Pharmacological Basis for Use of Armillaria mellea

Armillaria mellea, an edible fungus, exhibits various pharmacological activities, including antioxidant and antiapoptotic properties. However, the effects of A. mellea on Alzheimer’s disease (AD) have not been systemically reported. The present study aimed to explore the protective effects of mycelium polysaccharides (AMPS) obtained from A. mellea, especially AMPSc via 70% ethanol precipitation in a L-glutamic acid- (L-Glu-) induced HT22 cell apoptosis model and an AlCl3 plus D-galactose- (D-gal-) induced AD mouse model. AMPSc significantly enhanced cell viability, suppressed nuclear apoptosis, inhibited intracellular reactive oxygen species accumulation, prevented caspase-3 activation, and restored mitochondrial membrane potential (MMP). In AD mice, AMPSc enhanced horizontal movements in an autonomic activity test, improved endurance times in a rotarod test, and decreased escape latency time in a water maze test. Furthermore, AMPSc reduced the apoptosis rate, amyloid beta (Aβ) deposition, oxidative damage, and p-Tau aggregations in the AD mouse hippocampus. The central cholinergic system functions in AD mice improved after a 4-week course of AMPSc administration, as indicated by enhanced acetylcholine (Ach) and choline acetyltransferase (ChAT) concentrations, and reduced acetylcholine esterase (AchE) levels in serum and hypothalamus. Our findings provide experimental evidence suggesting A. mellea as a neuroprotective candidate for treating or preventing neurodegenerative diseases

Comparative safety of different recommended doses of sodium–glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials

ObjectiveThe safety results of different recommended doses of sodium-glucose cotransporter 2 inhibitors (SGLT-2i) for patients with type 2 diabetes mellitus (T2DM) remain uncertain. This study aims to comprehensively estimate and rank the relative safety outcomes with different doses of SGLT-2i for T2DM.MethodsPubMed, Embase, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, Chinese National Knowledge Infrastructure, WanFang database, and SinoMed database were searched from the inception to 31 May 2023. We included double-blind randomized controlled trials (RCTs) comparing SGLT-2i with placebo or another antihyperglycemic as oral monotherapy in the adults with a diagnosis of T2DM.ResultsTwenty-five RCTs with 12,990 patients randomly assigned to 10 pharmacological interventions and placebo were included. Regarding genital infections (GI), all SGLT-2i, except for ertugliflozin and ipragliflozin, were associated with a higher risk of GI compared to placebo. Empagliflozin 10mg/d (88.2%, odds ratio [OR] 7.90, 95% credible interval [CrI] 3.39 to 22.08) may be the riskiest, followed by empagliflozin 25mg/d (83.4%, OR 7.22, 95%CrI 3.11 to 20.04)) and canagliflozin 300mg/d (70.8%, OR 5.33, 95%CrI 2.25 to 13.83) based on probability rankings. Additionally, dapagliflozin 10mg/d ranked highest for urinary tract infections (UTI, OR 2.11, 95%CrI 1.20 to 3.79, 87.2%), renal impairment (80.7%), and nasopharyngitis (81.6%) when compared to placebo and other treatments. No increased risk of harm was observed with different doses of SGLT-2i regarding hypoglycemia, acute kidney injury, diabetic ketoacidosis, or fracture. Further subgroup analysis by gender revealed no significantly increased risk of UTI. Dapagliflozin 10mg/d (91.9%) and canagliflozin 300mg/d (88.8%) ranked first in the female and male subgroups, respectively, according to the probability rankings for GI.ConclusionCurrent evidence indicated that SGLT-2i did not significantly increase the risk of harm when comparing different doses, except for dapagliflozin 10mg/d, which showed an increased risk of UTI and may be associated with a higher risk of renal impairment and nasopharyngitis. Additionally, compared with placebo and metformin, the risk of GI was notably elevated for empagliflozin 10mg/d, canagliflozin 300mg/d, and dapagliflozin 10mg/d. However, it is important to note that further well-designed RCTs with larger sample sizes are necessary to verify and optimize the current body of evidence.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023396023

