Coenzyme Q10 Supplementation Increases Removal of the ATXN3 Polyglutamine Repeat, Reducing Cerebellar Degeneration and Improving Motor Dysfunction in Murine Spinocerebellar Ataxia Type 3.

Coenzyme Q10 (CoQ10), a well-known antioxidant, has been explored as a treatment in several neurodegenerative diseases, but its utility in spinocerebellar ataxia type 3 (SCA3) has not been explored. Herein, the protective effect of CoQ10 was examined using a transgenic mouse model of SCA3 onset. These results demonstrated that a diet supplemented with CoQ10 significantly improved murine locomotion, revealed by rotarod and open-field tests, compared with untreated controls. Additionally, a histological analysis showed the stratification of cerebellar layers indistinguishable from that of wild-type littermates. The increased survival of Purkinje cells was reflected by the reduced abundance of TUNEL-positive nuclei and apoptosis markers of activated p53, as well as lower levels of cleaved caspase 3 and cleaved poly-ADP-ribose polymerase. CoQ10 effects were related to the facilitation of the autophagy-mediated clearance of mutant ataxin-3 protein, as evidenced by the increased expression of heat shock protein 27 and autophagic markers p62, Beclin-1 and LC3II. The expression of antioxidant enzymes heme oxygenase 1 (HO-1), glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1) and 2 (SOD2), but not of glutathione peroxidase 2 (GPx2), were restored in 84Q SCA3 mice treated with CoQ10 to levels even higher than those measured in wild-type control mice. Furthermore, CoQ10 treatment also prevented skeletal muscle weight loss and muscle atrophy in diseased mice, revealed by significantly increased muscle fiber area and upregulated muscle protein synthesis pathways. In summary, our results demonstrated biochemical and pharmacological bases for the possible use of CoQ10 in SCA3 therapy.

Therapeutic Efficacy and Safety of Safflower Injection in the Treatment of Acute Coronary Syndrome.

BACKGROUND: Safflower injection (SFI), a popular Chinese patent drug, is commonly used to treat acute coronary syndromes (ACSs) in China. The research seeks to scientifically estimate the clinical efficacy of SFI for ACS patients. METHODS: Eight electronic databases were retrieved for eligible research from the founding date to September 8, 2020. Odds ratio (OR) was adopted to assess the total effective rate, ECG improvement, and adverse reaction, and mean difference (MD) was used for assessing the hemorheology indexes as well as the LVEF. RESULTS: Sixteen randomized controlled trials involving 1620 sufferers with ACS were incorporated. The outcomes showed that, in comparison to conventional medication alone, SFI combined with conventional treatment remarkably enhanced the total effective rate (OR = 3.66, 95% CI [2.73, 4.90], P < 0.00001), ECG improvement (OR = 2.85, 95% CI [2.04, 3.99], P < 0.00001), and LVEF (MD = 5.13, 95% CI [3.73, 6.53], P < 0.00001). Moreover, SFI combined with conventional treatment significantly decreased hemorheology indexes including BV (MD = -0.95, 95% CI [-1.76, -0.13], P=0.02), HCT (MD = -2.37, 95% CI [-3.25, -1.50], P < 0.00001), FIB (MD = -0.44, 95% CI [-0.60, -0.29], P < 0.00001), and PAR (OR = -7.65, 95% CI [-10.16, -5.14], P < 0.00001). However, no notable contrast was observed to link the experimental and the control team for PV (MD = -0.42, 95% CI [-0.83, 0.00], P=0.05) and adverse reactions (OR = 0.59, 95% CI [0.13, 2.74], P=0.50). CONCLUSION: Despite the limitations that existed in this meta-analysis, the outcomes demonstrated that SFI and conventional combined medication is an effective and relatively safe therapy for ACS sufferers.

Characterization, antioxidant activity, and biocompatibility of selenium nanoparticle-loaded thermosensitive chitosan hydrogels.

In this study, we recruited chitosan (CS) both for selenium nanoparticles (SeNPs) synthesis and for the development of a thermoresponsive nanocomposite hydrogel with the addition of glycerol phosphate (GP). Considering that SeNPs are toxic at high concentrations, five different ingredients of the nanocomposite hydrogel system with low concentrations of SeNPs (1.25-20 µg/mL) were prepared. The gelation conditions, structural characteristics, and mechanical properties of SeNPs-loaded thermosensitive CS/GP hydrogels were investigated. We also evaluated their antioxidizing activities and biocompatibility of the CS/GP/SeNPs hydrogels. Our study demonstrated that the incorporation of SeNPs in the hydrogel improved its mechanical properties, antioxidant activity, and degree of swelling. According to the properties of SeNPs and CS/GP thermosensitive hydrogels, the combination of these two technologies in an appropriate manner would be a promising antioxidant system for drug delivery and tissue engineering.

