Decreased salivary α-amylase activity responding to citric acid stimulation in Myasthenia gravis with malnutrition.

OBJECTIVES: Malnutrition, defined according to Nutritional risk screening (NRS 2002), is commonly observed in patients of Myasthenia gravis (MG), a neuromuscular disorder manifested by varied degrees of skeletal muscle weakness. Because biochemical composition of saliva changes in correspondence to alterations in nutritional status, we tested our hypothesis that a certain saliva component(s) might serve as a biomarker(s) for nutrition status of MG, particularly for those MG patients with high risk of malnutrition. MATERIALS AND METHODS: 60 MG patients and 60 subjects belonging to the healthy control group (HCG) were enrolled in this case-control study. The salivary α-amylase (sAA) activity, salivary flow rate (SFR), pH, total protein density (TPD), and the concentrations of chloride and calcium ions in MG group with or without malnutrition were measured before and after citric acid stimulation. Thereafter, the relationship between sAA activity and BMI was determined in MG and HCG. RESULTS: Compared with HCG, more patients with malnutrition, increased TPD and chloride and calcium concentrations but decreased pH value and SFR both before and after acid stimulation, as well as reduced sAA activity, pH and TPD responses to acid stimulation. MG with malnutrition showed decreased sAA activity and TPD responding to acid stimulation compared with those without malnutrition. Compared with normal BMI, sAA activity response to acid stimulation was reduced in low BMI. There was a significant strong positive correlation between the ratio of sAA activity and BMI in MG. CONCLUSIONS: Salivary biochemical characteristics are abnormally altered in MG with malnutrition. Altered sAA activity responding to acid stimulation was associated with malnutrition. CLINICAL RELEVANCE: Decreased sAA activity responding to acid stimulation can reflect malnutrition state and may be one potential screening marker for MG patients with high risk of malnutrition.

Management of delayed encephalopathy after CO poisoning: An evidence-based narrative review.

BACKGROUND: Approximately 10% to 30% patients develop delayed encephalopathy after acute CO poisoning (DEACMP). No specific treatment is available and poor prognosis is a characteristic of this disease. We aimed to evaluate the efficacy and safety of all therapies that have been tried in randomized controlled trial (RCT) for DEACMP. METHODS: We conducted a systematic search of the Cochrane, Embase, PubMed, and Web of Science databases. RESULTS: Overall, 4 RCTs were identified in our study. Both hyperbaric oxygen (HBO) and mesenchymal stem cell (MSC) transplantation were effective in DEACMP, and MSC seemed to be superior to HBO. The addition of dexamethasone, N-butylphthalide, or XingZhi-YiNao granules into HBO, or butylphthalide into MSC could achieve better neurological recovery in DEACMP patients but did not significantly increase the incidence of adverse events. CONCLUSION: Several therapies have shown positive results in treating DEACMP and need to be proven by further studies.

Experimental study on the apoptosis of cervical cancer Hela cells induced by juglone through c-Jun N-terminal kinase/c-Jun pathway.

OBJECTIVE: To study the regulatory effect and molecular mechanism of juglone on apoptosis of cervical cancer Hela cells. METHODS: Cervical cancer Hela cells were cultured and treated with different dosages of juglone (10, 20, and 40 µmol/L, respectively) and c-Jun N-terminal kinase (JNK) inhibitor SP600125 (10, 20, and 40 µmol/L, respectively). Then cellular proliferative activity and the expression of JNK/c-Jun pathway molecule and apoptotic molecule in the cells were detected. RESULTS: After 6, 12, 18 and 24 h of treatment, the value for proliferative activity of cells treated with juglone was significantly lower than that of control group (P < 0.05), and the anti-proliferative effect was more significant as the treatment period and juglone dosage increased (P < 0.05). The protein expressions of Bax, CytC, Fas, FasL, Caspase-3, p-JNK and p-c-Jun in cells treated with juglone were significantly higher than those of control group (P < 0.05), and the protein expressions of Bax, CytC, Fas, FasL, Caspase-3, p-JNK and p-c-Jun increased more remarkably as the juglone dosage increased (P < 0.05). In cells treated with 40 µmol/L juglone and SP600125, the protein expressions of Bax, CytC, Fas, FasL and Caspase-3 were significantly lower than those of cells treated with 40 µmol/L juglone (P < 0.05), and the protein expressions of Bax, CytC, Fas, FasL and Caspase-3 reduced more remarkably as the SP600125 dosage increased (P < 0.05). CONCLUSION: Juglone can increase the expression of apoptotic molecules in mitochondrial pathway and death receptor pathway by activating JNK/c-Jun pathway, thus inducing apoptosis of cervical cancer cells.

