Astragaloside IV-mediated inhibition of oxidative stress by upregulation of ghrelin in type 2 diabetes-induced cognitive impairment.

This study is to observe the upregulation effect of astragaloside IV on ghrelin in diabetic cognitive impairment (DCI) rats and to investigate the pathway in prevention and treatment by reducing oxidative stress. The DCI model was induced with streptozotocin (STZ) in conjunction with a high-fat and high-sugar diet and divided into three groups: model, low-dose (40 mg/kg), and high-dose (80 mg/kg) astragaloside IV. After 30 days of gavage, the learning and memory abilities of rats, as well as their body weight and blood glucose levels, were tested using the Morris water maze and then detection of insulin resistance, SOD activity, and serum MDA levels. The whole brain of rats was sampled for hematoxylin-eosin and Nissl staining to observe pathological changes in the hippocampal CA1 region. Immunohistochemistry was used to detect ghrelin expression in the hippocampal CA1 region. A Western blot was used to determine changes in GHS-R1α/AMPK/PGC-1α/UCP2. RT-qPCR was used to determine the levels of ghrelin mRNA. Astragaloside IV reduced nerve damage, increased superoxide dismutase (SOD) activity, decreased MDA levels, and improved insulin resistance. Ghrelin levels and expression increased in serum and hippocampal tissues, and ghrelin mRNA levels increased in rat stomach tissues. According to Western blot, it increased the expression of the ghrelin receptor GHS-R1α and upregulated the mitochondrial function associated-protein AMPK-PGC-1α-UCP2. Astragaloside IV increases ghrelin expression in the brain to reduce oxidative stress and delay diabetes-induced cognitive impairment. It may be related to the promotion of ghrelin mRNA levels.

Chemical Constituent Analysis of Ranunculus sceleratus L. Using Ultra-High-Performance Liquid Chromatography Coupled with Quadrupole-Orbitrap High-Resolution Mass Spectrometry.

Ranunculus sceleratus L.(RS) has shown various pharmacological effects in traditional Chinese medicine. In our previous study, the positive therapeutic effect on α-naphthylisothiocyanate induced intrahepatic cholestasis in rats was obtained using TianJiu treatment with fresh RS. However, the chemical profile of RS has not been clearly clarified, which impedes the research progress on the therapeutic effect of RS. Herein, an ultra-high performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) method was developed to rapidly separate and identify multiple constituents in the 80% methanol extract of RS. A total of sixty-nine compounds (19 flavonoids, 22 organic acids, 6 coumarins, 4 lignans, 14 nitrogenous compounds, and 4 anthraquinones) were successfully characterized. A total of 12 of these compounds were unambiguously identified by standard samples. Their mass spectrometric fragmentation pathways were investigated. It is worth noting that flavonoids and lignans were identified for the first time in RS. In this study, we successfully provide the first comprehensive report on identifying major chemical constituents in RS by UHPLC-Q-Orbitrap HRMS. The obtained results enrich the RS chemical profile, paving the way for further phytochemical study, quality control, and pharmacological investigation of RS.

Distinct gut microbiota and health outcomes in asymptomatic infection, viral nucleic acid test re-positive, and convalescent COVID-19 cases.

Gut microbiota composition is suggested to associate with coronavirus disease 2019 (COVID-19) severity, but the impact of gut microbiota on health outcomes is largely unclear. We recruited 81 individuals from Wuhan, China, including 13 asymptomatic infection cases (Group A), 24 COVID-19 convalescents with adverse outcomes (Group C), 31 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) re-positive cases (Group D), and 13 non-COVID-19 healthy controls (Group H). The microbial features of Groups A and D were similar and exhibited higher gut microbial diversity and more abundant short-chain fatty acid (SCFA)-producing species than Group C. Group C was enriched with opportunistic pathogens and virulence factors related to adhesion and toxin production. The abundance of SCFA-producing species was negatively correlated, while Escherichia coli was positively correlated with adverse outcomes. All three groups (A, C, and D) were enriched with the mucus-degrading species Akkermansia muciniphila, but decreased with Bacteroides-encoded carbohydrate-active enzymes. The pathways of vitamin B6 metabolic and folate biosynthesis were decreased, while selenocompound metabolism was increased in the three groups. Specifically, the secondary bile acid (BA) metabolic pathway was enriched in Group A. Antibiotic resistance genes were common among the three groups. Conclusively, the gut microbiota was related to the health outcomes of COVID-19. Dietary supplementations (SCFAs, BA, selenium, folate, vitamin B6) may be beneficial to COVID-19 patients.

Astragaloside and/or Hydroxysafflor Yellow A Attenuates Oxygen-Glucose Deprivation-Induced Cultured Brain Microvessel Endothelial Cell Death through Downregulation of PHLPP-1.