Tetraodon nigroviridis as a nonlethal model of infectious spleen and kidney necrosis virus (ISKNV) infection

AbstractInfectious spleen and kidney necrosis virus (ISKNV) is the type species of the genus Megalocytivirus, family Iridoviridae. We have previously established a high mortality ISKNV infection model of zebrafish (Danio rerio). In this study, a nonlethal Tetraodon nigroviridis model of ISKNV infection was established. ISKNV infection did not cause lethal disease in Tetraodon but could infect almost all the organs of this species. Electron microscopy showed ISKNV particles were present in infected tissues. Immunofluorescence and quantitative real-time PCR analysis showed that nearly all the virions and infected cells were cleared at 14d postinfection. The expression profiles of interferon-γ and tumor necrosis factor-α gene in response to ISKNV infection were significantly different in Tetraodon and zebrafish. The establishment of the nonlethal Tetraodon model of ISKNV infection can offer a valuable tool complementary to the zebrafish infection model for studying megalocytivirus disease, fish immune systems, and viral tropism

DiDang Tang Inhibits Endoplasmic Reticulum Stress-Mediated Apoptosis Induced by Oxygen Glucose Deprivation and Intracerebral Hemorrhage Through Blockade of the GRP78-IRE1/PERK Pathways

DiDang Tang (DDT), a Chinese traditional medicine formula, contains 4 Chinese traditional medicine substances, has been widely used to treat intracerebral hemorrhage (ICH) patients. However, the molecular mechanisms of DDT for protecting neurons from oxygen and glucose deprivation (OGD)-induced endoplasmic reticulum (ER) stress and apoptosis after ICH still remains elusive. In this study, high-performance liquid chromatography fingerprint analysis was performed to learn the features of the chemical compositions of DDT. OGD-induced ER stress, Ca2+ overload, and mitochondrial apoptosis were investigated in nerve growth factor -induced PC12, primary neuronal cells, and ICH rats to evaluate the protective effect of DDT. We found that DDT treatment protected neurons against OGD-induced damage and apoptosis by increasing cell viability and reducing the release of lactate dehydrogenase. DDT decreased OGD-induced Ca2+ overload and ER stress through the blockade of the glucose-regulated protein 78 (GRP78)- inositol-requiring protein 1α (IRE1)/ protein kinase RNA-like ER kinase (PERK) pathways and also inhibited apoptosis by decreasing mitochondrial damage. Moreover, we observed similar findings when we studied DDT for inhibition of ER stress in a rat model of ICH. In addition, our experiments further confirmed the neuroprotective potential of DDT against tunicamycin (TM)-induced neural damage. Our in vitro and in vivo results indicated that the neuroprotective effect of DDT against ER stress damage and apoptosis occurred mainly by blocking the GPR78-IRE1/PERK pathways. Taken together, it provides reliable experimental evidence and explains the molecular mechanism of DDT for the treatment of patients with ICH

Simultaneous suppression of PKM2 and PHGDH elicits synergistic anti-cancer effect in NSCLC

Metabolic reprogramming is a hallmark of human cancer. Cancer cells exhibit enhanced glycolysis, which allows glycolytic intermediates to be diverted into several other biosynthetic pathways, such as serine synthesis. Here, we explored the anti-cancer effects of the pyruvate kinase (PK) M2 inhibitor PKM2-IN-1 alone or in combination with the phosphoglycerate dehydrogenase (PHGDH) inhibitor NCT-503 in human NSCLC A549 cells in vitro and in vivo. PKM2-IN-1 inhibited proliferation and induced cell cycle arrest and apoptosis, with increased glycolytic intermediate 3-phosphoglycerate (3-PG) level and PHGDH expression. The combination of PKM2-IN-1 and NCT-503 further suppressed cancer cell proliferation and induced G2/M phase arrest, accompanied by the reduction of ATP, activation of AMPK and inhibition of its downstream mTOR and p70S6K, upregulation of p53 and p21, as well as downregulation of cyclin B1 and cdc2. In addition, combined treatment triggered ROS-dependent apoptosis by affecting the intrinsic Bcl-2/caspase-3/PARP pathway. Moreover, the combination suppressed glucose transporter type 1 (GLUT1) expression. In vivo, co-administration of PKM2-IN-1 and NCT-503 significantly inhibited A549 tumor growth. Taken together, PKM2-IN-1 in combination with NCT-503 exhibited remarkable anti-cancer effects through induction of G2/M cell cycle arrest and apoptosis, in which the metabolic stress induced ATP reduction and ROS augmented DNA damage might be involved. These results suggest that the combination of PKM2-IN-1 and NCT-503 might be a potential strategy for the therapy of lung cancer

