[Evaluation of the efficacy and safety of intravenous infusion of ferric derisomaltose in the treatment of iron deficiency anemia: a single-center retrospective analysis].

Objective: To investigate the clinical efficacy and safety of ferric derisomaltose injection versus iron sucrose injection in the treatment of iron deficiency anemia (IDA) . Methods: A total of 120 patients with iron deficiency anemia admitted from June 2021 to March 2023 were given intravenous iron supplementation with ferric derisomaltose to assess the efficacy and safety of hemoglobin (HGB) elevation before and after treatment. Simultaneously, the clinical effects of iron supplementation with iron sucrose were compared to those of inpatient patients during the same period. Results: Baseline values were comparable in both groups. Within 12 weeks of treatment, the elevated HGB level in the ferric derisomaltose group was higher than that of the iron sucrose group, with a statistical difference at all time points, and the proportion of HGB increased over 20 g/L in the patients treated for 4 weeks was higher (98.7%, 75.9% ). During the treatment with ferric derisomaltose and iron sucrose, the proportion of mild adverse reactions in the ferric derisomaltose group was slightly lower than that of the iron sucrose group, and neither group experienced any serious adverse reactions. The patients responded well to the infusion treatment, with no reports of pain or pigmentation at the injection site. Conclusion: The treatment of IDA patients with ferric derisomaltose has a satisfactory curative effect, with the advantages of rapidity, accuracy, and safety. Therefore, it is worthy of widespread clinical use.

Metformin inhibits LPS-induced inflammatory response in VSMCs by regulating TLR4 and PPAR-γ.

OBJECTIVE: This study aims to explore whether the inhibitory role of metformin could inhibit LPS-induced inflammatory response in vascular smooth muscle cells (VSMCs) and its underlying mechanism. MATERIALS AND METHODS: VSMCs were extracted from aorta of Sprague Dawley rats. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay was performed to detect VSMCs viability after treatment with different concentrations of metformin. Levels of monocyte chemoattractant protein-1 (MCP-1), interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) in VSMCs were detected by ELISA (enzyme-linked immunosorbent assay) and qRT-PCR (quantitative Real time-polymerase chain reaction). Protein and mRNA levels of toll like receptor 4 (TLR4) and peroxisome proliferators activated receptor γ (PPAR-γ) in VSMCs were detected by Western blot and qRT-PCR, respectively. Finally, VSMCs were treated with the PPAR-γ antagonist GW9662 and inflammatory indicators in cells were detected. RESULTS: No significant difference in VSMCs viability was found after 0-2 mM metformin treatment or 500 µg/L LPS induction for 24 h. After 500 µg/L LPS induction in VSMCs for 24 h, levels of MCP-1, TNF-α and IL-6 were remarkably elevated. Both mRNA and protein levels of TLR4 in VSMCs were upregulated after 500 µg/L LPS induction for 24 h, which were remarkably reversed by the treatment of different concentrations of metformin. Knockdown of TLR4 remarkably inhibited LPS-induced inflammatory response in VSMCs, manifesting as decreased levels of MCP1, TNF-α and IL-6, which were further downregulated after combination treatment of TLR4 knockdown and 20 mM metformin. Furthermore, both mRNA and protein levels of PPAR-γ in VSMCs were downregulated after 500 µg/L LPS induction for 24 h, which were remarkably reversed by the treatment of different concentrations of metformin. GW9662 treatment resulted in elevated expressions of MCP-1, TNF-α and IL-6, which were reversed by metformin treatment. CONCLUSIONS: Metformin can effectively inhibit the mRNA and protein expressions of IL-6, MCP-1, and TNF-α in LPS-induced VSMCs. The anti-inflammatory effects of metformin inhibit the inflammatory response through downregulating rely on the downregulation of TLR4 expression and upregulation ofng PPAR-γ activity.

Dietary luteolin activates browning and thermogenesis in mice through an AMPK/PGC1α pathway-mediated mechanism.

