Tonghua Liyan granules in the treatment of Laryngopharyngeal reflux disease with stagnation of phlegm and qi syndrome: a randomized, double-blind, placebo-controlled study.

Background: Laryngopharyngeal reflux disease (LPRD) is an extraesophageal syndromic manifestation of gastroesophageal reflux disease (GERD). Despite the increasing incidence of and concern about LPRD, treatment with proton pump inhibitors (PPIs) is unsatisfactory. Here, LPRD was treated with Tonghua Liyan (THLY) granules in combination with PPIs to evaluate treatment efficacy and possible adverse reactions. Methods: Seventy-six LPRD patients with stagnation of phlegm and qi syndrome (SPQS) were randomly divided into an experimental group and a control group. The experimental group received THLY granules combined with rabeprazole capsules. The control group received THLY granule placebo combined with rabeprazole capsules. A parallel, randomized, double-blind, placebo-controlled clinical trial was conducted with these two groups. The treatment cycle was 8 weeks. The reflux symptom index (RSI), clinical symptom score, salivary pepsin content, reflux finding score (RFS) and gastroesophageal reflux disease questionnaire (GerdQ) were used to evaluate clinical efficacy. The final efficacy rate was evaluated according to the RSI and clinical symptom score. Results: Compared with those at baseline, all the indicators in the experimental group and control group significantly improved (p < 0.01). In terms of the RSI, clinical symptom score, and RFS, the experimental group had a higher degree of improvement (p < 0.05), and the overall efficacy rate was higher (p < 0.05). In terms of the salivary pepsin concentration and GerdQ, there was no significant difference between the test group and the control group (p > 0.05). Both groups of safety indicators showed no abnormalities and did not cause any allergic reactions in the body. Conclusion: Compared with PPIs alone, THLY granules combined with PPIs are more effective in the treatment of LPRD patients with SPQS in terms of symptoms and signs. This combination treatment, because of its higher clinical efficacy and lack of obvious adverse reactions, is worthy of clinical promotion and further in-depth study. Clinical Trial Registration: www.chictr.org.cn, identifier ChiCTR2100046614.

Assessment of Individual and Mixed Effects of Six Minerals on Thyroid Hormones in Chinese Pregnant Women.

The biosynthesis of thyroid hormones is essential for brain and neurological development. It requires iodine as a key component but is also influenced by other nutrients. Evidence for the combined nutrient status in relation to thyroid hormones during pregnancy is limited. We aimed to investigate the joint associations of iodine, selenium, zinc, calcium, magnesium and iron with maternal thyroid functions in 489 pregnant women from Hangzhou, China. Serum levels of six essential minerals and thyroid function parameters were measured during the first antenatal visit. Linear regression, quantile g-computation and Bayesian kernel machine regression were used to explore the individual and joint relationships between the six minerals and thyroid hormones. Linear regression analyses revealed that calcium was positively associated with free triiodothyronine (FT3). Zinc was positively associated with free thyroxine (FT4). Iodine was negatively associated with thyroid-stimulating hormone (TSH) and positively associated with FT3 and FT4. The quantile g-computation and BKMR models indicated that the joint nutrient concentration was negatively associated with TSH and positively associated with FT3 and FT4. Among the six minerals, iodine contributed most to thyroid function. The findings suggested that maintaining the appropriate concentration of minerals, either as individuals or a mixture, is important for thyroid health during pregnancy.

Multienzyme-Like Nanozyme Encapsulated Ocular Microneedles for Keratitis Treatment.

