Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease.

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PPiase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.

Higher Risk of Acute Respiratory Distress Syndrome and Risk Factors among Patients with COVID-19: A Systematic Review, Meta-Analysis and Meta-Regression.

OBJECTIVE: To estimate the global risk and risk factors associated with acute respiratory distress syndrome (ARDS) among patients with COVID-19: Design: A systematic review, meta-analysis and meta-regression. SETTING AND PARTICIPANTS: Hospitals or nursing homes and patients with acute respiratory distress syndrome after COVID-19. METHODS: The literature review was systematically conducted on Embase, MEDLINE, CINAHL, and Web of Science, in addition to manual searches and reference list checking from 1 January 2019 to 2 March 2022. The search terms included coronavirus, acute respiratory syndrome, acute respiratory distress syndrome and observational studies. Three reviewers independently appraised the quality of the studies and extracted the relevant data using the Joanna Briggs Institute abstraction form and critical appraisal tools. A study protocol was registered in PROSPERO (CRD42022311957). Eligible studies were meta-analyzed and underwent meta-regression. RESULTS: A total of 12 studies were included, with 148,080 participants. The risk ratio (RR) of ARDS was 23%. Risk factors were age ≥ 41-64 years old (RR = 15.3%, 95% CI =0.14-2.92, p = 0.03); fever (RR = 10.3%, 95% CI = 0.03-2.03, p = 0.04); multilobe involvement of the chest (RR = 33.5%, 95% CI = 0.35-6.36, p = 0.02); lymphopenia (RR = 25.9%, 95% CI = 1.11-4.08, p = 0.01); mechanical ventilation with oxygen therapy (RR = 31.7%, 95% CI = 1.10-5.25, p = 0.002); European region (RR = 16.3%, 95% CI = 0.09-3.17, p = 0.03); sample size ≤ 500 (RR = 18.0%, 95% CI = 0.70-2.89, p = 0.001). CONCLUSIONS AND IMPLICATIONS: One in four patients experienced ARDS after having COVID-19. The age group 41-64 years old and the European region were high-risk groups. These findings can be used by policymakers to allocate resources for respiratory care facilities and can also provide scientific evidence in the design of protocols to manage COVID-19 worldwide.

Colloidal CdS sensitized nano-ZnO/chitosan hydrogel with fast and efficient photocatalytic removal of congo red under solar light irradiation.

Colloidal CdS sensitized nano-ZnO/chitosan (CdS@n-ZnO/CS) hydrogel was prepared and characterized extensively by XRD, SEM-EDS, TEM, UV-Vis DRS, FT-IR and TGA. The photocatalytic activity of CdS@n-ZnO/CS was evaluated with the photodegradation of congo red (CR) as an organic pollutant under solar light irradiation. The influences of initial dye concentration, catalyst dosage, recycling runs, and radical scavenger on decolorization of CR by CdS@n-ZnO/CS were investigated. 95% of CR was removed in just 1 min for 5.0 mg L-1 and 94.34% of CR was removed in 30 min for 100 mg L-1. CdS@n-ZnO/CS exhibited an excellent and ultra-fast performance toward CR removal under solar light due to the synergistic effect of adsorption by chitosan and photocatalysis by ZnO and CdS in CdS@n-ZnO/CS hydrogel. Radical trapping control experiments indicated that h+ and O2- played the major role for CR decolorization. The high performance of CdS@n-ZnO/CS hydrogel was also demonstrated under natural solar light irradiation, suggesting that CdS@n-ZnO/CS hydrogel could be used in practical wastewater treatment.

Repetitive hyperbaric oxygen therapy provides better effects on brain inflammation and oxidative damage in rats with focal cerebral ischemia.

BACKGROUND/PURPOSE: Repetitive hyperbaric oxygen (HBO2) therapy may cause excessive generation of reactive oxygen species. This study assessed whether repetitive or 2-4-day trials of HBO2 therapy (2 treatments daily for 2-4 consecutive days) provides better effects in reducing brain inflammation and oxidative stress caused by middle cerebral artery occlusion (MCAO) in rats than did a 1-day trial of HBO2 therapy (2 treatments for 1 day). METHODS: Rats were randomly divided into four groups: sham; MCAO without HBO2 treatment; MCAO treated with 1-day trial of HBO2; and MCAO treated with 2-4-day trials of HBO2. One treatment of HBO2 (100% O2 at 253 kPa) lasted for 1 hour in a hyperbaric chamber. RESULTS: Therapy with the 2-4-day trials of HBO2 significantly and dose-dependently attenuated the MCAO-induced cerebral infarction and neurological deficits more than the 1-day trial of HBO2 therapy. The beneficial effects of repetitive HBO2 therapy were associated with: (1) reduced inflammatory status in ischemic brain tissues (evidenced by decreased levels of tumor necrosis factor-α, interleukin-1ß, and myeloperoxidase activity); (2) decreased oxidative damage in ischemic brain tissues (evidenced by decreased levels of reactive oxygen and nitrogen species, lipid peroxidation, and enzymatic pro-oxidants, but increased levels of enzymatic antioxidant defenses); and (3) increased production of an anti-inflammatory cytokine, interleukin-10. CONCLUSION: The results provide the apparently contradictory finding that heightened oxygen tension reduced oxidative stress (and inflammation), which was reflected by increased antioxidant and decreased oxidant contents under focal cerebral ischemia.

