Selective COX-2 inhibition prevents progressive dopamine neuron degeneration in a rat model of Parkinson's disease

Several lines of evidence point to a significant role of neuroinflammation in Parkinson's disease (PD) and other neurodegenerative disorders. In the present study we examined the protective effect of celecoxib, a selective inhibitor of the inducible form of cyclooxygenase (COX-2), on dopamine (DA) cell loss in a rat model of PD. We used the intrastriatal administration of 6-hydroxydopamine (6-OHDA) that induces a retrograde neuronal damage and death, which progresses over weeks. Animals were randomized to receive celecoxib (20 mg/kg/day) or vehicle starting 1 hour before the intrastriatal administration of 6-OHDA. Evaluation was performed in vivo using micro PET and selective radiotracers for DA terminals and microglia. Post mortem analysis included stereological quantification of tyrosine hydroxylase, astrocytes and microglia. 12 days after the 6-OHDA lesion there were no differences in DA cell or fiber loss between groups, although the microglial cell density and activation was markedly reduced in animals receiving celecoxib (p < 0.01). COX-2 inhibition did not reduce the typical astroglial response in the striatum at any stage. Between 12 and 21 days, there was a significant progression of DA cell loss in the vehicle group (from 40 to 65%) that was prevented by celecoxib. Therefore, inhibition of COX-2 by celecoxib appears to be able, either directly or through inhibition of microglia activation to prevent or slow down DA cell degeneration

Composite Edible Film Containing Microcapsules Composed of Shrimp-derived Bioactive Peptide Preparation and Preservation Potential

Shrimp body had to face with spoilage and melanosis when it come to food preservation. In this study, a kind of composite edible film (CEF) composed of hydroxypropyl methyl cellulose (HPMC) and shrimp-derived bioactive peptide microcapsule (SBPM), was developed to preserve the body of Penaeus vannamei. First of all, single-factor experiments were conducted by monitoring the mechanical performance and the water vapor permeability (WVP) of CEF, in order to investigate the influence of the dosages of HPMC, glycerol and SBPM, upon the formulation properties and mechanical strength of the film. The FTIR and free radical scavenging capacity of CEF were also determined when the SBPM addition changed and then, the optimum preparation process of CEF was ascertained based on the results mentioned above. In addition, the preservation-effect of CEF on fresh Penaeus vannamei was evaluated by inspecting some important items such as the sensory evaluation, pH, total volatile basic nitrogen (TVB-N) and aerobic bacterial count of shrimp flesh. The results of the single-factor experiments indicated the optimum amounts of HPMC, glycerol and SBPM were 12%, 0.4% and 3%, respectively, and the comprehensive performance of CEF was satisfied under this optimum condition. The antioxidant ability of CEF was excellent when the dosage of SBPM was not less than 3% and, the interaction between SBPM and other membrane fractions was powerful when the addition amount of SBPM came to be 3%~4%, which was indicated by the FTIR results. More importantly, the spoilage of shrimp body could be controlled by covering the body with CEF and, the sensory of seafood might be maintained by this film, as evidenced by the inhibitory effects of CEF on the raising of body pH, the jump of TVB-N and the increase of aerobic bacterial count in shrimp fresh. The quality guarantee period of fresh body in CEF group could be prolonged by 3~4 days as compared with that in unprotected group, while the overall freshness-keeping ablility of CEF was superior to that of HPMC film even PE film, indicating the potent protective effect of CEF on the fresh of Penaeus vannamei

Synthesis, structure and electrical properties of the two-dimensional organic conductor, (BEDT-TTF)2BrI2

Single crystals of &#945;-(BEDT-TTF)2BrI2 and &#946;-(BEDT-TTF)2BrI2 were prepared using standard electrochemical techniques in nitrogen saturated benzonitrile using containing (n-C4H10)NBrI2 as supporting electrolyte. The crystals have nearly identical structure features of &#945;-(BEDT-TTF)2I3 and &#946;-(BEDT-TTF)2I3, except that the BrI&#8722;2 anions are disordered in &#945;-(BEDT-TTF)2BrI2 and &#946;-(BEDT-TTF)2BrI2. Their electrical behavior is different from the corresponding &#945;-,&#946;-(BEDT-TTF)2I3 species