The Effect of Different Trigger Thresholds on the Quality of Pulmonary Artery CT Angiography Images

Objective: To study the effect of different triggering thresholds on the quality of pulmonary artery CT angiography (CTA) images. Materials and Methods: A prospective study included 112 patients with suspected pulmonary embolism admitted to Tinglin Hospital in the Jinshan District of Shanghai between December 2021 to April 2023. Among them, there were 49 males and 63 females aged between 37 and 93 years, with an average age of 64.28 years. Patients were randomly assigned to three groups based on trigger thresholds. Group A included 38 cases with a trigger threshold of 120 HU, Group B included 37 cases with a trigger threshold of 200 HU, and Group C included 37 cases with a trigger threshold of 250 HU. There were no statistically significant differences in gender, age, height, or weight among the three groups. One-way ANOVA was used to compare the CT values and subjective image quality scores of the superior vena cava, main pulmonary artery, left and right pulmonary arteries, and right pulmonary vein among the three groups. Result: There were no statistical differences in the CT values of the main pulmonary artery and left and right pulmonary arteries among the three groups, but there were statistical differences in the CT values of the superior vena cava and right pulmonary vein. There was a statistical difference in the subjective score of image quality among the three groups; the subjective evaluation of the obtained image quality between the two physicians was highly consistent (κ=0.78). Conclusion: When the triggering threshold of pulmonary artery CTA is 200 HU, it can not only ensure the concentration of pulmonary artery trunk CT value meets the clinical diagnosis, but also ensures that the contrast agent is fully injected into the 5~6 grade branches, leading to less retention of superior vena cava, weak pulmonary vein development, and the highest image quality of pulmonary artery CTA

Prediction and Optimal Scheduling of Advertisements in Linear Television

Advertising is a crucial component of marketing and an important way for companies to raise awareness of goods and services in the marketplace. Advertising campaigns are designed to convey a marketing image or message to an audience of potential consumers and television commercials can be an effective way of transmitting these messages to a large audience. In order to meet the requirements for a typical advertising order, television content providers must provide advertisers with a predetermined number of impressions in the target demographic. However, because the number of impressions for a given program is not known a priori and because there are a limited number of time slots available for commercials, scheduling advertisements efficiently can be a challenging computational problem. In this case study, we compare a variety of methods for estimating future viewership patterns in a target demographic from past data. We also present a method for using those predictions to generate an optimal advertising schedule that satisfies campaign requirements while maximizing advertising revenue

Prediction and Optimal Scheduling of Advertisements in Linear Television

Advertising is a crucial component of marketing and an important way for companies to raise awareness of goods and services in the marketplace. Advertising campaigns are designed to convey a marketing image or message to an audience of potential consumers and television commercials can be an effective way of transmitting these messages to a large audience. In order to meet the requirements for a typical advertising order, television content providers must provide advertisers with a predetermined number of impressions in the target demographic. However, because the number of impressions for a given program is not known a priori and because there are a limited number of time slots available for commercials, scheduling advertisements efficiently can be a challenging computational problem. In this case study, we compare a variety of methods for estimating future viewership patterns in a target demographic from past data. We also present a method for using those predictions to generate an optimal advertising schedule that satisfies campaign requirements while maximizing advertising revenue