The Efficacy and Safety of Compound Danshen Dripping Pill Combined with Percutaneous Coronary Intervention for Coronary Heart Disease.

OBJECTIVE: Compound Danshen dripping pill (CDDP) is a well-known Chinese patent medicine, which is commonly used for the treatment of coronary heart disease (CHD) in China. This study is aimed at systematically assessing the clinical efficacy of CDDP for CHD patients. METHODS: Eight databases were retrieved for eligible research studies from the founding date to April 20, 2020. Risk ratio (RR) was used to assess major adverse cardiac events (MACE) and adverse reactions, and mean difference (MD) was adopted to evaluate the hemorheology and blood lipid indexes, vascular endothelial function, cardiac function, and inflammation. RESULT: Twenty randomized controlled trials involving 2574 participants with CHD were included. The results indicated that, compared with percutaneous coronary intervention (PCI) alone, the combination of CDDP with PCI treatment remarkably reduced MACE (RR = 0.53, 95% confidence interval (CI) (0.44, 0.65), P < 0.00001). Moreover, hemorheology and blood lipid parameters and inflammatory mediators of CHD patients were also dramatically mitigated after the combined therapy (P < 0.01). In addition, vascular endothelial function and cardiac function were prominently improved by this combination (P < 0.001). However, there was no significant difference in adverse reactions between the two groups (P > 0.05). CONCLUSION: Evidence from the meta-analysis demonstrated that CDDP combined with PCI treatment prominently reduced the incidence of MACE, improved cardiovascular functions, and inhibited inflammation in CHD patients. Therefore, CDDP combined with PCI treatment could be an effective and safe therapeutic method for CHD patients.

Preclinical Characterization of an Antibody-Drug Conjugate Targeting CS-1 and the Identification of Uncharacterized Populations of CS-1-Positive Cells.

Multiple myeloma is a hematologic cancer that disrupts normal bone marrow function and has multiple lines of therapeutic options, but is incurable as patients ultimately relapse. We developed a novel antibody-drug conjugate (ADC) targeting CS-1, a protein that is highly expressed on multiple myeloma tumor cells. The anti-CS-1 mAb specifically bound to cells expressing CS-1 and, when conjugated to a cytotoxic pyrrolobenzodiazepine payload, reduced the viability of multiple myeloma cell lines in vitro In mouse models of multiple myeloma, a single administration of the CS-1 ADC caused durable regressions in disseminated models and complete regression in a subcutaneous model. In an exploratory study in cynomolgus monkeys, the CS-1 ADC demonstrated a half-life of 3 to 6 days; however, no highest nonseverely toxic dose was achieved, as bone marrow toxicity was dose limiting. Bone marrow from dosed monkeys showed reductions in progenitor cells as compared with normal marrow. In vitro cell killing assays demonstrated that the CS-1 ADC substantially reduced the number of progenitor cells in healthy bone marrow, leading us to identify previously unreported CS-1 expression on a small population of progenitor cells in the myeloid-erythroid lineage. This finding suggests that bone marrow toxicity is the result of both on-target and off-target killing by the ADC.

Evaluation of marine sediment contamination by polycyclic aromatic hydrocarbons along the Karachi coast, Pakistan, 11 years after the Tasman Spirit oil spill.

On July 27, 2003, a spill of approximately 31,000 tons of Iranian light crude oil affected the coast of Karachi, Pakistan. Approximately 11 years after the spill, we analyzed polycyclic aromatic hydrocarbons (PAHs) and their alkylated homologues (alkyl-PAHs) as the indicators to evaluate the residual effect of oil spill to the sediment along the Karachi coast. The total concentrations (dry weight) of parent PAHs and alkyl-PAHs ranged from 121.9 to 735.4 and 42.3-1149.9 ng/g, respectively. The estuary and harbor were the two regions with the highest levels of PAHs in the sediment. Conversely, sedimentary PAHs in the oil spill areas and remote coastal areas showed significantly lower levels. Although the results of the source identification indicated the up to 75.2% of the contribution from petroleum and its derivatives, this could only reflect the direct impact of the Karachi city on the presence of PAHs in the coastal sedimentary environment and did not indicated that the oil spill continues to stay 11 years later. Compared with 11 years ago, the sharply reduced PAH content, great changed composition, and the degradation driven trend of diagnostic ratios all indicated a sharp decrease in the influence of PAHs caused by the oil spill. Finally, the ecological risk caused by the PAH residual in the marine sedimentary ecosystem had disappeared along the Karachi coasts, Pakistan.

