Pamiparib as consolidation treatment after concurrent chemoradiotherapy of limited-stage small cell lung cancer: a single-arm, open-label phase 2 trial.

BACKGROUND: Small cell lung cancer (SCLC) is highly invasive with poor prognosis, and its treatment has historically been hindered due to the absence of targetable driver genomic alterations. However, the high genomic instability and replication stress in SCLC have made poly(ADP-ribose) polymerases (PARPs) inhibitors a focus of research. Pamiparib is an orally available PARP1/2 inhibitor with high selectivity, strong PARP trapping activity, and excellent brain penetration. Utilizing pamiparib as consolidation maintenance therapy in limited-stage SCLC holds promise for improving survival outcomes and offering a viable therapeutic approach. METHODS: This single-arm, open-label phase II trial will enroll patients aged 18-75 years with histologically/cytologically confirmed, limited-stage SCLC who have not progressed following definitive platinum-based cCRT and have an ECOG PS of 0 or 1. Patients will be excluded if they have histologically confirmed mixed SCLC or NSCLC, or have undergone previous tumor resection, or can be treated with surgery or stereotactic body radiation therapy/stereotactic ablative radiation therapy. Participants will receive pamiparib 40 mg twice daily every 3 weeks within 2 to 6 weeks after cCRT for up to 1 year or until disease progression according to RECIST v1.1. The primary endpoint is the 1-year progression-free survival (PFS) rate assessed by investigators per RECIST v1.1. Secondary endpoints include PFS, objective response rate, and duration of response assessed by investigators per RECIST 1.1, overall survival, time to distant metastasis, and safety. DISCUSSION: The study will provide valuable data on the feasibility, safety, and effectiveness of pamiparib as a consolidation therapy after cCRT in patients with LS-SCLC. The correlation between molecular typing or gene expression profile of the disease and curative response will be further explored. TRIAL REGISTRATION: NCT05483543 at clinicaltrials.gov.

Ascorbic acid enhanced the circulation between Fe(II) and Fe(III) in peroxymonosulfate system for fluoranthene degradation.

In this research, ascorbic acid (AA) was used to enhance Fe(II)/Fe(III)-activated permonosulfate (PMS) systems for the degradation of fluoranthene (FLT). AA enhanced the production of ROS in both PMS/Fe(II) and PMS/Fe(III) systems through chelation and reduction and thus improved the degradation performance of FLT. The optimal molar ratio in PMS/Fe(II)/AA/FLT and PMS/Fe(III)/AA/FLT processes were 2/2/4/1 and 5/10/5/1, respectively. In addition, the experimental results on the effect of FLT degradation under different groundwater matrixes indicated that PMS/Fe(III)/AA system was more adaptable to different water quality conditions than the PMS/Fe(II)/AA system. SO4·- was the major reactive oxygen species (ROS) responsible for FLT removal through the probe and scavenging tests in both systems. Furthermore, the degradation intermediates of FLT were analyzed using gas chromatograph-mass spectrometry (GC-MS), and the probable degradation pathways of FLT degradation were proposed. In addition, the removal of FLT was also tested in actual groundwater and the results showed that by increasing the dose and pre-adjusting the solution pH, 88.8 and 100% of the FLT was removed for PMS/Fe(II)/AA and PMS/Fe(III)/AA systems. The above experimental results demonstrated that PMS/Fe(II)/AA and PMS/Fe(III)/AA processes have a great perspective in practice for the rehabilitation of FLT-polluted groundwater.

Fluorimetric Detection of Insulin Misfolding by Probes Derived from Functionalized Fluorene Frameworks.

A group of functionalized fluorene derivatives that are structurally similar to the cellular prion protein ligand N,N'-(methylenedi-4,1-phenylene)bis [2-(1-pyrrolidinyl)acetamide] (GN8) have been synthesized. These compounds show remarkable native fluorescence due to the fluorene ring. The substituents introduced at positions 2 and 7 of the fluorene moiety are sufficiently flexible to accommodate the beta-conformational folding that develops in amyloidogenic proteins. Changes in the native fluorescence of these fluorene derivatives provide evidence of transformations in the amyloidogenic aggregation processes of insulin. The increase observed in the fluorescence intensity of the sensors in the presence of native insulin or amyloid aggregates suggest their potential use as fluorescence probes for detecting abnormal conformations; therefore, the compounds can be proposed for use as "turn-on" fluorescence sensors. Protein-sensor dissociation constants are in the 5-10 µM range and an intermolecular charge transfer process between the protein and the sensors can be successfully exploited for the sensitive detection of abnormal insulin conformations. The values obtained for the Stern-Volmer quenching constant for compound 4 as a consequence of the sensor-protein interaction are comparable to those obtained for the reference compound GN8. Fluorene derivatives showed good performance in scavenging reactive oxygen species (ROS), and they show antioxidant capacity according to the FRAP and DPPH assays.