Honokiol Protected against Heatstroke-Induced Oxidative Stress and Inflammation in Diabetic Rats.

We aimed at investigating the effect of honokiol on heatstroke in an experimental rat model. Sprogue-Dawley rats were divided into 3 groups: normothermic diabetic rats treated with vehicle solution (NTDR+V), heatstroke-diabetic rats treated with vehicle (HSDR+V), and heatstroke rats treated with konokiol (0.5-5 mg/ml/kg) (HSDR+H). Sixty minutes before the start of heat stress, honokiol or vehicle solution was administered. (HSDR+H) significantly (a) attenuated hyperthermia, hypotension and hypothalamic ischemia, hypoxia, and neuronal apoptosis; (b) reduced the plasma index of the toxic oxidizing radicals; (c) diminished the indices of hepatic and renal dysfunction; (d) attenuated the plasma systemic inflammatory response molecules; (e) promoted plasma levels of an anti-inflammatory cytokine; (f) reduced the index of infiltration of polymorphonuclear neutrophils in the serum; and (g) promoted the survival time fourfold compared with the (HSDR+V) group. In conclusion, honokiol protected against the outcome of heatstroke by reducing inflammation and oxidative stress-mediated multiple organ dysfunction in diabetic rats.

An endogenous factor enhances ferulic acid decarboxylation catalyzed by phenolic acid decarboxylase from Candida guilliermondii.

The gene for a eukaryotic phenolic acid decarboxylase of Candida guilliermondii was cloned, sequenced, and expressed in Escherichia coli for the first time. The structural gene contained an open reading frame of 504 bp, corresponding to 168 amino acids with a calculated molecular mass of 19,828 Da. The deduced amino sequence exhibited low similarity to those of functional phenolic acid decarboxylases previously reported from bacteria with 25-39% identity and to those of PAD1 and FDC1 proteins from Saccharomyces cerevisiae with less than 14% identity. The C. guilliermondii phenolic acid decarboxylase converted the main substrates ferulic acid and p-coumaric acid to the respective corresponding products. Surprisingly, the ultrafiltrate (Mr 10,000-cut-off) of the cell-free extract of C. guilliermondii remarkably activated the ferulic acid decarboxylation by the purified enzyme, whereas it was almost without effect on the p-coumaric acid decarboxylation. Gel-filtration chromatography of the ultrafiltrate suggested that an endogenous amino thiol-like compound with a molecular weight greater than Mr 1,400 was responsible for the activation.

[Retrospective review and analysis of the results of taiwan nurses association nursing projects from 2004 to 2005].

Although a nursing project is one of the important N4 professional competence training courses in the clinical ladder system, little research on its effectiveness can be found. This study therefore aimed to analyze the demographics, hospital characteristics, scores, and pass rates for the Taiwan Nurses Association's 2004 to 2005 nursing projects and to compare the differences between them. The design was retrospective content analysis and the data sources were nursing project reviewer sheets from the years 2004 and 2005. Data were analyzed using descriptive statistics, such as number, percentage, mean, standard deviation, and Chi-square test, or Fisher exact test. We analyzed 1,062 nursing projects. Of these, 423 projects had third reviewers. After that, 2,547 reviewer sheets were used as final samples. The average project score was 59.7 points (SD = 9.3 points) and the majority of the projects were categorized as administrative and from medical centers, or private hospitals in northern areas of Taiwan. The pass rate was found to be higher in public hospitals, however, than in private hospitals. Almost all the projects (n = 2,515; 98.7%) included reviewers'comments. There was no significant difference between project pass rate and clinical specialty, scope, hospital location, and level of hospital accreditation (p > .05). A significant difference was found, however, between project scores and hospital characteristics (p = .01). These findings may serve as references in the development of future requirements for nursing projects in the clinical ladder system, to improve the quality and quantity of such projects.

Molecular modeling of averaged rigor crossbridges from tomograms of insect flight muscle.

Electron tomography, correspondence analysis, molecular model building, and real-space refinement provide detailed 3-D structures for in situ myosin crossbridges in the nucleotide-free state (rigor), thought to represent the end of the power stroke. Unaveraged tomograms from a 25-nm longitudinal section of insect flight muscle preserved native structural variation. Recurring crossbridge motifs that repeat every 38.7 nm along the actin filament were extracted from the tomogram and classified by correspondence analysis into 25 class averages, which improved the signal to noise ratio. Models based on the atomic structures of actin and of myosin subfragment 1 were rebuilt to fit 11 class averages. A real-space refinement procedure was applied to quantitatively fit the reconstructions and to minimize steric clashes between domains introduced during the fitting. These combined procedures show that no single myosin head structure can fit all the in situ crossbridges. The validity of the approach is supported by agreement of these atomic models with fluorescent probe data from vertebrate muscle as well as with data from regulatory light chain crosslinking between heads of smooth muscle heavy meromyosin when bound to actin.