BACKGROUND: Two brown-like adipocytes, including classical brown adipocytes from brown adipose tissues and beige cells from white adipose tissues, regulate thermogenesis. The developmental and functional induction of brown-like cells provides a defense against obesity and associated metabolic diseases. Our previous study suggests dietary luteolin can improve diet-induced obesity and insulin resistance in mice. Here we further elucidated the action of the natural flavonoid on energy expenditure and adaptive thermogenesis. METHODS: Five-week-old male C57BL/6 mice were fed low-fat diet (LFD), high-fat diet (HFD) and HFD supplemented with 0.01% luteolin. After 12 weeks, their energy expenditure were detected using a combined indirect calorimetry system. Moreover, thermogenic program and associated molecular regulators were assessed in adipose tissues. In another independent study, even-aged mice were fed LFD and luteolin-containing LFD for 12 weeks, and their energy expenditure and thermogenic program were also investigated. Finally, differentiated primary brown and subcutaneous adipocytes were used to identify the critical participation of AMPK/PGC1α signaling in luteolin-regulated browning and thermogenesis. RESULTS: In mice fed either HFD or LFD, dietary luteolin supplement increased oxygen consumption, carbon dioxide production and respiratory exchange ratio. The enhancement in energy expenditure was accompanied by the upregulation of thermogenic genes in brown and subcutaneous adipose tissues. Meanwhile, several important AMPK/PGC1α signaling molecules were activated by dietary luteolin in the tissues. Further, luteolin treatment directly elevated thermogenic gene expressions and activated AMPK/PGC1α signaling in differentiated primary brown and subcutaneous adipocytes, whereas AMPK inhibitor Compound C reversed the efficiencies. CONCLUSIONS: Dietary luteolin activated browning and thermogenesis through an AMPK/PGC1α pathway-mediated mechanism.

Magnolol, a major bioactive constituent of the bark of Magnolia officinalis, exerts antiepileptic effects via the GABA/benzodiazepine receptor complex in mice.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate the anti-convulsant effects of magnolol (6, 6', 7, 12-tetramethoxy-2, 2'-dimethyl-1-ß-berbaman, C18H18O2) and the mechanisms involved. EXPERIMENTAL APPROACH: Mice were treated with magnolol (20, 40 and 80 mg·kg(-1)) 30 min before injection with pentylenetetrazol (PTZ, 60 mg·kg(-1), i.p.). The anti-seizure effects of magnolol were analysed using seizure models of behaviour, EEG and in vitro electrophysiology and c-Fos expression in the hippocampus and cortex. KEY RESULTS: Magnolol at doses of 40 and 80 mg·kg(-1) significantly delayed the onset of myoclonic jerks and generalized clonic seizures, and decreased the seizure stage and mortality compared with those of the vehicle-treated animals. EEG recordings showed that magnolol (40 and 80 mg·kg(-1)) prolonged the latency of seizure onset and decreased the number of seizure spikes. The anti-epileptic effect of magnolol was reversed by the GABA(A)/benzodiazepine receptor antagonist flumazenil. Pretreatment with flumazenil decreased the effects of magnolol on prolongation of seizure latency and decline of seizure stage. In a Mg(2+)-free model of epileptiform activity, using multi-electrode array recordings in mouse hippocampal slices, magnolol decreased spontaneous epileptiform discharges. Magnolol also significantly decreased seizure-induced Fos immunoreactivity in the piriform cortex, dentate gyrus and hippocampal area CA1. These effects were attenuated by pretreatment with flumazenil. CONCLUSIONS AND IMPLICATIONS: These findings indicate that the inhibitory effects of magnolol on epileptiform activity were mediated by the GABA(A) /benzodiazepine receptor complex.

Effect of an antidiabetic polysaccharide from Inula japonica on constipation in normal and two models of experimental constipated mice.

OBJECTIVES: The aim of the present study was to investigate the effect of an antidiabetic polysaccharide (IJP) from Inula japonica on gastrointestinal transit in normal mice and on constipation in two models of constipated mice. METHODS: Two models of constipation in mice were respectively induced by fasted water for 4 days or induced by diphenoxylate. The normal and constipated mice were administered IJP once at doses of 100 and 400 mg/kg (p.o.), the gastrointestinal vermicular motion, start time of defecation, number and weight of stool were investigated. RESULTS: After administration of IJP, the gastrointestinal propulsive rate was increased by 9.79% and 10.42%, the start time of defecation was shortened by 37.27% and 44.06%, the number of feces increased by 115.4% and 130.8% in normal mice. In fasting-water constipated mice, the start time of defecation was shortened by 9.69% and 30.52% by IJP, defecation granules raised by 22.09% and 39.53%, wet feces weights were increased by 23.50% and 39.14% compared with the untreated constipated mice. In diphenoxylate-induced mice, the start time of defecation was shortened by 25.48% and 28.13%, defecation granules raised by 100.0% and 118.0%. CONCLUSIONS: Consumption of IJP effectively improved bowel movement, stool output observed in this study. IJP may be practical in relieving constipation in the elderly diabetic population.

RAGE and arthritis: the G82S polymorphism amplifies the inflammatory response.

