Global Health Drug Discovery Institute

Inflammation, a vital component of the body’s immune response, serves to eliminate harmful stimuli and initiate healing. This intricate process involves five main stages: recognition, recruitment, removal, regulation, and repair. Functional foods, rich in anti-inflammatory compounds like omega-3 fatty acids and antioxidants, have potential to modulate inflammation. Chronic inflammation can lead to dysfunctions through altered blood vessel permeability, leukocyte activation and migration, and phagocytosis. Nutraceuticals, derived from food sources, present a promising avenue for combating chronic inflammation and associated diseases. The intricate interplay of inflammatory mediators, such as vasoactive amines, arachidonic acid metabolites, cytokines, complement proteins, and kinins, regulates inflammation. Arachidonic acid metabolism, mediated by cyclooxygenase and lipoxygenase pathways, is a key player, and its dysregulation contributes to various diseases. Nutraceuticals, including hydroxytyrosol and vitamin C, show promise in mitigating atherosclerosis progression by countering LDL oxidation and inflammation. Understanding the stages of atherosclerosis, from initial lesion to thrombosis, provides insights into nutraceutical interventions. This chapter concludes by highlighting the potential of nutraceuticals in reducing the burden of atherosclerosis and improving patient outcomes, calling for further research to optimize their use as adjunct therapies.

In-Sensor Computing An organic heterostructure with a 5 µm channel length was fabricated by a conventional photolithography technique. Intriguingly, by modulating gate voltage, both positive and negative photoresponses to near-infrared light were attained due to the photogating effect, making it ideal for efficient and precise in-sensor computing applications including image processing and nondestructive reading and classification. More details can be found in article number 2402903 by Mengmeng Li and co-workers.

Amyloid transthyretin (ATTR) amyloidosis caused by transthyretin misfolded into amyloid deposits in nerve and heart is a progressive rare disease. The unknown pathogenesis and the lack of therapy make the 5-year survival prognosis extremely poor. Currently available ATTR drugs can only relieve symptoms and slow down progression, but no drug has demonstrated curable effect for this disease. The growing volume of pharmacological data and large-scale genome and transcriptome data bring new opportunities to find potential new ATTR drugs through computational drug repositioning. We collected the ATTR-related in the disease pathogenesis and differentially expressed (DE) genes from five public databases and Gene Expression Omnibus expression profiles, respectively, then screened drug candidates by a corrected protein-protein network analysis of the ATTR-related genes as well as the drug targets from DrugBank database, and then filtered the drug candidates on the basis of gene expression data perturbed by compounds. We collected 139 and 56 ATTR-related genes from five public databases and transcriptome data, respectively, and performed functional enrichment analysis. We screened out 355 drug candidates based on the proximity to ATTR-related genes in the corrected interactome network, refined by graph neural networks. An Inverted Gene Set Enrichment analysis was further applied to estimate the effect of perturbations on ATTR-related and DE genes. High probability drug candidates were discussed. Drug repositioning using systematic computational processes on an interactome network with transcriptome data were performed to screen out several potential new drug candidates for ATTR.

The Legionella pneumophilaSde family of translocated proteins promote host tubular endoplasmic reticulum (ER) rearrangements that are tightly linked to phosphoribosyl-ubiquitin (pR-Ub) modification of Reticulon 4 (Rtn4). Sde proteins have two additional activities of unclear relevance to the infection process: K63 linkage-specific deubiquitination and phosphoribosyl modification of polyubiquitin (pR-Ub). We show here that the deubiquitination activity (DUB) stimulates ER rearrangements while pR-Ub protects the replication vacuole from cytosolic surveillance by autophagy. Loss of DUB activity was tightly linked to lowered pR-Ub modification of Rtn4, consistent with the DUB activity fueling the production of pR-Ub-Rtn4. In parallel, phosphoribosyl modification of polyUb, in a region of the protein known as the isoleucine patch, caused an absolute block in binding by the autophagy adapter p62. An inability of Sde mutants to modify polyUb resulted in immediate p62 association, a critical precursor to autophagic attack. The ability of Sde WT to block p62 association decayed quickly after bacterial infection, as predicted by the presence of previously characterized L. pneumophila effectors that inactivate Sde and remove polyUb. In sum, these results show that the accessory Sde activities act to stimulate ER rearrangements and protect from host innate immune sensing in a temporal fashion.

