Berberine ameliorates contrast-induced acute kidney injury by regulating HDAC4-FoxO3a axis-induced autophagy: In vivo and in vitro.

In hospitals, contrast-induced acute kidney injury (CI-AKI) is a major cause of renal failure. This study evaluates berberine's (BBR) renal protection and its potential HDAC4 mechanism. CI-AKI in rats was induced with 10 mL kg-1 ioversol. Rats were divided into five groups: Ctrl, BBR, CI-AKI, CI-AKI + BBR, and CI-AKI + Tasq. The renal function of CI-AKI rats was determined by measuring serum creatinine and blood urea nitrogen. Histopathological changes and apoptosis of renal tubular epithelial cells were observed by HE and terminal deoxynucleotidyl transferase (TdTase)-mediated dUTP-biotin nick end labeling (TUNEL) staining. Transmission electron microscopy was used to observe autophagic structures. In vitro, a CI-AKI cell model was created with ioversol-treated HK-2 cells. Treatments included BBR, Rapa, HCQ, and Tasq. Analyses focused on proteins and genes associated with kidney injury, apoptosis, autophagy, and the HDAC4-FoxO3a axis. BBR showed significant protective effects against CI-AKI both in vivo and in vitro. It inhibited apoptosis by increasing Bcl-2 protein levels and decreasing Bax levels. BBR also activated autophagy, as indicated by changes in autophagy-related proteins and autophagic flux. The study further revealed that the contrast agent ioversol increased the expression of HDAC4, which led to elevated levels of phosphorylated FoxO3a (p-FoxO3a) and acetylated FoxO3a (Ac-FoxO3a). However, BBR inhibited HDAC4 expression, resulting in decreased levels of p-FoxO3a and Ac-FoxO3a. This activation of autophagy-related genes, regulated by the transcription factor FoxO3a, played a role in BBR's protective effects. BBR, a traditional Chinese medicine, shows promise against CI-AKI. It may counteract CI-AKI by modulating HDAC4 and FoxO3a, enhancing autophagy, and limiting apoptosis.

Case Report: Torsade de Pointes Induced by the Third-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Osimertinib Combined With Litsea Cubeba.

Torsades de Pointes (TdP) occurred in a 68-year-old female with epidermal growth factor receptor (EGFR) mutant lung cancer administered osimertinib, the third-generation EGFR tyrosine kinase inhibitor (TKI). Electrocardiogram (ECG) recorded at Tdp showed QT prolongation (QTc = 515 ms), to which a Traditional Chinese Medicine (TCM) named "Litsea Cubeba" may have contributed. After discontinuation of osimertinib and Litsea Cubeba, magnesium supplementation, potassium supplementation, lidocaine infusion, and the pacemaker frequency adjustment, Tdp terminated. However, QT prolongation sustained at discharge (QTc = 528 ms), partly because of the emergency use of amiodarone. Osimertinib may prolong the QT interval leading to TdP, especially when multiple risk factors to lengthen QT interval are incidentally overlapped. Thus, regular monitoring of ECG and appropriate management of concomitant drugs are highly recommended.

The involvement of Parkin-dependent mitophagy in the anti-cancer activity of Ginsenoside.

Colon cancer, the third most frequent occurred cancer, has high mortality and extremely poor prognosis. Ginsenoside, the active components of traditional Chinese herbal medicine Panax ginseng, exerts antitumor effect in various cancers, including colon cancer. However, the detailed molecular mechanism of Ginsenoside in the tumor suppression have not been fully elucidated. Here, we chose the representative ginsenoside Rg3 and reported for the first time that Rg3 induces mitophagy in human colon cancer cells, which is responsible for its anticancer effect. Rg3 treatment leads to mitochondria damage and the formation of mitophagosome; when autophagy is inhibited, the clearance of damaged mitochondria can be reversed. Next, our results showed that Rg3 treatment activates the PINK1-Parkin signaling pathway and recruits Parkin and ubiquitin proteins to mitochondria to induce mitophagy. GO analysis of Parkin targets showed that Parkin interacts with a large number of mitochondrial proteins and regulates the molecular function of mitochondria. The cellular energy metabolism enzyme GAPDH is validated as a novel substrate of Parkin, which is ubiquitinated by Parkin. Moreover, GAPDH participates in the Rg3-induced mitophagy and regulates the translocation of Parkin to mitochondria. Functionally, Rg3 exerts the inhibitory effect through regulating the nonglycolytic activity of GAPDH, which could be associated with the cellular oxidative stress. Thus, our results revealed GAPDH ubiquitination by Parkin as a crucial mechanism for mitophagy induction that contributes to the tumor-suppressive function of ginsenoside, which could be a novel treatment strategy for colon cancer.