Characterization of persistent organic contaminants in the atmosphere of Gadani's ship breaking yards and its surrounding: Implications for sustainable ship recycling practices.

Gadani is internationally renowned for its extensive ship-breaking operations, positioning it as one of the globe's primary ship-breaking hubs. A comprehensive study was conducted to evaluate the presence of organic contaminants in the air within Gadani, encompassing the areas surrounding ship-breaking facilities, proximate residential settlements, and adjacent roadways. Passive air samplers were employed to collect a total of 30 air samples. The analytical results unveiled a notably elevated concentration of specific organic compounds, with a pronounced prevalence of polycyclic aromatic hydrocarbons (PAHs), short-chain chlorinated paraffins (SCCPs), and polychlorinated biphenyls (PCBs) at the ship-breaking yard. Notably, dichlorodiphenyltrichloroethanes (DDTs) and DDE were detected at substantially lower levels. In particular, sites in close proximity to ship-breaking activities exhibited elevated concentrations of PCBs (Σ7PCB 0.065429 to 7.345714 ng/sample), PAHs (Σ8PAH 2.44 to 134.23 ng/sample), and SCCPs (0.18 to 25.6 ng/sample). Conversely, DDTs and DDE demonstrated higher concentrations near residential settlements. The evaluation of Molecular Diagnostic Ratios for PAHs revealed anthracene/anthracene + phenanthrene ratios of 0.88, 0.69, and 0.5 for ship-breaking areas, roadside locations, and community surroundings, respectively. Furthermore, the benz[a]anthracene/benz-[a]anthracene + chrysene molecular ratios were measured at 0.77 (ship-breaking sites), 0.82 (roadside), and 0.83 (community), respectively. The molecular ratio of fluoranthene/fluoranthene + pyrene at ship-breaking sites was 0.23, while roadside and community ratios were 0.36 and 0.89, respectively. These findings underscore the significant contribution of ship-recycling activities to the atmospheric release of SCCPs, PCBs, and PAHs, emphasizing the global imperative for responsible ship recycling practices.

Comparison of Glecaprevir/Pibrentasvir and Sofosbuvir/Ledipasvir in Patients with Hepatitis C Virus Genotype 1 and 2 in South Korea.

Background/Aims: This study compared the effectiveness and safety of glecaprevir/pibrentasvir (GLE/PIB) and sofosbuvir/ledipasvir (SOF/LDV) in real-life clinical practice. Methods: The data from genotype 1 or 2 chronic hepatitis C patients treated with GLE/PIB or sofosbuvir + ribavirin or SOF/LDV in South Korea were collected retrospectively. The analysis included the treatment completion rate, sustained virologic response at 12 weeks (SVR12) test rate, treatment effectiveness, and adverse events. Results: Seven hundred and eighty-two patients with genotype 1 or 2 chronic hepatitis C who were treated with GLE/PIB (n=575) or SOF/LDV (n=207) were included in this retrospective study. The baseline demographic and clinical characteristics revealed significant statistical differences in age, genotype, ascites, liver cirrhosis, and hepatocellular carcinoma between the GLE/PIB and SOF/LDV groups. Twenty-two patients did not complete the treatment protocol. The treatment completion rate was high for both regimens without statistical significance (97.7% vs. 95.7%, p=0.08). The overall SVR12 of intention-to-treat analysis was 81.2% vs. 80.7% without statistical significance (p=0.87). The overall SVR12 of per protocol analysis was 98.7% vs. 100% without statistical significance (p=0.14). Six patients treated with GLE/PIB experienced treatment failure. They were all male, genotype 2, and showed a negative hepatitis C virus RNA level at the end of treatment. Two patients treated with GLE/PIB stopped medication because of fever and abdominal discomfort. Conclusions: Both regimens had similar treatment completion rates, effectiveness, and safety profiles. Therefore, the SOF/LDV regimen can also be considered a viable DAA for the treatment of patients with genotype 1 or 2 chronic hepatitis C.