Keratitis, an inflammation of the cornea caused by bacterial or fungal infections, is one of the leading causes of severe visual disability and blindness. Keratitis treatment requires both the prevention of infection and the reduction of inflammation. However, owing to their limited therapeutic functions, in addition to the ocular barrier, existing conventional medications are characterized by poor efficacy and low bioavailability, requiring high dosages or frequent topical treatment, which represents a burden on patients and increases the risk of side effects. In this study, manganese oxide nanocluster-decorated graphdiyne nanosheets (MnOx/GDY) are developed as multienzyme-like nanozymes for the treatment of infectious keratitis and loaded into hyaluronic acid and polymethyl methacrylate-based ocular microneedles (MGMN). MGMN not only exhibits antimicrobial and anti-inflammatory effects owing to its multienzyme-like activities, including oxidase, peroxidase, catalase, and superoxide dismutase mimics but also crosses the ocular barrier and shows increased bioavailability via the microneedle system. Moreover, MGMN is demonstrated to eliminate pathogens, prevent biofilm formation, reduce inflammation, alleviate ocular hypoxia, and promote the repair of corneal epithelial damage in in vitro, ex vivo, and in vivo experiments, thus providing a better therapeutic effect than commercial ophthalmic voriconazole, with no obvious microbial resistance or cytotoxicity.

Iron metabolism disorder regulated by BMP signaling in hypoxic pulmonary hypertension.

BACKGROUNDS AND AIMS: Unexplained iron deficiency is associated with poorer survival in patients with pulmonary hypertension (PH). Bone morphogenetic protein (BMP) signaling and BMP protein type II receptor (BMPR2) expression are important in the pathogenesis of PH. BMP6 in hepatocytes is a central transcriptional regulator of the iron hormone hepcidin that controls systemic iron balance. This study aimed to investigate the effects of BMP signaling on iron metabolism and its implication in hypoxia-induced PH. METHODS AND RESULTS: PH was induced in Sprague-Dawley Rats under hypoxia for 4 weeks. Compared with the control group, right ventricular systolic pressure and right ventricle hypertrophy index were both markedly increased, and serum iron level was significantly decreased with iron metabolic disorder in the hypoxia group. In cultured human pulmonary artery endothelial cells (HPAECs), hypoxia increased oxidative stress and apoptosis, which were reversed by supplementation with Fe agent. Meanwhile, iron chelator deferoxamine triggered oxidative stress and apoptosis in HPAECs, and treatment with antioxidant alleviated iron-deficiency-induced apoptosis by reducing reactive oxygen species production. Expression of hepcidin, BMP6 and hypoxia-inducible factor (HIF)-1α were significantly upregulated, while expression of BMPR2 was downregulated in hepatocytes in the hypoxia group, both in vivo and in vitro. Expression of hepcidin and HIF-1α were significantly increased by BMP6, while pretreatment with siRNA-BMPR2 augmented the enhanced expression of hepcidin and HIF-1α induced by BMP6. CONCLUSIONS: Iron deficiency promoted oxidative stress and apoptosis in HPAECs in hypoxia-induced PH, and enhanced expression of hepcidin regulated by BMP6/BMPR2 signaling may contribute to iron metabolic disorder.

Mechanism of Yangxin Tongmai Decoction in the Treatment of Coronary Heart Disease with Blood Stasis Syndrome Based on Network Pharmacology and Molecular Docking.