[Lycium barbarum Polysaccharide Pretreatment Attenuates Cerebral Ischemic Reperfusion Injury by Inhibiting Apoptosis in Mice].

OBJECTIVE: To observe the protective effects of Lycium barbarum polysaccharide(LBP) on focal cerebral ischemic reperfusion injury in mice, and to explore its mechanism. METHODS: Male mice were randomly divided into six groups: sham-operated group, middle cerebral artery occlusion(MCAO) mice group, MCAO mice treating with 4 mg/kg Nimodipine group and MCAO mice treating with 10, 20 and 40 mg/kg LBP groups. The mice were preventively administrated with LBP by intragastric administration for seven days. After 2 h of cerebral ischemia and 24 h of reperfusion, neurological scores in each group mice were estimated. Morphological changes in ischemic brain neurons were performed for HE staining. The number of apoptotic neurons was detected by Tunel staining. The Caspase-3 protein activity was measured by spectrophotometry. BAX and BCL-2 protein expressions in ischemic brains were investigated by Western blot analysis. RESULTS: Compared to the vehicle group, neurological deficit scores were significantly reduced in LBP pretreatment group(P <0.01). LBP( 10,20 and 40 mg/kg) groups relieved neuronal morphological damage respectively and also obviously attenuated the neuronal apoptosis (P <0. 05). Caspase-3 protein activity and BAX protein expression were obviously decreased(P <0. 05, P <0. 01) and BCL-2 protein expression was markedly increased(P <0. 01) in LBP pretreatment groups. CONCLUSION: LBP can protect against focal cerebral ischemic reperfusion injury in mice,the mechanism may be related with attenuating the apoptosis in ischemic brains.

Quercetin protects against the Aß(25-35)-induced amnesic injury: involvement of inactivation of rage-mediated pathway and conservation of the NVU.

Quercetin has demonstrated protective effects against Aß-induced toxicity on both neurons and endothelial cells. However, whether or not quercetin has an effect on the neurovascular coupling is unclear. In the present study, we aim to investigate the anti-amnesic effects of quercetin and to explore the underlying mechanisms. Aß(25-35) (10 nmol) was administrated to mice i.c.v. Quercetin was administrated orally for 8 days after injection. Learning and memory behaviors were evaluated by measuring spontaneous alternation in Morris Water Maze test and the step-through positive avoidance test. The regional cerebral blood flow was monitored before the Aß(25-35) injection and on seven consecutive days after injection. Mice were sacrificed and cerebral cortices were isolated on the last day. The effects of quercetin on the neurovascular unit (NVU) integrity, microvascular function and cholinergic neuronal changes, and the modification of signaling pathways were tested. Our results demonstrate that quercetin treatment for Aß(25-35)-induced amnesic mice improved the learning and memory capabilities and conferred robust neurovascular coupling protection, involving maintenance of the NVU integrity, reduction of neurovascular oxidation, modulation of microvascular function, improvement of cholinergic system, and regulation of neurovascular RAGE signaling pathway and ERK/CREB/BDNF pathway. In conclusion, in Aß(25-35)-induced amnesic mice, optimal doses of quercetin administration were beneficial. Quercetin protected the NVU likely through reduction of oxidative damage, inactivation of RAGE-mediated pathway and preservation of cholinergic neurons, offering an alternative medication for Alzheimer's disease.

[Effects of yiqi huoxue qufeng decoction on the diamine oxidase and immunoglobin E of patients with chronic urticaria].