Arsenic effectively improves the degradation of fluorene by Rhodococcus sp. 2021 under the combined pollution of arsenic and fluorene.

The performance of bacterial strains in executing degradative functions under the coexistence of heavy metals/heavy metal-like elements and organic contaminants is understudied. In this study, we isolated a fluorene-degrading bacterium, highly arsenic-resistant, designated as strain 2021, from contaminated soil at the abandoned site of an old coking plant. It was identified as a member of the genus Rhodococcus sp. strain 2021 exhibited efficient fluorene-degrading ability under optimal conditions of 400 mg/L fluorene, 30 °C, pH 7.0, and 250 mg/L trivalent arsenic. It was noted that the addition of arsenic could promote the growth of strain 2021 and improve the degradation of fluorene - a phenomenon that has not been described yet. The results further indicated that strain 2021 can oxidize As3+ to As5+; here, approximately 13.1% of As3+ was converted to As5+ after aerobic cultivation for 8 days at 30 °C. The addition of arsenic could greatly up-regulate the expression of arsR/A/B/C/D and pcaG/H gene clusters involved in arsenic resistance and aromatic hydrocarbon degradation; it also aided in maintaining the continuously high expression of cstA that codes for carbon starvation protein and prmA/B that codes for monooxygenase. These results suggest that strain 2021 holds great potential for the bioremediation of environments contaminated by a combination of arsenic and polycyclic aromatic hydrocarbons. This study provides new insights into the interactions among microbes, as well as inorganic and organic pollutants.

Dermal absorption of high molecular weight parent and alkylated polycyclic aromatic hydrocarbons from manufactured gas plant soils using in vitro assessment.

An enhanced in vitro human dermal bioavailability method was developed to measure the release of twenty parent and seven alkylated high molecular weight (HMW) polycyclic aromatic hydrocarbons (PAHs) from contaminated soils collected from five former manufactured Gas Plants (MGP) in England. GC-MS/MS was used to quantify HMW PAHs in soil, Strat-M artificial membrane representing skin, and synthetic receptor solution (RS) representing systemic circulation at 1-h, 10-h, and 24-h timesteps. Fluoranthene and pyrene exhibited the highest fluxes from soils to membrane (ranging from 9.5 - 281 ng/cm2/h) and soil to RS (

9-Fluorenylmethyl Chloroformate Labeling for O-Glycan Analysis.

Structural analysis of O-glycans from mucins and characterization of the interaction of these glycans with other biomolecules are essential for a full understanding of mucins. Various techniques have been developed for the structural and functional analysis of glycans. While 9-fluorenylmethyl chloroformate (Fmoc-Cl) is generally used to protect amino groups in peptide synthesis, it can also be used as a glycan-labeling reagent for structural analysis. Fmoc-labeled glycans are strongly fluorescent and can be analyzed with high sensitivity using liquid chromatography-fluorescence detection (LC-FD) analysis as well as being analyzed with high sensitivity by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS). Fmoc-labeled glycans can be easily delabeled and converted to glycosylamine-form or free (hemiacetal or aldehyde)-form glycans that can be used to fabricate glycan arrays or synthesize glycosyl dendrimers. This derivatization allows for the isolation from biological samples of glycans that are difficult to synthesize chemically, as well as the fabrication of immobilized-glycan devices. The Fmoc labeling method promises to be a tool for accelerating O-glycan structural analysis and an understanding of molecular interactions. In this chapter, we introduce the Fmoc labeling method for analysis of O-glycans and fabrication of O-glycan arrays.

Effectiveness of artemether-lumefantrine for treating uncomplicated malaria in low- and high-transmission areas of Ghana.