The incidence of ischemic stroke, a life-threatening condition in humans, amongst Asians is high and the prognosis is poor. In the absence of effective therapeutics, traditional Chinese medicines have been used that have shown promising results. It is crucial to identify traditional Chinese medicine formulas that protect the blood-brain barrier, which is damaged by an ischemic stroke. In this study, we aimed to elucidate such formulas. Brain microvascular endothelial cells (BMECs) were used to establish an in vitro ischemia-reperfusion model for oxygen-glucose deprivation (OGD) experiments to evaluate the function of two traditional Chinese medicines, namely, astragaloside (AS-IV) and hydroxysafflor yellow A (HSYA), in protecting against BMEC. Our results revealed that AS-IV and HSYA attenuated the cell loss caused by OGD by increasing cell proliferation and inhibiting cell apoptosis. In addition, these compounds promoted the migration and invasion of BMECs in vitro. Furthermore, we found that BMECs rescued by AS-IV and HSYA could be functionally activated in vitro, with AS-IV and HSYA showing synergetic effects in rescuing BMECs survival in vitro by reducing the expression of PHLPP-1 and activating Akt signaling. Our results elucidated the potential of AS-IV and HSYA in the prevention and treatment of stroke by protecting against cerebral ischemia-reperfusion injury.

Argatroban plus aspirin versus aspirin in acute ischemic stroke.

OBJECTIVES: Anticoagulant therapy in the acute phase of AIS remains controversial. The aim of this study was to investigate whether argatroban benefited early stroke outcomes compared with antiplatelet treatment. METHODS: We reviewed data from 1,485 patients with AIS hospitalized at Tianjin Union Medical Center (TUMC) between 1 January 2013 and 31 December 2015 from the TUMC registry database. Patients were divided into two groups: an antiplatelet group (aspirin 300 mg daily) and an argatroban group (argatroban 60 mg for 2 days followed by 20 mg daily; or 20 mg daily - both regimens combination with aspirin 100 mg daily). Two primary outcomes, change in NIHSS score (baseline-discharge) and intracerebral hemorrhage, were investigated. RESULTS: No major symptomatic intracerebral hemorrhages were observed in either group. Both groups had significantly decreased NIHSS scores at discharge (Z = -14.617, P < 0.001 and Z = -6.385, P < 0.001, respectively), and there were no significant group differences in NIHSS score change (Z = -1.888, P = 0.059). In the mild stroke subgroup, the argatroban group had a worse NIHSS score at discharge (Z = -6.148, P = 0.002), while the aspirin group had an improved NIHSS score (Z = -4,423, P < 0.001). In the moderate stroke subgroup, both groups had significantly decreased NIHSS scores at discharge (Z = -13.260, P < 0.001 and Z = -7.108, P < 0.001, respectively) and there were no significant group differences in NIHSS score changes (Z = -1.888, P = 0.059). CONCLUSION: Argatroban is effective and safe for the treatment of moderate AIS with similar efficacy to high-dose aspirin in the acute phase of AIS, although no additional benefit on short-term outcome was observed. For patients with mild AIS, argatroban may be inferior to high-dose aspirin.

Iridoid glycosides from the flowers of Gentiana macrophylla Pall. ameliorate collagen-induced arthritis in rats.

BACKGROUND: The flowers of Gentiana macrophylla have been usually applied to cure the joint inflammation and rheumatoid arthritis in Traditional Chinese Medicine. HYPOTHESIS/PURPOSE: This work aimed to investigate the anti-rheumatoid arthritic effect and possible mechanism of iridoid glycosides from G. macrophylla (GMI) using an animal model of collagen-induced rheumatoid arthritis (CIA) in rats. STUDY DESIGN: All rats were randomly divided into five groups: normal control, CIA, dexamethasone, 15mg/kg and 30mg/kg GMI. METHODS: CIA was induced (day 0) in male Sprague-Dawley rats by intradermal injection of complete Bovine CII at the base of the tail. Dexamethasone was chosen as the positive drug. The administration of different drugs started from day 1 and continued for 28 days. Paw swelling, arthritis score and histopathological changes were examined to assess the severity of arthritis. In addition, the serum levels of tumor necrosis factor α (TNF-α), interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expressions in joint synovial tissues were detected. RESULTS: GMI reduced paw edema, arthritis scores and the index of spleen and thymus from day 7 to 21 after CIA compared with those in the CIA group. Our data also demonstrated that GMI inhibited pro-inflammatory cytokines such as TNF-α, IL-1ß and IL-6, regulated the expression of iNOS and COX-2 compared with those in the CIA group. We also obtained four major components from GMI, identified as loganic acid, swertamarin, gentiopicroside and sweroside, and the contents of them were also calculated respectively. CONCLUSION: Taken together, our results shed light on the therapeutic efficacy of GMI in rats rheumatoid arthritis model by reducing the levels of IL-1ß, IL-6 and TNF-α in serum as well as down-regulating the levels of iNOS and COX-2. Therefore, GMI may be an effective therapy for the treatment of rheumatoid arthritis.

Insulinotropic effect of Chikusetsu saponin IVa in diabetic rats and pancreatic ß-cells.