OBJECTIVE: To observe effects of Yiqi Huoxue Qufeng Decoction (YHQD, with the actions of replenishing qi, activating blood, and dispelling wind) on diamine oxidase (DAO) and immunoglobulin E (IgE) of patients with chronic urticaria. METHODS: Eighty-five chronic urticaria patients from the clinics of dermatology, Shaanxi Hospital of Traditional Chinese Medicine were randomly assigned to the treatment group (50 cases) and the control group (35 cases). Besides, another 15 healthy volunteers were recruited as the healthy group. Patients in the treatment group took YHQD, one dose daily, once in the morning and once in the evening. Patients in the control group took Fuyang Granule (FYG), 6 g each time, three times daily. The therapeutic course for the two groups was 8 weeks. The effective rates of the two groups were observed after treatment and 2 months after quitting treatment. The levels of DAO and IgE were observed in the three groups before and after treatment. RESULTS: The post-treatment recovery rate (20 cases, 44.0%) and the effective rate 2 months after quitting treatment (62.0%) were higher in the treatment group than in the control group (7 cases, 20.0%; 31.4%) with statistical difference (P<0.05). The DAO level in the two treatment groups (6.9 +/- 1.8 in the treatment group and 6.5 +/- 1.8 in the control group) was obviously higher than that in the healthy group (1.1 +/- 0.4), showing statistical difference (P<0.05). The post-treatment DAO and IgE both decreased in the treatment group and the control group when compared with before treatment in the same group. Those were lower in the treatment group than in the control group with statistical difference (P<0.05). CONCLUSION: YHQD could improve the symptoms of chronic urticaria patients, ameliorate the intestines mucosa barrier function and the immunity.

Effects of CS-1 on A431 cell proliferation, cell cycle, and epidermal growth factor receptor signal transduction.

CS-1, a new alkaloid with a molecular formula of C(21)H(20)O(8)N(2)S, is extracted from traditional Chinese medicine. Previous studies have shown that CS-1 can inhibit the proliferation of several human carcinoma cells in vivo and in vitro. The aims of this study are to investigate the anti-tumor effect and mechanism of CS-1 in epidermal growth factor receptor (EGFR) signaling pathway in human A431 cell line. Through the sulforhodamine B assay, we found that CS-1 inhibited A431 cell proliferation in the concentration- and time-dependent manners. The inhibitory rate ranged from 14.5% to 87.8% after 24 h of incubation. High content screening (HCS) multi-parameters cytotoxicity analysis showed that CS-1 at high concentration had slight cytotoxicity that resulted from the cell permeabilization and slight reduction in total mitochondrial mass, whereas no change in nucleus size/morphology and lysosomal mass-pH was found. The cytotoxicity of CS-1 was not a major reason for its anti-proliferative effect. Cell cycle analysis indicated that CS-1 induced G1-phase arrest in A431 cells in a time-dependent manner at high concentration (2.5 µM), and S-phase arrest at low concentration (0.625 µM). The HCS assay also showed that CS-1 could inhibit the EGFR internalization, extracellular-signal-regulated kinase (Erk)/mitogen-activated protein kinase translocation to nucleus, the accumulation of phosphorylated protein kinase B (Akt), signal transducer and activator of transcription 3 (STAT3), and cyclin D1 in the nucleus. These results were confirmed by the western blot analysis. CS-1 might inhibit the epidermal growth factor binding to its receptor, resulting in the inhibition of the accumulation of phosphorylated Erk and Akt, and STAT3 in the nucleus, and affecting the transcription of cyclin D1 and cell cycle arrest in G1/S phase.

[Protective effect of effective parts of Zingiber Offecinal on vascular endothelium of the experimental hyperlipidemic rats].

OBJECTIVE: To observe the influence of effective parts of Zingiber Officinale on serum IL-6, TNF-alpha in oroler to investigate the protective effects of the effective parts of Zingiber Officinal (EPZ) on endothelium of the experimental hyperlipidemic rats and the mechanism of its effects. METHODS: The hyperlipidemia model of rats was constructed by feeding high-fat forage and filled with the effective parts of Zingiber Officinale 200 mg/kg, 400 mg/kg, 800 mg/kg every day for 13 weeks. Blood was drawn to determine both the level of serum IL-6 and TNF-alpha. All the aortaes were taken to oberserve morphologic change and the intima-media thickness were detected. RESULTS: The effective parts of Zingiber Officinale could markedly decrease intima-media thickness, but had no marked influence in the level of serum IL-6 and TNF-alpha. CONCLUSION: The Effect Parts of Zingiber Officinale has the effect of protection of the endothelia of hyperlipidemia rats, which has nothing with the level of serum IL-6 and TNF-alpha.