Cystatin C Deficiency Promotes Epidermal Dysplasia in K14-HPV16 Transgenic Mice

Cysteine protease cathepsins are important in extracellular matrix protein degradation, cell apoptosis, and angiogenesis. Mice lacking cathepsins are protected from tumor progression in several animal models, suggesting that the regulation of cathepsin activities controls the growth of various malignant tumors.We tested the role of cathepsins using a mouse model of multistage epithelial carcinogenesis, in which the human keratin-14 promoter/enhancer drove the expression of human papillomavirus type 16 (HPV16) early region E6/E7 transgenes. During the progression of premalignant dysplasia, we observed increased expression of cysteine protease cathepsin S, but concomitantly reduced expression of cathepsin endogenous inhibitor cystatin C in the skin tissue extract. Absence of cystatin C in these transgenic mice resulted in more progression of dysplasia to carcinoma in situ on the face, ear, chest, and tail. Chest and ear skin extract real time PCR and immunoblot analysis, mouse serum sample ELISA, tissue immunohistological analysis, and tissue extract-mediated in vitro elastinolysis and collagenolysis assays demonstrated that cystatin C deficiency significantly increased cathepsin expression and activity. In skin from both the chest and ear, we found that the absence of cystatin C reduced epithelial cell apoptosis but increased proliferation. From the same tissue preparations, we detected significantly higher levels of pro-angiogenic laminin 5-derived γ2 peptides and concurrently increased neovascularization in cystatin C-deficient mice, compared to those from wild-type control mice.Enhanced cathepsin expression and activity in cystatin C-deficient mice contributed to the progression of dysplasia by altering premalignant tissue epithelial proliferation, apoptosis, and neovascularization

Phosphoenolpyruvate carboxykinase in cell metabolism: Roles and mechanisms beyond gluconeogenesis

Background: Phosphoenolpyruvate carboxykinase (PCK) has been almost exclusively recognized as a critical enzyme in gluconeogenesis, especially in the liver and kidney. Accumulating evidence has shown that the enhanced activity of PCK leads to increased glucose output and exacerbation of diabetes, whereas the defects of PCK result in lethal hypoglycemia. Genetic mutations or polymorphisms are reported to be related to the onset and progression of diabetes in humans. Scope of review: Recent studies revealed that the PCK pathway is more complex than just gluconeogenesis, depending on the health or disease condition. Dysregulation of PCK may contribute to the development of obesity, cardiac hypertrophy, stroke, and cancer. Moreover, a regulatory network with multiple layers, from epigenetic regulation, transcription regulation, to posttranscription regulation, precisely tunes the expression of PCK. Deciphering the molecular basis that regulates PCK may pave the way for developing practical strategies to treat metabolic dysfunction. Major conclusions: In this review, we summarize the metabolic and non-metabolic roles of the PCK enzyme in cells, especially beyond gluconeogenesis. We highlight the distinct functions of PCK isoforms (PCK1 and PCK2), depict a detailed network regulating PCK's expression, and discuss its clinical relevance. We also discuss the therapeutic potential targeting PCK and the future direction that is highly in need to better understand PCK-mediated signaling under diverse conditions

The Prevalence and Characteristics of Mitral Regurgitation in Heart Failure: A Chart Review Study

Background: Mitral regurgitation (MR) is one of the common complications of heart failure (HF). The prevalence and characteristics of MR are rarely investigated, especially in the Chinese population. Objectives: The purpose of this study was to determine the prevalence and characteristics of non-organic MR in HF patients and subgroups defined by ejection fraction. Methods: A single-center, hospital-based, and retrospective chart review study included patients with heart failure admitted to the cardiovascular department from January 2017 to April 2020. Demographic characteristics, laboratory results, and echocardiogram results before discharge were analyzed in different groups defined by left ventricular ejection fraction (EF) using logistic regression and adjusted for confounders. Results: Finally, 2418 validated HF patients (age 67.2 ± 13.5 years; 68.03% men) were included. The prevalence of MR was 32.7% in HF, 16.7% in HF with preserve EF patients, 28.4% in HF with mid-range EF patients and 49.7% in HF with reduced EF (HFrEF) patients. In the HF with preserved EF group, multivariable logistic regression showed that 4 factors associated with MR including EF (odds ratio (OR) 0.954 (0.928–0.981), p = 0.001), left ventricular posterior wall thickness in diastolic phase (LVPWd) (OR 0.274 (0.081–0.932), p = 0.038), left atrium (LA) dimension (OR 2.049 (1.631–2.576), p < 0.001) and age (OR 1.024 (1.007–1.041), p = 0.007). In the HF with midrange EF group, multivariable logistic regression showed that 3 factors associated with MR including LA dimension (OR 2.009 (1.427–2.829), p < 0.001), triglycerides (TG) (OR 0.552 (0.359–0.849), p = 0.007) and digoxin (OR 2.836 (1.624–4.951), p < 0.001). In the HFrEF group, multivariable logistic regression showed that 7 factors associated with MR including EF (OR 0.969 (0.949–0.990), p = 0.004), (OR 0.161 (0.067–0.387), p < 0.001), LA dimension (OR 2.289 (1.821–2.878), p < 0.001), age (OR 1.016 (1.004–1.027)), p = 0.009), TG (OR 0.746 (0.595–0.936), p = 0.011), diuretics (OR 0.559 (0.334–0.934), p = 0.026) and ICD (OR 1.898 (1.074–3.354), p = 0.027). Conclusions: HF patients had a high burden of MR, particularly in the HFrEF group. Worsen cardiac structure (LA dimension and LVPWd) and function (EF), age, and medical treatment strategy played essential roles in MR