Background Renal replacement therapy (RRT), as a cornerstone of supportive treatment, has long been performed in critically ill patients with acute kidney injury (AKI). However, the majority of studies may have neglected the effect of the duration of RRT on the outcome of AKI patients. This paper is aiming to explore the effect of the long duration of RRT on the outcome of critically ill patients with AKI. Methods This retrospective study was conducted by using the Multiparameter Intelligent Monitoring in Intensive Care II (MIMIC-II) database. The primary outcome measure of this study was the mortality at 28 days, 60 days, and 90 days in the long-duration RRT group and the non-long-duration RRT group. The secondary outcomes assessed the difference in clinical outcome in these two groups. Lastly, the effect of the duration of RRT on mortality in AKI patients was determined as the third outcome. Results We selected 1,020 patients in total who received RRT according to the MIMIC-II database. According to the inclusion and exclusion criteria, we finally selected 506 patients with AKI: 286 AKI patients in the non-long-duration RRT group and 220 in the long-duration RRT group. After 28 days, there was a significant difference in all-cause mortality between the long-duration RRT group and the non-long-duration RRT group (P=0.001). However, the difference disappeared after 60 days and 90 days (P=0.803 and P=0.925, respectively). The length of ICU stay, length of hospital stay, and duration of mechanical ventilation were significantly longer in the long-duration RRT group than those in the non-long-duration RRT group. Considering 28-day mortality, the longer duration of RRT was shown to be a protective factor (HR = 0.995, 95% CI 0.993–0.997, P < 0.0001), while 60-day and 90-day mortality were not correlated with improved protection. Conclusions The long duration of RRT can improve the short-term prognosis of AKI patients, but it does not affect the long-term prognosis of these patients. Prognosis is determined by the severity of the illness itself. This suggests that RRT can protect AKI patients through the most critical time; however, the final outcome cannot be altered.

Abstract The outbreak of SARS in 2002-2003 caused by SARS-CoV, and the pandemic of COVID-19 in 2020 caused by 2019-nCoV (SARS-CoV-2), have threatened human health globally and raised the urgency to develop effective antivirals against the viruses. In this study, we expressed and purified the RNA-dependent RNA polymerase (RdRp) nsp12 of SARS-CoV and developed a primer extension assay for the evaluation of nsp12 activity. We found that nsp12 could efficiently extend single-stranded RNA, while having low activity towards double-stranded RNA. Nsp12 required a catalytic metal (Mg2+or Mn2+) for polymerase activity and the activity was also K+-dependent, while Na+promoted pyrophosphorylation, the reverse process of polymerization. To identify antivirals against nsp12, a competitive assay was developed containing 4 natural rNTPs and a nucleotide analog, and the inhibitory effects of 24 FDA-approved nucleotide analogs were evaluated in their corresponding active triphosphate forms. Ten of the analogs, including 2 HIV NRTIs, could inhibit the RNA extension of nsp12 by more than 40%. The 10 hits were verified which showed dose-dependent inhibition. In addition, the 24 nucleotide analogs were screened on SARS-CoV primase nsp8 which revealed stavudine and remdesivir were specific inhibitors to nsp12. Furthermore, the 2 HIV NRTIs were evaluated on 2019-nCoV nsp12 which showed inhibition as well. Then we expanded the evaluation to all 8 FDA-approved HIV NRTIs and discovered 5 of them, tenofovir, stavudine, abacavir, zidovudine and zalcitabine, could inhibit the RNA extension by nsp12 of SARS-CoV and 2019-nCoV. In conclusion, 5 FDA-approved HIV NRTIs inhibited the RNA extension by nsp12 and were promising candidates for the treatment of SARS and COVID-19.