Rhynchophylline suppresses soluble Aß1-42-induced impairment of spatial cognition function via inhibiting excessive activation of extrasynaptic NR2B-containing NMDA receptors.

Rhynchophylline (RIN) is a significant active component isolated from the Chinese herbal medicine Uncaria rhynchophylla. The overproduction of soluble amyloid ß protein (Aß) oligomers in the hippocampus is closely involved in impairments in cognitive function at the early stage of Alzheimer's disease (AD). Growing evidences show that RIN possesses neuroprotective effects against Aß-induced neurotoxicity. However, whether RIN can prevent soluble Aß1-42-induced impairments in spatial cognitive function and synaptic plasticity is still unclear. Using the combined methods of behavioral tests, immunofluorescence and electrophysiological recordings, we characterized the key neuroprotective properties of RIN and its possible cellular and molecular mechanisms against soluble Aß1-42-related impairments in rats. Our findings are as follows: (1) RIN efficiently rescued the soluble Aß1-42-induced spatial learning and memory deficits in the Morris water maze test and prevented soluble Aß1-42-induced suppression in long term potentiation (LTP) in the entorhinal cortex (EC)-dentate gyrus (DG) circuit. (2) Excessive activation of extrasynaptic GluN2B-NMDAR and subsequent Ca2+ overload contributed to the soluble Aß1-42-induced impairments in spatial cognitive function and synaptic plasticity. (3) RIN prevented Aß1-42-induced excessive activation of extrasynaptic NMDARs by reducing extrasynaptic NMDARs -mediated excitatory postsynaptic currents and down regulating GluN2B-NMDAR expression in the DG region, which inhibited Aß1-42-induced Ca2+ overload mediated by extrasynanptic NMDARs. The results suggest that RIN could be an effective therapeutic candidate for cognitive impairment in AD.

A new periplogenin cardenolide from the seeds of Antiaris toxicaria.

A new periplogenin cardenolide, periplogulcoside (1), together with three known cardenolides, was isolated from the seeds of Antiaris toxicaria. The structure of the new compound was characterized as periplogenin-3-O-ß-D-glucopyranosyl-(1 → 4)-ß-D-glucopyranoside (1) by spectroscopic methods including 1D and 2D NMR, HR-TOF-MS, and CD spectrometry, and the known compounds were identified by comparison of their NMR and HR-TOF-MS data with those reported in the literature. Compound 1 showed significant cytotoxicity against Hela and HepG-2 cell lines.

Indigofera suffruticosa Mill extracts up-regulate the expression of the π class of glutathione S-transferase and NAD(P)H: quinone oxidoreductase 1 in rat Clone 9 liver cells.

Because induction of phase II detoxification enzyme is important for chemoprevention, we study the effects of Indigofera suffruticosa Mill, a medicinal herb, on the expression of π class of glutathione S-transferase (GSTP) and NAD(P)H: quinone oxidoreductase 1 (NQO1) in rat Clone 9 liver cells. Both water and ethanolic extracts of I. suffruticosa significantly increased the expression and enzyme activities of GSTP and NQO1. I. suffruticosa extracts up-regulated GSTP promoter activity and the binding affinity of nuclear factor erythroid 2-related factor 2 (Nrf2) with the GSTP enhancer I oligonucleotide. Moreover, I. suffruticosa extracts increased nuclear Nrf2 accumulation as well as ARE transcriptional activity. The level of phospho-ERK was augmented by I. suffruticosa extracts, and the ERK inhibitor PD98059 abolished the I. suffruticosa extract-induced ERK activation and GSTP and NQO-1 expression. Moreover, I. suffruticosa extracts, especially the ethanolic extract increased the glutathione level in mouse liver and red blood cells as well as Clone 9 liver cells. The efficacy of I. suffruticosa extracts in induction of phase II detoxification enzymes and glutathione content implies that I. suffruticosa could be considered as a potential chemopreventive agent.