This study aimed to explore the mechanism of Yangxin Tongmai decoction (YXTMD) in the treatment of coronary heart disease (CHD) with blood stasis syndrome (BSS) using network pharmacology and molecular docking, and to verify these results through clinical trials. The active compounds of YXTMD were identified using the Traditional Chinese Medicine Systems Pharmacology database, and the targets of the active compounds were predicted using the SwissTarget Prediction database. The targets of CHD and BSS were predicted using the GeneCards, OMIM, PharmGKB, TTD, and DrugBank databases. The common targets of "herb-disease-phenotype" were obtained using a Venn diagram, then used Cytoscape software 3.8.2 and its plug-in CytoNCA and STRING database to construct the "herb active compounds-common target" and protein-protein interaction networks. R language software and bioconductor plug-in were used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. AutoDock was used for the molecular docking analysis. Finally, clinical trials were conducted to confirm the results of network pharmacology. Eighty-three active components were obtained, and the core active components were 5,7,4'-trimethoxyflavone, tetramethoxyluteolin, isosinensetin, sinensetin, and 5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one. A total of 140 common targets were identified, and the core targets were EGFR, VEGFA, AKT1, STAT3, TP53, ERBB2, and PIK3CA. Biological processes identified by the GO analysis primarily involved wound healing, regulation of body fluid levels, and vascular process in circulatory system. The cellular components were primarily located in the membrane raft, membrane microdomain, and plasma membrane raft. The primary molecular functions were activity of transmembrane receptor protein kinase, transmembrane receptor protein tyrosine kinase, and protein tyrosine kinase. KEGG analysis showed that the PI3K-Akt signaling pathway was closely related to the treatment of CHD with BSS by YXTMD. Molecular docking results showed that the core active components had a good binding activity with the core targets. The clinical trial results showed that YXTMD improved the BSS scores and decreased the serum levels of total cholesterol and low-density lipoprotein cholesterol. Moreover, the levels of PI3k and AKt mRNA were upregulated and the levels of GSK-3ß mRNA were downregulated. YXTMD has multicomponent, multitarget, and multipathway effects in the treatment of CHD with BSS, and its mechanism of action may involve activation of the PI3K-AKt signaling pathway, downregulation of GSK-3ß, and mediation of in vivo lipid metabolism-based metabolic processes.

Effects of processing parameters on furan formation in canned strawberry jam.

The formation mechanism of furan has been studied extensively in model systems, however, furan formation in real foods are complex and far from being fully understood. In this study, the effects of acid-regulating agent (citric acid), sugar addition (glucose, fructose and sucrose) and thickening agents (xanthan gum, κ-carrageenan and pectin) on furan levels in strawberry jams were studied; meanwhile the formation pathway of furan in canned strawberry jam was proposed by carbon module labeling (CAMOLA) technique. Our results suggested low pH promoted furan formation in strawberry jam. Besides, fructose produces more furans than sucrose and glucose, and the addition of xanthan gum reduced furan levels significantly. The kinetic data showed that ascorbic and dehydroascorbic acid degradation followed first-order kinetics while rate of furan formation followed zero-order kinetics. This study presented the possibility of mitigating furan formation in canned strawberry jams by optimization of processing parameters and addition of xanthan gum.

Excessive ROS production and enhanced autophagy contribute to myocardial injury induced by branched-chain amino acids: Roles for the AMPK-ULK1 signaling pathway and α7nAChR.

BACKGROUNDS AND AIMS: Leucine, isoleucine, and valine are diet derived and essential amino acids that are termed branched-chain amino acids (BCAA). BCAA are widely used as dietary supplements to boost muscle growth and enhance exercise performance. However, the effects of BCAA on myocardial function are largely unknown. This study was designed to investigate whether BCAA affect heart function and, if so, to further explore the underlying molecular basis for the observed effects. METHODS AND RESULTS: C57BL/6J mice were randomly divided into two groups, the control group received solvent (water) and the BCAA group received 2% BCAA dissolved in water, for a successive period of 12 weeks. Compared with control, BCAA treatment significantly increased water consumption without changing body weight or diet consumption; heart tissue BCAA levels were increased, markers representative of myocardial injury in heart tissue including c-reactive protein and cardiac muscle troponin were increased ; and creatine kinase, creatine kinase-MB, and lactate dehydrogenase were increased in serum; severe myocardial fibrosis was observed by Masson staining, which was accompanied by increased reactive oxygen species (ROS) production and decreased superoxide dismutase activity in heart tissue; both p-AMPK and p-ULK1 were significantly increased as was autophagy, judged by the presence of LC3 by western blotting and immunofluorescence, increased numbers of autophagosomes were found by transmission electron microscopy in the BCAA group. In vitro, 20 mmol/L BCAA significantly decreased cell viability and increased the production of ROS, as well as the expression of p-AMPK/AMPK and p-ULK1/ULK1 in cultured H9C2 cells. Treatment with the ROS scavenger N-acetyl-L-cysteine (NAC) improved cell viability and reversed ROS changes. Decreased H9C2 cell viability induced with 20 mmol/L BCAA was reversed by either blocking AMPK or inhibition of ULK1. Furthermore, blocking AMPK significantly decreased p-ULK1/ULK1, while inhibition of ULK1 reversed the enhanced expression of LC3-II/LC3-I induced by BCAA. Excessive ROS production and decreased cell viability induced by BCAA were further confirmed in primary cultured murine cardiomyocytes. Pharmacological activation of α7nAChR with PNU-282987 attenuated BCAA-induced injury in primary murine cardiomyocytes. However, this compound failed to suppress BCAA activation of AMPK and autophagy (LC3-II/I ratio). CONCLUSION: These results provide the first evidence that treatment of mice with BCAA induced myocardial injury by triggering excessive ROS production and by enhancing AMPK-ULK1 pathway-dependent autophagy. These findings suggested that inhibition of either ROS production or autophagy may alleviate myocardial injury induced by BCAA.

