Field trial assessing the antimicrobial decontamination efficacy of gaseous ozone in a public bus setting.

The widespread COVID-19 pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) necessitated measures aimed at preventing the spread of SARS-CoV-2. To mitigate the risk of fomite-mediated transmission, environmental cleaning and disinfection regimes have been widely implemented. However, conventional cleaning approaches such as surface wipe downs can be laborious and more efficient and effective disinfecting technologies are needed. Gaseous ozone disinfection is one technology which has been shown to be effective in laboratory studies. Here, we evaluated its efficacy and feasibility in a public bus setting, using murine hepatitis virus (a related betacoronavirus surrogate) and the bacteria Staphylococcus aureus as test organisms. An optimal gaseous ozone regime resulted in a 3.65-log reduction of murine hepatitis virus and a 4.73-log reduction of S. aureus, and decontamination efficacy correlated with exposure duration and relative humidity in the application space. These findings demonstrated gaseous ozone disinfection in field settings which can be suitably translated to public and private fleets that share analogous characteristics.

Perfluoroalkyl substances and lipid concentrations in the blood: A systematic review of epidemiological studies.

BACKGROUND: Perfluoroalkyl substances (PFAS) are widely used synthetic aliphatic compounds. This systematic review aims to assess PFAS associations with low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), total cholesterol (TC) and total triglyceride (TG) concentrations in human populations. METHOD: We systematically searched four online databases, PubMed, Scopus, Embase, and Cochrane Library for relevant peer-reviewed English language articles published until July 2021. Additional relevant articles identified were also included in the search results. We categorised populations into adults (≥18 years old) and children. Primary findings were the associations between PFAS concentrations and LDL, HDL, TC, and TG concentrations in the serum, plasma, or whole blood; secondary findings were the associations between PFAS concentrations and the odds of lipid-related health outcomes. Quantitative synthesis was done by vote counting of the effect directions between concentrations of PFAS and lipids/health outcomes, repeated on articles with sample size >1000. Sign tests were performed to assess the statistical significance of the differences between positive and negative associations. Sensitivity analysis was performed by separating out articles with populations having high concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). Quality was assessed with the STROBE checklist and NHBLI Study Quality Assessment Tool. RESULTS: A total of 58 articles were included for review. There was evidence that PFAS exposure is associated with higher concentrations of LDL, HDL, and TC, particularly for PFOA-LDL, PFOA-TC, PFOS-TC, and PFNA-LDL. Associations between PFAS and TG tended to be negative, especially for perfluoroundecanoic acid (PFUnDA). Associations between PFAS concentration and the odds of secondary outcomes generally supported a positive association between PFAS and cholesterol concentrations. CONCLUSION: We found evidence of associations between the concentrations of some PFAS-lipid pairs in human populations. Future research should be conducted on the less well-studied PFAS to explore their effects on human health and in regions where such studies are currently lacking. (300 words).

Optical fiber bio-sensor for phospholipase using liquid crystal.

A cost-effective and label-free optical fiber sensor was proposed to detect phospholipase A2 (PLA2) in nM concentration. The sensor is made of an alkoxysilane-modified side-polished fiber (SPF) coated with 4'-pentyl-4-cyanobiphenyl (5CB) and self-assembled phospholipid (L-DLPC). It is found that the relative transmission optical power (RTOP) of the fiber sensor decreases due to the 5CB realignment and redistribution induced by the PLA2 hydrolysis of L-DLPC. The response-time at 5 dB RTOP variation exhibits an exponential dependence on PLA2 concentration, allowing us to detect the PLA2 by the 5 dB-response time. This detection method can reduce the detection time. Compare with the traditional copper-grid sensor, the proposed novel fiber sensor has a lower detection limit (<1 nM). Furthermore, the sensor has good repeat-ability and specificity.The sensor's RTOP variation for PLA2 detection at 1 nM is ~21 times higher than that for five other enzymes (trypsin, amylase, thrombin, glucose oxidase, pepsin) at 1000 nM and lipase at 50 nM. This confirms the sensor's excellent PLA2 specificity. The fiber sensor provides a potential way to be incorporated into micro-flow chips to quantitatively detect biological molecules in a real-time and online manner.

Synthetic 4-Hydroxy Auxarconjugatin B, a Novel Autophagy Inducer, Attenuates Gouty Inflammation by Inhibiting the NLRP3 Inflammasome.

Gouty arthritis results from the generation of uric acid crystals within the joints. These uric acid crystals activate the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome, which is involved in chronic inflammatory diseases, including gouty arthritis. This study identified the polyenylpyrrole derivative 4-hydroxy auxarconjugatin B (4-HAB), a novel autophagy inducer, which attenuated uric acid crystals-mediated activation of the NLRP3 inflammasome in vitro and in vivo. 4-HAB dose-dependently reduced the release of interleukin (IL)-1ß, IL-18, active caspase-1 and apoptosis-associated speck-like protein (ASC) in uric acid crystals-activated macrophages. In a mechanistic study, 4-HAB was shown to inhibit uric acid crystals-induced mitochondrial damage, lysosomal rupture and ASC oligomerization. Additionally, 4-HAB inhibited the NLRP3 inflammasome through Sirt1-dependent autophagy induction. Furthermore, the anti-inflammatory properties of 4-HAB were confirmed in a mouse model of uric acid crystals-mediated peritonitis by the reduced levels of neutrophil influx, IL-1ß, active caspase-1, IL-6 and MCP-1 in lavage fluids. In conclusion, 4-HAB attenuates gouty inflammation, in part by attenuating activation of the NLRP3 inflammasome through the Sirt1/autophagy induction pathway.

Affinity-Driven Covalent Modulator of the Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) Cascade.