The receptor for advanced glycation end products (RAGE) and its proinflammatory S100/calgranulin ligands are enriched in joints of subjects with rheumatoid arthritis (RA) and amplify the immune/inflammatory response. In a model of inflammatory arthritis, blockade of RAGE in mice immunized and challenged with bovine type II collagen suppressed clinical and histologic evidence of arthritis, in parallel with diminished levels of TNF-alpha, IL-6, and matrix metalloproteinases (MMP) 3, 9 and 13 in affected tissues. Allelic variation within key domains of RAGE may influence these proinflammatory mechanisms, thereby predisposing individuals to heightened inflammatory responses. A polymorphism of the RAGE gene within the ligand-binding domain of the receptor has been identified, consisting of a glycine to serine change at position 82. Cells bearing the RAGE 82S allele displayed enhanced binding and cytokine/MMP generation following ligation by a prototypic S100/calgranulin compared with cells expressing the RAGE 82G allele. In human subjects, a case-control study demonstrated an increased prevalence of the 82S allele in patients with RA compared with control subjects. These data suggest that RAGE 82S upregulates the inflammatory response upon engagement of S100/calgranulins, and, thereby, may contribute to enhanced proinflammatory mechanisms in immune/inflammatory diseases.

Lake sediment resuspension and caused phosphate release--a simulation study.

Intact sediment cores and wet/dried surficial sediments sampled from the two sublakes in Taihu Lake, Meiliang Bay and Wuli Lake, were incubated in the laboratory to determine the effects of resuspension on internal phosphorus loading by simulating different resuspension events. Soluble reactive phosphorus (SRP) release from undisturbed core sediment sampled in the Meiliang Bay and Wuli Lake in July 1998 was 1.53 mg/m2 and 2.24 mg/m2 within 4 days, respectively. However during one hour experimental simulation of resuspension, SRP increased by 0.041 mg/L and 0.077 mg/L in the above cores, which indicate that a typical resuspension event in the lake would be accompanied by the release of 10.77 mgSRP/m2 and 23.1 mgSRP/m2, respectively. The internal phosphorus loading induced by resuspension is estimated to be 8-10 times greater than the release from undisturbed sediment. SRP release from the dried sediments during simulation of resuspension was mainly dependent on the disturbing intensity. Only when the wind strength gets to certain level, the influence of wind speed on phosphorus release appears significant, indicating that an exchangeable P pool, capable of altering equilibrium conditions in the lake areas, is built up under strongly wind-exposed resuspension events.

[Effect of the decoction of tribulus terrestris on mice gluconeogenesis].

The decoction of Tribulus terresteis could significantly inhibit the gluconeogenesis and influence glycometabolism on normal mice. The decoction could also reduce the level of triglyceride and the content of cholesterol in the plasma.

Arousal effect of orexin A depends on activation of the histaminergic system.

Orexin neurons are exclusively localized in the lateral hypothalamic area and project their fibers to the entire central nervous system, including the histaminergic tuberomammillary nucleus (TMN). Dysfunction of the orexin system results in the sleep disorder narcolepsy, but the role of orexin in physiological sleep-wake regulation and the mechanisms involved remain to be elucidated. Here we provide several lines of evidence that orexin A induces wakefulness by means of the TMN and histamine H(1) receptor (H1R). Perfusion of orexin A (5 and 25 pmol/min) for 1 hr into the TMN of rats through a microdialysis probe promptly increased wakefulness for 2 hr after starting the perfusion by 2.5- and 4-fold, respectively, concomitant with a reduction in rapid eye movement (REM) and non-REM sleep. Microdialysis studies showed that application of orexin A to the TMN increased histamine release from both the medial preoptic area and the frontal cortex by approximately 2-fold over the baseline for 80 to 160 min in a dose-dependent manner. Furthermore, infusion of orexin A (1.5 pmol/min) for 6 hr into the lateral ventricle of mice produced a significant increase in wakefulness during the 8 hr after starting infusion to the same level as the wakefulness observed during the active period in wild-type mice, but not at all in H1R gene knockout mice. These findings strongly indicate that the arousal effect of orexin A depends on the activation of histaminergic neurotransmission mediated by H1R.

Cytochrome P450 CYP2J9, a new mouse arachidonic acid omega-1 hydroxylase predominantly expressed in brain.

