OH) D, dietary vitamin D, and total vitamin D intake was found, but with no association between supplemental vitamin D intake and the risk of HU.

Loss of MAGEL2 in Prader-Willi syndrome leads to decreased secretory granule and neuropeptide production.

Prader-Willi syndrome (PWS) is a developmental disorder caused by loss of maternally imprinted genes on 15q11-q13, including melanoma antigen gene family member L2 (MAGEL2). The clinical phenotypes of PWS suggest impaired hypothalamic neuroendocrine function; however, the exact cellular defects are unknown. Here, we report deficits in secretory granule (SG) abundance and bioactive neuropeptide production upon loss of MAGEL2 in humans and mice. Unbiased proteomic analysis of Magel2pΔ/m+ mice revealed a reduction in components of SG in the hypothalamus that was confirmed in 2 PWS patient-derived neuronal cell models. Mechanistically, we show that proper endosomal trafficking by the MAGEL2-regulated WASH complex is required to prevent aberrant lysosomal degradation of SG proteins and reduction of mature SG abundance. Importantly, loss of MAGEL2 in mice, NGN2-induced neurons, and human patients led to reduced neuropeptide production. Thus, MAGEL2 plays an important role in hypothalamic neuroendocrine function, and cellular defects in this pathway may contribute to PWS disease etiology. Moreover, these findings suggest unanticipated approaches for therapeutic intervention.

Study on Mechanism of Iridoid Glycosides Derivatives from Fructus Gardeniae in Jiangxi Province by Network Pharmacology.

OBJECTIVE: To investigate the pharmacological mechanism of the iridoid glycosides from Fructus Gardeniae in Jiangxi province by network pharmacology. To provide a valuable research strategy for the rational use and in-depth research and development of Fructus Gardeniae from Jiangxi. METHOD: Previous research results of our group show that the contents of iridoid glycosides in Fructus Gardeniae from Jiangxi province have a significant difference compared with other regions (P < 0.05). Based on our previous experimental results, this study selected six characteristic high-content bioactive iridoid glycosides components of Fructus Gardeniae from Jiangxi province as candidate components. TCMSP database was used to obtain the process parameters of absorption, distribution, metabolism, and excretion (ADME) of candidate components. PubChem and SWISS online database were used to predict the related targets. Cytoscape software was used to the construct compound-target-disease (C-T-D) network of the Fructus Gardeniae iridoid glycosides ingredients. Furthermore, the GO biological process analysis and the pathway enrichment analysis were carried out using the CTD online analysis platform; then, an illustrated network that contains the main "chemicals-targets-pathway (C-T-P)" was constructed to analyze main biological pathways for obtaining the deep mechanism of Fructus Gardeniae in Jiangxi. RESULTS: 6 iridoid glycosides, namely geniposide, gardenoside, geniposidic acid, genipin 1-gentiobioside, gardoside, and shanzhiside, from Fructus Gardeniae in Jiangxi province were obtained as candidate components through previous work and network pharmacology screening. 36 corresponding targets were acted, such as BCL2, MAPT, F2, BCL2L1, PRKCD, PRKCB, HIF1A, and PRKCA. These targets could joint in pathways, such as signaling by GPCR, neuroactive ligand-receptor interaction, inflammatory mediator regulation of TRP channels, and ion channel transport. Interestingly, these pathways were highly associated with liver diseases, neurological diseases, hypertension, neoplasms, hyperalgesia, and inflammation. Remarkably, we boldly speculate that the Fructus Gardeniae from Jiangxi province can play a pharmacological role in hepatic encephalopathy through regulating multiple signaling pathways in an integrated manner. CONCLUSION: The method based on system pharmacology could help to find the key targets of characteristic high-content chemical constituents of herb from different producing areas, the signaling pathway and disease network of TCM, and provide useful information and data support for giving a further study on traditional Chinese medicine resources in different regions of China.

Nasal nebulization inhalation of budesonide for chronic rhinosinusitis with nasal polyps: A protocol for systematic review and meta-analysis.