Traditional medicines provide a fertile ground to explore potent lead compounds, yet their transformation into modern drugs is fraught with challenges in deciphering the target that is mechanistically valid for its biological activity. Herein we reveal that (Z)-(+)-isochaihulactone (1) exhibited significant inhibition against multiple-drug-resistant (MDR) cancer cell lines and mice xenografts. NMR spectroscopy showed that 1 resisted an off-target thiolate, thus indicating that 1 was a target covalent inhibitor (TCI). By identifying the pharmacophore of 1 (α,ß-unsaturated moiety), a probe derived from 1 was designed and synthesized for TCI-oriented activity-based proteome profiling. By MS/MS and computer-guided molecular biology approaches, an affinity-driven Michael addition of the noncatalytic C247 residue of GAPDH was found to control the "ON/OFF" switch of apoptosis through non-canonically nuclear GAPDH translocation, which bypasses the common apoptosis-resistant route of MDR cancers.

Polyenylpyrrole derivatives inhibit NLRP3 inflammasome activation and inflammatory mediator expression by reducing reactive oxygen species production and mitogen-activated protein kinase activation.

Two polyenylpyrroles from a soil ascomycete Gymnoascus reessii were previously identified as hit compounds in screening for cytotoxicity against lung cancer cells. These compounds and various analogs, which have been previously synthesized and tested for anti-lung cancer cell activity, were tested for anti-inflammatory activity. After preliminary screening for cytotoxicity for RAW 264.7 murine macrophage cells, the non-toxic compounds were tested for anti-inflammatory activity using lipopolysaccharide (LPS)-activated RAW 264.7 cells. Compounds 1h, 1i, and 1n reduced LPS-induced nitric oxide (NO) production, with respective ED50 values of 15 ± 2, 16 ± 2, and 17 ± 2 µM. They also reduced expression of inducible NO synthase and interleukin-6 (IL-6) without affecting cyclooxygenase-2 expression. Compound 1h also reduced secretion of IL-6 and tumor necrosis factor-α by LPS-activated J774A.1 murine macrophage cells, primary mice peritoneal macrophages, and JAWSII murine bone marrow-derived dendritic cells and reduced NLRP3 inflammasome-mediated interleukin-1ß (IL-1ß) secretion by LPS + adenosine triphosphate-activated J774A.1 and JAWSII cells. The underlying mechanisms for the anti-inflammatory activity of compound 1h were found to be a decrease in LPS-induced reactive oxygen species (ROS) production, mitogen-activated protein kinase phosphorylation, and NF-κB activation and a decrease in ATP-induced ROS production and PKC-α phosphorylation. These results provide promising insights into the anti-inflammatory activity of these conjugated polyenes and a molecular rationale for future therapeutic intervention in inflammation-related diseases. They also show how compound 1h regulates inflammation and suggest it may be a new source for the development of anti-inflammatory agents to ameliorate inflammation- and NLRP3 inflammasome-related diseases.

Generation of reactive oxygen species by polyenylpyrroles derivatives causes DNA damage leading to G2/M arrest and apoptosis in human oral squamous cell carcinoma cells.

Oral squamous cell carcinoma (OSCC) accounts for 5.8% of all malignancies in Taiwan and the incidence of OSCC is on the rise. OSCC is also a common malignancy worldwide and the five-year survival rate remains poor. Therefore, new and effective treatments are needed to control OSCC. In the present study we have investigated the efficacy and associated mechanisms of polyenylpyrroles and their analogs in both in vitro cell culture and in vivo nude mice xenografts. Auxarconjugatin B (compound 1a) resulted in cell cycle arrest in the G2/M phase and caspase-dependent apoptosis in OEC-M1 and HSC-3 cells by activating DNA damage and mitochondria dysfunction through the loss of mitochondrial membrane potential, release of cytochrome c, increase in B-cell lymphoma-2-associated X protein level, and decrease in B-cell lymphoma-2 level. Compound 1a-induced generation of intracellular reactive oxygen species through cytochrome P450 1A1 was identified as a major mechanism of its effect for DNA damage, mitochondria dysfunction and apoptosis, which was reversed by antioxidant N-acetylcysteine as well as cytochrome P450 1A1 inhibitor and specific siRNA. Furthermore, compound 1a-treated nude mice showed a reduction in the OEC-M1 xenograft tumor growth and an increase in the caspase-3 activation in xenograft tissue. These results provide promising insights as to how compound 1a mediates cytotoxicity and may prove to be a molecular rationale for its translation into a potential therapeutic against OSCC.

Synthesis and biological evaluation of polyenylpyrrole derivatives as anticancer agents acting through caspases-dependent apoptosis.

A class of polyenylpyrroles and their analogues were designed from a hit compound identified in a fungus. The compounds synthesized were evaluated for their cell cytotoxicity against human non-small-cell lung carcinoma cell lines A549. Two compounds were found to exhibit high cytotoxicity against A549 cells with IC(50) of 0.6 and 0.01 µM, respectively. The underlying mechanisms for the anticancer activity were demonstrated as caspases activation dependent apoptosis induction through loss of mitochondrial membrane potential, release of cytochrome c, increase in B-cell lymphoma-2-associated X protein (Bax) level, and decrease in B-cell lymphoma-2 (Bcl-2) level. The two compounds were nontoxic to normal human lung Beas-2b cells (IC(50) > 80 µM), indicating that they are highly selective in their cytotoxicity activities. Furthermore, one compound showed in vivo anticancer activity in human-lung-cancer-cell-bearing mice. These results open promising insights on how these conjugated polyenes mediate cytotoxicity and may provide a molecular rationale for future therapeutic interventions in carcinogenesis.