A cDNA encoding a new cytochrome P450 was isolated from a mouse brain library. Sequence analysis reveals that this 1,958-base pair cDNA encodes a 57-58-kDa 502-amino acid polypeptide that is 70-91% identical to CYP2J subfamily P450s and is designated CYP2J9. Recombinant CYP2J9 was co-expressed with NADPH-cytochrome P450 oxidoreductase (CYPOR) in Sf9 cells using a baculovirus system. Microsomes of CYP2J9/CYPOR-transfected cells metabolize arachidonic acid to 19-hydroxyeicosatetraenoic acid (HETE) thus CYP2J9 is enzymologically distinct from other P450s. Northern analysis reveals that CYP2J9 transcripts are present at high levels in mouse brain. Mouse brain microsomes biosynthesize 19-HETE. RNA polymerase chain reaction analysis demonstrates that CYP2J9 mRNAs are widely distributed in brain and most abundant in the cerebellum. Immunoblotting using an antibody raised against human CYP2J2 that cross-reacts with CYP2J9 detects a 56-kDa protein band that is expressed in cerebellum and other brain segments and is regulated during postnatal development. In situ hybridization of mouse brain sections with a CYP2J9-specific riboprobe and immunohistochemical staining with the anti-human CYP2J2 IgG reveals abundant CYP2J9 mRNA and protein in cerebellar Purkinje cells. Importantly, 19-HETE inhibits the activity of recombinant P/Q-type Ca(2+) channels that are known to be expressed preferentially in cerebellar Purkinje cells and are involved in triggering neurotransmitter release. Based on these data, we conclude that CYP2J9 is a developmentally regulated P450 that is abundant in brain, localized to cerebellar Purkinje cells, and active in the biosynthesis of 19-HETE, an eicosanoid that inhibits activity of P/Q-type Ca(2+) channels. We postulate that CYP2J9 arachidonic acid products play important functional roles in the brain.

Kupffer cells contain a glycine-gated chloride channel.

Here the effect of glycine on intracellular Ca2+ concentration ([Ca2+]i) in cultured Kupffer cells stimulated with lipopolysaccharide (LPS) was investigated to assess the possibility that they contain a glycine-gated chloride channel. LPS (10 micrograms/ml) increased [Ca2+]i rapidly, with peak values reaching 307 +/- 29 nM. Glycine (1 mM) prevented this increase nearly completely. Low concentrations of strychnine (1 microM), a glycine receptor antagonist, reversed the inhibitory effect of glycine completely; however, high concentrations of strychnine (1 mM) mimicked glycine. The effects of glycine and high-dose strychnine were prevented when cells were incubated in chloride-free buffer. Furthermore, potassium (25 mM) and LPS depolarized the Kupffer cell plasma membrane, whereas glycine caused hyperpolarization and prevented depolarization due to potassium and LPS. Moreover, tumor necrosis factor-alpha (TNF-alpha) production in cultured Kupffer cells due to LPS was decreased significantly by glycine. Therefore, it is concluded that Kupffer cells contain a glycine-gated chloride channel similar to that described previously in the central nervous system. Prevention of increases in [Ca2+]i due to LPS by activation of chloride influx reduced synthesis and release of toxic mediators by Kupffer cells.

Food restriction and stimulation of monooxygenation of p-nitroanisole in perfused rat liver.

This study assessed the effect of food restriction on the metabolism of model monooxygenase substrates in the perfused rat liver. Female Sprague-Dawley rats has access ad lib. to a Purina 5001 nonpurified diet (control) or were given 65% of the intake of controls for 3 weeks. Livers were perfused with oxygenated Krebs-Henseleit buffer using a non-recirculating system, and the rates of monooxygenation of p-nitroanisole and 7-ethoxycoumarin were measured. The results indicate that food restriction stimulated p-nitroanisole O-demethylation from 2.9 +/- 0.2 to 4.6 +/- 0.5 mumol/(g.hr) when saturating concentrations of p-nitroanisole were infused. Concomitantly, the ratio of beta-hydroxybutyrate to acetoacetate (B/A) and the rates of ketogenesis (B + A) were increased significantly by food restriction. Further, p-nitroanisole (200 mumol/L) increased hepatic malate concentration nearly 3-fold in liver extracts from food-restricted rats. However, infusion of either a low concentration of p-nitroanisole (50 mumol/L) or 7-ethoxycoumarin (200 mumol/L) did not alter these parameters. On the other hand, food restriction did not alter rates of monooxygenation in isolated microsomes supplemented with excess NADPH. Taken together, these data support the hypothesis that high concentrations of p-nitroanisole increased monooxygenation in food-restricted rats by stimulating fatty acid oxidation, which elevates the mitochondrial NADH/NAD+ ratio. This, in turn, increases the availability of reducing equivalents in the form of NADPH by a malate-pyruvate exchange system, leading to increased drug metabolism.