BACKGROUND: Artemisinin-based combination therapy (ACT) has been effective in the supervised treatment of uncomplicated malaria in Ghana. Since ACT usage is primarily unsupervised, this study aimed to determine the effectiveness of artemether-lumefantrine (AL) for treating malaria patients in two transmission settings in Ghana. METHODS: Eighty-four individuals with uncomplicated Plasmodium falciparum malaria were recruited from Lekma Hospital (LH) in Accra (low-transmission area; N = 28), southern Ghana, and King's Medical Centre (KMC) in Kumbungu (high-transmission area; N = 56), northern Ghana. Participants were followed up for 28 days after unsupervised treatment with AL. The presence of asexual parasites was determined by microscopic examination of Giemsa-stained blood smears. Plasmodium species identification was confirmed using species-specific primers targeting the 18S rRNA gene. Parasite recrudescence or reinfection was determined by genotyping the Pfmsp 1 and Pfmsp 2 genes. RESULTS: After AL treatment, 3.6% (2/56) of the patients from KMC were parasitaemic on day 3 compared to none from the LH patients. One patient from KMC with delayed parasite clearance on day 3 remained parasite-positive by microscopy on day 7 but was parasite-free by day 14. While none of the patients from LH experienced parasite recurrence during the 28-day follow-up, three and two patients from KMC had recurrent parasitaemia on days 21 and 28, respectively. Percentage reduction in parasite densities from day 1, 2, and 3 for participants from the KMC was 63.2%, 89.5%, and 84.5%. Parasite densities for participants from the LH reduced from 98.2%, 99.8% on day 1, and 2 to 100% on day 3. The 28-day cumulative incidence rate of treatment failure for KMC was 12.8% (95% confidence interval: 1.9-23.7%), while the per-protocol effectiveness of AL in KMC was 89.47%. All recurrent cases were assigned to recrudescence after parasite genotyping by Pfmsp 1 and Pfmsp 2. CONCLUSION: While AL is efficacious in treating uncomplicated malaria in Ghana, when taken under unsupervised conditions, it showed an 89.4% PCR-corrected cure rate in northern Ghana, which is slightly below the WHO-defined threshold.

The toxicity response of the electrochemical signal of the cell to the drug metabolized by the S9 system.

The electrochemical detection method of cytotoxicity using intracellular purines as biomarkers has shown great potential for in vitro drug toxicity evaluation. However, no electrochemical detection system based on an in vitro drug metabolism mechanism has been devised. In this paper, electrochemical voltammetry was used to investigate the effect of the S9 system on the electrochemical behavior of HepG2 cells, and benzo[a]pyrene, fluoranthene, and pyrene were employed to investigate the sensitivity of electrochemical signals of cells to the cytotoxicity of drugs metabolized by the S9 system. The results showed that, within 8 h of exposure to the S9 system, the electrochemical signal of HepG2 cells at 0.7 V did not alter noticeably. The levels of xanthine, guanine, hypoxanthine, and adenine in the cells were not significantly altered. Compared with the absence of S9 system metabolism, benzo[a]pyrene and fluoranthene processed by the S9 system decreased the electrochemical signal of the cells in a dose-dependent manner, while pyrene did not change it appreciably. HPLC also revealed that benzo[a]pyrene and fluoranthene metabolized by the S9 system decreased the intracellular purine levels, whereas pyrene had no effect on them before and after S9 system metabolism. The cytotoxicity results of the three drugs examined by electrochemical voltammetry and MTT assay showed a strong correlation and good agreement. The S9 system had no effect on the intracellular purine levels or the electrochemical signal of cells. When the drug was metabolized by the S9 system, variations in cytotoxicity could be precisely detected by electrochemical voltammetry.

Photocatalytic degradation of fluoranthene in soil suspension by TiO2/α-FeOOH with enhanced charge transfer capacity.

Polycyclic aromatic hydrocarbons (PAHs) in soil are potentially harmful to human health. However, the use of photocatalysis technology to treat soil contaminated with PAHs remains challenging. Therefore, TiO2/α-FeOOH composite photocatalyst has been synthesized by hydrothermal method and sol-gel method and applied to photocatalytic degradation of fluoranthene in soil. The morphology, elements, crystal structure, optical properties, electrochemical characteristics, and photocatalytic activity of TiO2/α-FeOOH have been characterized. Results showed that TiO2 is tightly fixed on the surface of α-FeOOH, and TiO2/α-FeOOH had higher photocatalytic activity on photocatalytic degradation of fluoranthene in soil under simulated sunlight. The degradation efficiency of TiO2/α-FeOOH is 3.0 and 4.8 times higher than that of TiO2 and α-FeOOH, respectively. This is attributed to enhanced photocatalytic ability by enhancing the transfer capacity of electrons and holes and broadening the spectrum absorption range. The highest degradation efficiency was achieved when the pH of the soil is neutral, the ratio of water/soil is 10:1, and the dosage of catalyst is 50 mg/g. In addition, it was proved that •O2-, h+, and 1O2 are the main active substances in the photocatalysis of TiO2/α-FeOOH. The possible mechanism of a Z-type electron transfer structure was also proposed. The degradation products of fluoranthene were detected, and the degradation pathway was deduced.