ETHNOPHARMACOLOGICAL RELEVANCE: As a well-known traditional Chinese medicine the root bark of Aralia taibaiensis has traditionally been used as the medicine considered alleviating several disorders including diabetes mellitus (DM). Chikusetsu saponin IVa (CHS) has been defined as a major active ingredient of triterpenoid saponins extracted from Aralia taibaiensis. The scientific evidence of anti-diabetic effect for CHS remains unknown and the purpose of our study was to study its hypoglycemic and insulin secretagogue activities. MATERIALS AND METHODS: In vivo studies were performed on type 2 diabetic mellitus (T2DM) rats given CHS for 28 days to test the antihyperglycemic activity. The in vitro effects and possible mechanisms of CHS on the insulin secretion in pancreatic ß-cell line ßTC3 were determined. RESULTS: Oral administration of CHS dose-dependently increased the level of serum insulin and decreased the rise in blood glucose level in an in vivo treatment. In vitro, CHS potently stimulated the release of insulin from ßTC3 cells at both basal and stimulatory glucose concentrations, the effect which was changed by the removal of extracellular Ca(2+). Two methods showed that CHS enhanced the intracellular calcium levels in ßTC3 cells. CHS was capable of enhancing the phosphorylation of extracellular signal-regulated protein kinases C (PKC), which could be reversed by a PKC inhibitor (RO320432), and the insulin secretion induced by CHS was also inhibited by RO320432. Further study also showed that the insulinotropic effect, intracellular calcium levels and the phosphorylation of PKC were reduced by inhibiting G protein-coupled receptor 40 (GPR40) by a GPR40 inhibitor (DC126026). CONCLUSION: These observations suggest that the signaling of CHS-induced insulin secretion from ßTC3 cells via GPR40 mediated calcium and PKC pathways and thus CHS might be developed into a new potential for therapeutic agent used in T2DM patients.

[Effect of Cornus officinalis fruit core extract on the cardiac hypertrophy induced by two kidney two clip].

OBJECTIVE: To observe the effect of Cornus officinalis fruit core extract on cardiac hypertrophy induced by two kidney two clip (2K2C) and its mechanism. METHODS: Male Sprague-Dawley rats were randomly divided into 4 groups: sham-operated group, model group and treatment groups (300, 600 mg/kg). Rats were intragastric administered medicine for 4 weeks from the fourth week after surgery. Sham-operated and 2K2C rats were given vehicle for 4 weeks. Blood pressure and hemodynamic parameters were measured. Left ventricular weight to body weight (LVM/BM) ratio was calculated. Paraffin-embedded hearts were cut into 5 microm slices, which were stained with hematoxylin-eosin (HE) and Masson for morphological analysis; Western-blot analysis was performed to investigate the effects of Cornus officinalis fruit core extract on the expression of P47phox, Nox4 in myocardium. RESULTS: Compared with sham-operated group, the blood pressure and LVM/BM ratios were markedly elevated in model groups. Meanwhile cardiomyocyte cross sectional areas was markedly increased and myocardial fibers showed disordered arrangement while these parameters were markedly reversed after treatment with Cornus officinalis fruit core extract for 4 weeks. At 8th weeks after operation, model rats developed obvious LV hypertrophy. Cornus officinalis fruit core extract, more significant in high dose, decreased the blood pressure and LVM/BM ratios and reversed the cardiomyocyte hypertrophy and myocardial fibrosis. Moreover, Cornus officinalis fruit core extract decreased the expression of P47phox and Nox4 which elevated in LV in model rats. CONCLUSION: Cornus officinalis fruit core extract could significantly decrease the blood pressure, reverse cardiac hypertrophy and improve the function of heart which is possibly associated with the down-regulation of P47phox and Nox4.

[Distribution and enrichment of nutrients in superficial sediment in Tianjin typical waters].

Concentrations of organic matter (OM), total nitrogen (TN), total phosphorus (TP) and bioavailable phosphorus (BAP) were determined in superficial sediment (0-25 cm) collected from 4 selected typical waters (Yuqiao reservoir, Haihe River, Haihe estuary and Bohai Bay) in Tianjin, China. Pollution index (P(i)) and enrichment factors (EF) were taken to analyze nutrients enrichment and dynamic characteristic. The results show that 4 typical waters are polluted by anthropogenic source and much higher than the permissible limits which most benthos can bearing, the concentrations of OM, TN, TP and BAP are decreasing progressively by the order: Haihe River > Haihe estuary> Bohai Bay Tianjin Sea Area. EF for OM, TN, TP and BAP reaches 1.6-6.5, 0.9-2.7, 0.9-2.6 and 4.4-9.2, respectively. The concentrations of BAP in different waters are inconsistent with those of TP, the ratio of BAP to TP in Yuqiao reservoir is the biggest, 16.3%, which shows endogenous source release is serious and eutrophication is the key problems of water pollution. The concentrations of OM and BAP increase in large scale between 1988 and 2005, TP basically keeps unchanging and TN slightly increases. Around Haihe River sediment dredging, nutrient concentrations (OM, TN and TP) of superficial sediments in Haihe River reduce to 57.7%, 82.8% and 85.2% of original concentration, respectively. And sediment dredging plays a positive role in nutrients removal.