Expression and clinical significance of high risk human papillomavirus and invasive gene in cervical carcinoma.

OBJECTIVE: To study the expression of E6 and E7 mRNA in high-risk human papillomavirus (HPV) HPV-18 and the relationship between the expression of invasive gene and cervical carcinoma. METHODS: A total of 119 patients with cervical cancer, cervical erosion and cervical HPV infection who were diagnosed in our hospital were selected and randomly divided into two groups: cervical cancer group (n = 58) and non-cancerous group (n = 61). Another 60 patients with uterine leiomyoma were selected as normal control group. Detection of HPV18 E6, E7 mRNA expression and invasion, migration, proliferation inhibition genes, epithelial mesenchymal transition genes and proliferation related protein content. RESULTS: The relative expression of E6 and E7 HPV-18 in cervical cancer group was significant higher than that in non-cancerous group and control group (mRNA) (P < 0.05). The content of TRAF6 and c-FLIP in invasive cervical cancer group was significantly higher than that in non-cancerous group and control group (P < 0.05). The mRNA content of CD44v6 and MMP-9 in cervical cancer group was significantly higher than that in non-cancerous group and control group (P < 0.05). The content of DEC-1, IKK16, MBP-1 in cervical cancer group was significant lower than that in non-cancerous group and control group (P < 0.05). The mRNA content of beta -catenin and Vimentin in cervical cancer group was significantly lower than that in non cancerous group and control group (P < 0.05). The proliferation related protein E2F1 of cervical cancer group was significantly lower than that of non-cancerous group and control group, Bmi-1 content was significantly higher than non-cancerous group and control group (P < 0.05). CONCLUSIONS: The expression of the detection of cervical cancer in high-risk human papilloma virus HPV-18 E6 and E7 mRNA, and the invasion, migration, proliferation inhibition gene, epithelial mesenchymal transition and proliferation related gene protein content, HPV expression rate of mRNA increased with the development of cervical cancer, the expression is also enhanced. The expression has a certain correlation between the level and development of cervical cancer. Through the above indicators, the development of cervical cancer monitoring and treatment to provide important clinical guidance.

Lead optimization and modulation of hERG activity in a series of aminooxazoline xanthene ß-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors.

The optimization of a series of aminooxazoline xanthene inhibitors of ß-site amyloid precursor protein cleaving enzyme 1 (BACE1) is described. An early lead compound showed robust Aß lowering activity in a rat pharmacodynamic model, but advancement was precluded by a low therapeutic window to QTc prolongation in cardiovascular models consistent with in vitro activity on the hERG ion channel. While the introduction of polar groups was effective in reducing hERG binding affinity, this came at the expense of higher than desired Pgp-mediated efflux. A balance of low Pgp efflux and hERG activity was achieved by lowering the polar surface area of the P3 substituent while retaining polarity in the P2' side chain. The introduction of a fluorine in position 4 of the xanthene ring improved BACE1 potency (5-10-fold). The combination of these optimized fragments resulted in identification of compound 40, which showed robust Aß reduction in a rat pharmacodynamic model (78% Aß reduction in CSF at 10 mg/kg po) and also showed acceptable cardiovascular safety in vivo.

Identification of a potent, state-dependent inhibitor of Nav1.7 with oral efficacy in the formalin model of persistent pain.

Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.