Experimental determination of the partitioning of representative organic pollutants to the air-water interface.

Using glancing-angle laser-induced fluorescence (GALIF) spectroscopy as a probe, the partitioning of naphthalene, fluoranthene, pyrene, umbelliferone, phenol red, and bisphenol A from bulk solution to the air-water interface was examined in both pure water and aqueous solutions of 6 mM octanol. Previous studies provided similar Langmuir adsorption isotherms for anthracene and imidazole 2-carboxaldehyde. The surface partitioning behaviour of each compound in both environments was well described using a Langmuir adsorption model; partitioning coefficients were derived from the fits to such isotherms. Only the PAH molecules, naphthalene, fluoranthene and pyrene, saw an enhancement in the surface partitioning in octanol solution compared to pure water. The surface partitioning to pure water surfaces could be fairly well described using a one parameter linear free energy relationship based on either solubility or KOW.

Fluorene-induced stress in the benthic oligochaete Tubifex tubifex: A multi-biomarker assessment of toxicological pathways and mechanisms under acute and subchronic exposures.

This study examined the multifaceted impacts of fluorene exposure on Tubifex tubifex, encompassing acute (survival analysis and behavioral responses) and subchronic exposure regimens (antioxidant enzyme response and histopathology), molecular docking studies, and generalized read-across analysis. Survival analysis revealed concentration-dependent increases in toxicity over varying time intervals, with LC50 values decreasing from 30.072 mg/L at 24 h to 12.365 mg/L at 96 h, emphasizing the time-sensitive and concentration-responsive nature of the stressor. Behavioral responses were both concentration- and duration-dependent. While Erratic Movement and Clumping Tendency exhibited earlier responses (within 24 h) at lower concentrations, the wrinkling effect and mucus secretion) exhibited delayed onset, suggesting intricate regulatory mechanisms underlying adaptability to environmental challenges; moreover, the wrinkling effect was consistently induced at higher concentrations, indicating greater sensitivity to the toxic effects of fluorene. With sublethal environmentally relevant concentrations-1.24 mg/l and 2.47 mg/L i.e., 10% and 20% 96 h, respectively-the antioxidant enzyme response (i.e., upregulation of SOD, CAT, and GST) with increasing fluorene concentration, revealing a nonlinear, hormetic response, suggested adaptive protection at lower doses but inhibition at higher concentrations. Histopathological examination indicated that higher fluorene concentrations caused cellular proliferation, inflammation, and severe tissue damage in the digestive tract and body wall. Molecular docking studies demonstrated robust interactions between fluorene and major stress biomarker enzymes, disrupting their functions and inducing oxidative stress. Interactions with cytochrome c oxidase suggested interference with cellular energy production. Generalized Read-Across (GenRA) analysis unveiled shared toxicity mechanisms among fluorene and its analogs, involving the formation of reactive epoxides and the influence of cytochrome P450 enzymes. The diverse functional groups of these analogs, particularly chlorine-containing compounds, were implicated in toxicity through lipid peroxidation and membrane damage. Adverse outcome pathways and broader consequences for aquatic ecosystem health are discussed.

TNFSF15 inhibits progression of diabetic retinopathy by blocking pyroptosis via interacting with GSDME.

Diabetic retinopathy is a common microvascular complication of diabetes and a leading cause of blindness. Pyroptosis has emerged as a mechanism of cell death involved in diabetic retinopathy pathology. This study explored the role of GSDME-mediated pyroptosis and its regulation by TNFSF15 in diabetic retinopathy. We found GSDME was upregulated in the progression of diabetic retinopathy. High glucose promoted GSDME-induced pyroptosis in retinal endothelial cells and retinal pigment epithelial cells, attributed to the activation of caspase-3 which cleaves GSDME to generate the pyroptosis-executing N-terminal fragment. TNFSF15 was identified as a binding partner and inhibitor of GSDME-mediated pyroptosis. TNFSF15 expression was increased by high glucose but suppressed by the caspase-3 activator Raptinal. Moreover, TNFSF15 protein inhibited high glucose- and Raptinal-induced pyroptosis by interacting with GSDME in retinal cells. Collectively, our results demonstrate TNFSF15 inhibits diabetic retinopathy progression by blocking GSDME-dependent pyroptosis of retinal cells, suggesting the TNFSF15-GSDME interaction as a promising therapeutic target for diabetic retinopathy.