Bergenin as a Novel Urate-Lowering Therapeutic Strategy for Hyperuricemia.

Bergenin is a C-glucoside of 4-O-methyl gallic acid isolated from several medicinal plants and has multiple biological activities. The aim of this study was to assess the potential usefulness of bergenin in hyperuricemia. We found that bergenin reduced serum urate levels in hyperuricemia mice by promoting renal and gut uric acid excretion. Bergenin treatment increased Abcg2 expression both in the kidneys and intestine, while the expression of Slc2a9 was suppressed in the kidney and increased in the intestine. Moreover, bergenin induced ABCG2 expression in HK-2 and Caco-2 cells, as well as SLC2A9 in Caco-2 cells, via the activation of PPARγ. Nevertheless, bergenin suppressed SLC2A9 expression in HK-2 cells by inhibiting the nuclear translocation of p53. Furthermore, bergenin decreased the serum levels of IL-6, IL-1ß, and TNF-α in hyperuricemia mice, and promoted a polarization shift from the M1 to M2 phenotype in RAW264.7 cells. In conclusion, these findings provide evidence supporting the further development of bergenin as a novel therapeutic strategy for hyperuricemia.

Serum Se, Ni, and As are associated with HPV infection and CIN2+ among Uyghur women in rural China.

BACKGROUND: Cervical cancer incidence and mortality is high in Uyghur ethnics. Their life style and dietary habit were different from other ethnics living together. Study on the role of trace elements in HPV infection and cervical lesion of Uyghur minority is needed for future intervention and prevention work. METHODS: In total, 833 Uyghur women were randomly selected from the screening site and hospital. The concentrations of the trace elements As, Fe, Cd, Ni, Cu, Zn, Mn, and Se were determined by atomic absorption spectrophotometry and inductively coupled plasma atomic emission spectroscopy. Univariate analysis was performed with chi-squared test between the HPV-positive and HPV-negative groups and between the case group and the control group. Multivariate analysis was performed with logistic regression. RESULTS: An As concentration ≥ 0.02 mg/kg was a risk factor for HPV infection (OR > 1, P < 0.05), and Ni concentration ≥ 0.1232 mg/kg and Se concentration ≥ 0.02 mg/kg were protective factors (OR < 1, P < 0.05). Concentrations of Fe ≥ 6.9153 mmol/L and As ≥0.02 mg/kg were risk factors for CIN2+ (OR > 1, P < 0.05), and concentrations of Ni ≥0.0965 mg/kg and Se ≥0.02 mg/kg were protective factors (OR < 1, P < 0.05). CONCLUSIONS: Low serum concentrations of Se and Ni and a high serum concentration of As might be related to HPV infection and CIN2+ in Uyghur women in rural China.