Serum Magnesium Concentration Is Inversely Associated with Albuminuria and Retinopathy among Patients with Diabetes

Aim. To investigate the association between serum magnesium levels and microvascular complications among patients with diabetes. Methods. Patients with diabetes were recruited between April 2012 and January 2015. All patients received an assay of serum magnesium concentration, were screened for 24 h albumin excretion rate, and underwent nonmydriatic fundus photography. Albuminuria and retinopathy were defined accordingly. A total of 3,100 patients with normal serum magnesium levels were included in this study. Results. Patients with albuminuria and/or retinopathy had lower levels of serum magnesium than patients without these complications (P<0.001). The prevalence of isolated albuminuria, isolated retinopathy, and combined albuminuria and retinopathy decreased as the concentration of serum magnesium increased. Multiple logistic regression analysis indicated that the odds ratio for isolated albuminuria, isolated retinopathy, and concomitant albuminuria and retinopathy decreased by approximately 20% for every 0.1 mmol/L increase in serum magnesium concentration. Conclusion. Serum magnesium levels were negatively associated with the risk of diabetic microvascular complications among patients with serum magnesium levels within the normal range

Identify the Key Active Ingredients and Pharmacological Mechanisms of Compound XiongShao Capsule in Treating Diabetic Peripheral Neuropathy by Network Pharmacology Approach

Compound XiongShao Capsule (CXSC), a traditional herb mixture, has shown significant clinical efficacy against diabetic peripheral neuropathy (DPN). However, its multicomponent and multitarget features cause difficulty in deciphering its molecular mechanisms. Our study aimed to identify the key active ingredients and potential pharmacological mechanisms of CXSC in treating DPN by network pharmacology and provide scientific evidence of its clinical efficacy. CXSC active ingredients were identified from both the Traditional Chinese Medicine Systems Pharmacology database, with parameters of oral bioavailability ≥ 30% and drug-likeness ≥ 0.18, and the Herbal Ingredients’ Targets (HIT) database. The targets of those active ingredients were identified using ChemMapper based on 3D-structure similarity and using HIT database. DPN-related genes were acquired from microarray dataset GSE95849 and five widely used databases (TTD, Drugbank, KEGG, DisGeNET, and OMIM). Next, we obtained candidate targets with therapeutic effects against DPN by mapping active ingredient targets and DPN-related genes and identifying the proteins interacting with those candidate targets using STITCH 5.0. We constructed an “active ingredients-candidate targets-proteins” network using Cytoscape 3.61 and identified key active ingredients and key targets in the network. We identified 172 active ingredients in CXSC, 898 targets of the active ingredients, 110 DPN-related genes, and 38 candidate targets with therapeutic effects against DPN. Three key active ingredients, namely, quercetin, kaempferol, and baicalein, and 25 key targets were identified. Next, we input all key targets into ClueGO plugin for KEGG enrichment and molecular function analyses. The AGE-RAGE signaling pathway in diabetic complications and MAP kinase activity were determined as the main KEGG pathway and molecular function involved, respectively. We determined quercetin, kaempferol, and baicalein as the key active ingredients of CXSC and the AGE-RAGE signaling pathway and MAP kinase activity as the main pharmacological mechanisms of CXSC against DPN, proving the clinical efficacy of CXSC against DPN