Antimicrobial Potency of Fmoc-Phe-Phe Dipeptide Hydrogels with Encapsulated Porphyrin Chromophores Is a Promising Alternative in Antimicrobial Resistance.

Antimicrobial resistance (AMR) poses a significant global health risk as a consequence of misuse of antibiotics. Owing to the increasing antimicrobial resistance, it became imperative to develop novel molecules and materials with antimicrobial properties. Porphyrins and metalloporphyrins are compounds which present antimicrobial properties especially after irradiation. As a consequence, porphyrinoids have recently been utilized as antimicrobial agents in antimicrobial photodynamic inactivation in bacteria and other microorganisms. Herein, we report the encapsulation of porphyrins into peptide hydrogels which serve as delivery vehicles. We selected the self-assembling Fmoc-Phe-Phe dipeptide, a potent gelator, as a scaffold due to its previously reported biocompatibility and three different water-soluble porphyrins as photosensitizers. We evaluated the structural, mechanical and in vitro degradation properties of these hydrogels, their interaction with NIH3T3 mouse skin fibroblasts, and we assessed their antimicrobial efficacy against Gram-positive Staphylococcus aureus (S. aureus) and Gram-negative Escherichia coli (E. coli) bacteria. We found out that the hydrogels are cytocompatible and display antimicrobial efficiency against both strains with the zinc porphyrins being more efficient. Therefore, these hydrogels present a promising alternative for combating bacterial infections in the face of growing AMR concerns.

Enhanced washing of polycyclic aromatic hydrocarbons from contaminated soils by the empowered surfactant properties of de novo O-alkylated humic matter.

Aqueous solutions of humic acid (HA) derivatized by a catalyzed O-alkylation reaction with methyl, pentyl, and benzyl groups at 40, 60, and 80% of total HA acidity were used to wash off polycyclic aromatic hydrocarbons (PAHs) from two contaminated soils. The enhanced surfactant properties enabled the alkylated HA to remove phenanthrene, anthracene, fluoranthene, and pyrene from both soils more extensively than the original unmodified HA, the 60% benzylation generally showing the greatest soil washing efficiency. For both soils, all alkylated HA revealed greater PAH removals than Triton X-100 nonionic surfactant, while the benzylated and methylated HA nearly and fully matched pollutants release by the anionic SDS in the coarse- and fine-textured soils, respectively. A consecutive second washing with 60% benzylated HA removed additional PAHs, in respect to the first washing, from the coarser-textured soil, except for fluoranthene, while removal from the finer-textured soil incremented even more for all PAHs. These findings indicate that the enhanced hydrophobicity obtained by a simple and unexpensive chemical derivatization of a natural humic surfactant can be usefully exploited in the washing of polluted soils, without being toxic to the soil biota and by potentially promoting the subsequent bio-attenuation of organic pollutants.

The small molecule raptinal can simultaneously induce apoptosis and inhibit PANX1 activity.

Discovery of new small molecules that can activate distinct programmed cell death pathway is of significant interest as a research tool and for the development of novel therapeutics for pathological conditions such as cancer and infectious diseases. The small molecule raptinal was discovered as a pro-apoptotic compound that can rapidly trigger apoptosis by promoting the release of cytochrome c from the mitochondria and subsequently activating the intrinsic apoptotic pathway. As raptinal is very effective at inducing apoptosis in a variety of different cell types in vitro and in vivo, it has been used in many studies investigating cell death as well as the clearance of dying cells. While examining raptinal as an apoptosis inducer, we unexpectedly identified that in addition to its pro-apoptotic activities, raptinal can also inhibit the activity of caspase-activated Pannexin 1 (PANX1), a ubiquitously expressed transmembrane channel that regulates many cell death-associated processes. By implementing numerous biochemical, cell biological and electrophysiological approaches, we discovered that raptinal can simultaneously induce apoptosis and inhibit PANX1 activity. Surprisingly, raptinal was found to inhibit cleavage-activated PANX1 via a mechanism distinct to other well-described PANX1 inhibitors such as carbenoxolone and trovafloxacin. Furthermore, raptinal also interfered with PANX1-regulated apoptotic processes including the release of the 'find-me' signal ATP, the formation of apoptotic cell-derived extracellular vesicles, as well as NLRP3 inflammasome activation. Taken together, these data identify raptinal as the first compound that can simultaneously induce apoptosis and inhibit PANX1 channels. This has broad implications for the use of raptinal in cell death studies as well as in the development new PANX1 inhibitors.