Correlation of screening and confirmatory results in tiered immunogenicity testing by solution-phase bridging assays.

Biotherapeutic proteins induce undesired immune responses that can affect drug efficacy and safety. For this reason, immunogenicity assessment is an integral part of drug development and is mandated by the regulatory authorities. Immunogenicity is typically evaluated by a tiered approach consisting of a screening assay followed by a competitive inhibition with unlabeled drug serving as confirmatory assay and additional characterization of the immune response. The confirmatory assay is intended to reduce the number of false positive responses generated in the screening tier and ensure that all samples are correctly classified as positive or negative. The positive-negative sample decisions are based on screening and confirmatory assay cut points that are statistically derived through evaluation of drug-naive samples. In this paper, we describe the analysis of cut point data for the presence of statistical correlation between the screening and confirmatory results. Data were obtained from validations of solution-phase bridging assays for detection of anti-drug antibodies against monoclonal antibody therapeutics. All data sets showed moderate to strong positive correlation, indicating that the screening and confirmatory assays were not independent and were likely to generate similar information. We present theoretical evidence that correlated results may be a general feature of the tiered approach when the same test platform is used for both screening and confirmatory assays. The competitive inhibition test, therefore, may be of limited value beyond reduction of the overall false positive rate. Our results indicate that similar sample results could be obtained by using just the screening assay with the false positive rate set to 1%.

Suppressive effects of extracts from the aerial part of Coriandrum sativum L. on LPS-induced inflammatory responses in murine RAW 264.7 macrophages.

BACKGROUND: Coriandrum sativum is used not only as a spice to aid flavour and taste values in food, but also as a folk medicine in many countries. Since little is known about the anti-inflammatory ability of the aerial parts (stem and leaf) of C. sativum, the present study investigated the effect of aerial parts of C. sativum on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. We further explored the molecular mechanism underlying these pharmacological properties of C. sativum. RESULTS: Ethanolic extracts from both stem and leaf of C. sativum (CSEE) significantly decreased LPS-induced nitric oxide and prostaglandin E(2) production as well as inducible nitric oxide synthase, cyclooxygenase-2, and pro-interleukin-1beta expression. Moreover, LPS-induced IkappaB-alpha phosphorylation and nuclear p65 protein expression as well as nuclear factor-kappaB (NF-kappaB) nuclear protein-DNA binding affinity and reporter gene activity were dramatically inhibited by aerial parts of CSEE. Exogenous addition of CSEE stem and leaf significantly reduced LPS-induced expression of phosphorylated mitogen-activated protein kinases (MAPKs). CONCLUSION: Our data demonstrated that aerial parts of CSEE have a strong anti-inflammatory property which inhibits pro-inflammatory mediator expression by suppressing NF-kappaB activation and MAPK signal transduction pathway in LPS-induced macrophages.

Propolis extracts exhibit an immunoregulatory activity in an OVA-sensitized airway inflammatory animal model.

Propolis, which has been used widely in folk medicine, has been shown to exhibit various biological activities but its immunoregulatory and anti-inflammatory activities in intact animals have not been well studied. We investigated these activities of propolis using an ovalbumin-induced asthma animal model. Mice were immunized and sensitized by exposure to ovalbumin (OVA) antigen and administered with low- (65 mg/kg body weight) and high-dose (325 mg/kg body weight) propolis water extracts by tube feeding. The serum OVA-specific IgE titer and cytokine profiles in cultured splenocytes and bronchoalveolar lavage fluids (BALF) were analyzed. The number of eosinophils in BALF was counted. Here we demonstrate that propolis extracts can suppress the serum levels of OVA-specific IgE and IgG(1), and airway hyperresponsiveness (AHR) in OVA-sensitized mice. There are no significant differences in the concentration of eotaxin or the number of eosinophils in BALF among the four groups. However, the higher dose of propolis extracts decreases the level of IL-5 in BALF. The splenocytes from mice administered with propolis extracts (low- and high-dose groups) exhibit a strong inhibition of IL-10 secretion and up-regulation of IFN-gamma secretion in splenocytes stimulated with concanavalin A (ConA). In addition, cytokine (IFN-gamma, IL-6, and IL-10) secretion in OVA-stimulated splenocytes from the propolis groups was significantly lower than that in the control group. These results suggest that propolis extracts may be a potential novel therapeutic agent for asthma.