BACKGROUND: Chronic rhinosinusitis and nasal polyps (CRNP) is a common public health concern for general population, and is thought to negatively impact their quality of life. Although previous studies have reported that nasal nebulization inhalation of budesonide (NNIB) can benefit patients with such condition, its conclusions are still inconsistent. Thus, this study will assess the efficacy and safety of NNIB for the treatment of CRNP. METHODS: To identify any associated studies, we will comprehensively and systematically search Cochrane Library, PubMed, EMBASE, Web of Science, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, and China National Knowledge Infrastructure. We will search all electronic databases from inception to the present with no limitations of language and publication status. Two independent reviewers will undertake selection of study, data collection, and study quality evaluation, respectively. Another reviewer will help to settle down any different opinions between both of them. Study quality will be checked using Cochrane risk of bias tool, and statistical analysis will be performed using RevMan 5.3 software. RESULTS: This study will assess the efficacy and safety of NNIB for the treatment of CRNP through assessing primary outcomes of nasal symptoms and polyp sizes, and secondary outcomes of serum cortisol levels, health-related quality of life, and any expected and unexpected adverse events. CONCLUSION: The results of this study will summarize the up-to-date evidence on assessing the efficacy and safety of NNIB for the treatment of CRNP. STUDY REGISTRATION NUMBER: INPLASY202040108.

Effect of CO2 laser for the management of primary otosclerosis: A protocol for systematic review and meta-analysis.

BACKGROUND: This study will explore the effect and safety of CO2 laser (COL) for the management of patients with primary otosclerosis (PO). METHODS: The following electronic databases will be searched from inception to the present: PUBMED, EMBASE, The Cochrane Library, Web of Science, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, Chinese Biomedical Literature Database, VIP, WANGFANG, and China National Knowledge Infrastructure. No language limitation will be applied. All relevant randomized controlled trials using COL to treat patients with PO will be included. Two researchers will identify studies, collect data and evaluate the risk of bias of each included study independently. Any different views between 2 researchers will be resolved by a third researcher via discussion. Data analysis will be carried out using RevMan 5.3 software. RESULTS: This study will evaluate the effect and safety of COL for the treatment of PO through hearing gain, tinnitus severity, incidence of intraoperative, health-related quality of life, other morbidities, and adverse events. CONCLUSION: This study will provide evidence for the effect and safety of COL in patients with PO. STUDY REGISTRATION NUMBER: INPLASY202040110.

Identification of metabolites of FR429, a potential antitumor ellagitannin, transformed by rat intestinal bacteria in vitro, based on liquid chromatography-ion trap-time of flight mass spectrometry analysis.

FR429 is an ellagitannin with a potential antitumor activity, isolated and purified from Polygonum capitatum Buch.-Ham.ex D.Don, which is a traditional Miao-nationality herbal medicine in Guizhou and Yunnan of China. Our preliminary result of pharmacology study has indicated that the antitumor activity of FR429. However, the metabolism of FR429 has not been reported yet. In this study, LC-ion trap-time of flight mass spectrometry (LC-IT-TOF/MS) was used to characterize unpredictable metabolites of FR429 biotransformed by intestinal bacteria in vitro. Total thirteen metabolites were detected and characterized via comparisons of their accurate molecular masses and fragment ions of each MS(n) stage with those of the parent drug, and four of them were also elucidated by NMR. The results demonstrated that FR429 could be transformed by intestinal bacteria in vitro, mainly via hydrolysis and reduction reaction. This work provided a basis for the further study on the biotansformation of FR429 in vivo.

In vitro study on metabolite profiles of bioactive xanthones isolated from Halenia elliptica D. Don by high performance liquid chromatography coupled to ion trap time-of-flight mass spectrometry.

The metabolisms of five xanthones isolated from a Tibetan medicinal herb Halenia elliptica D. Don, including 1-hydroxy-2,3,5-trimethoxy-xanthone (HM-1), 1-hydroxy-2,3,4,7-tetramethoxy-xanthone (HM-2), 1-hydroxy-2,3,4,5-tetramethoxy-xanthone (HM-3), 1,7-dihydroxy-2,3,4,5-tetramethoxy-xanthone (HM-4) and 1,5-dihydroxy-2,3-dimethoxy-xanthone (HM-5), were studied in rat liver microsomes in vitro. High performance liquid chromatography coupled to ion trap time-of-flight mass spectrometry (LC-ESI-IT-TOF) was applied for identification of metabolites of five xanthones mentioned above and (1)H NMR was used to elucidate the major metabolites. The structures of thirteen metabolites were identified and seven of them had not been reported before. Moreover, xanthone isomers herein could be distinguished by difference of fragmentation behaviors with increase of stages or relative abundances. The results indicated that in vitro metabolic transformation of HM-1, HM-2, HM-3, HM-4 and HM-5 occurred mainly at 2-, 4-, 5-, 7-carbonic positions on their structures of parent drugs. The metabolites could be new vasoactive substances. This work will provide a basis for study on the structure-activity relationships of these xanthones and their derivatives from Tibetan herbal in the next work.