Toxic effects of polystyrene nanoplastics and polycyclic aromatic hydrocarbons (chrysene and fluoranthene) on the growth and physiological characteristics of Chlamydomonas reinhardtii.

While the toxicity of nano-microplastics and polycyclic aromatic hydrocarbons (PAHs) to aquatic organisms is well-studied, their joint impact on microalgae is less explored. This study focused on single and combined effects of PS-NPs (30 nm; concentrations: 2, 5, 10, and 25 mg/L) and two PAHs (chrysene and fluoranthene at 10, 100 µg/L) for 96 h on the accumulation, growth, photosynthetic parameters, and oxidative stress in the Chlamydomonas reinhardtii. The findings revealed that exposure to increasing concentrations of PS-NPs significantly reduced the growth inhibition ratio and chlorophyll-a content after 96 h. Both PAHs (100 µg/L) + PS-NPs (25 mg/L), significantly reduced the growth inhibition ratio and chlorophyll-a levels. Individual and combined exposures of PS-NPs and PAHs can prompt antioxidant responses like SOD, GPx, and GST, as well as an unaffected level of non-enzymatic antioxidant GSH and diminished CAT activity. Furthermore, both PAHs + PS-NPs triggered ROS levels, resulting in cell membrane damage. However, the reduced oxidative effect of LPO of combined exposures can be attributed to the activation of antioxidant defenses. In addition, the microscopic visualization data shows that PS-NPs adhered to the surface of microalgae. Also, PS-NPs reduced the adsorption of PAHs on the surface of C. reinhardtii. Altogether, this study implied that the influence of coexistent PS-NPs should be considered in the environmental risk assessment of PAHs in aquatic environments.

Simultaneous volatile fatty acids promotion and antibiotic resistance genes reduction in fluoranthene-induced sludge alkaline fermentation: Regulation of microbial consortia and cell functions.

The impact and mechanism of fluoranthene (Flr), a typical polycyclic aromatic hydrocarbon highly detected in sludge, on alkaline fermentation for volatile fatty acids (VFAs) recovery and antibiotic resistance genes (ARGs) transfer were studied. The results demonstrated that VFAs production increased from 2189 to 4272 mg COD/L with a simultaneous reduction of ARGs with Flr. The hydrolytic enzymes and genes related to glucose and amino acid metabolism were provoked. Also, Flr benefited for the enrichment of hydrolytic-acidifying consortia (i.e., Parabacteroides and Alkalibaculum) while reduced VFAs consumers (i.e., Rubrivivax) and ARGs potential hosts (i.e., Rubrivivax and Pseudomonas). Metagenomic analysis indicated that the genes related to cell wall synthesis, biofilm formation and substrate transporters to maintain high VFAs-producer activities were upregulated. Moreover, cell functions of efflux pump and Type IV secretion system were suppressed to inhibit ARGs proliferation. This study provided intrinsic mechanisms of Flr-induced VFAs promotion and ARGs reduction during alkaline fermentation.

Benzo(k)fluoranthene and benzo(b)fluoranthene degradation by Selenastrum capricornutum and identification of metabolites using HPLC-FD and HPLC-ESI-QqQ-MS/MS.

Selenastrum capricornutum efficiently degrades high molecular weight polycyclic aromatic hydrocarbons (HMW PAHs). Until now, there are few studies on the benzo(k)fluoranthene (BkF) and benzo(b)fluoranthene (BbF) biodegradation by this microalga. For this reason, in the present work, extracts obtained from cultures of S. capricornutum were incubated with BkF and BbF individually, and analyzed by HPLC with fluorescence and different mass spectrometry detection modes: i) the HPLC-ESI(+)-MS/MS (MRM mode) analysis that confirmed the formation of monohydroxylated and dihydrodiol metabolites indicating that these PAHs could be simultaneously degraded through the monooxygenase and dioxygenase; ii) HPLC-ESI(+)-MS (full scan mode) that showed the formation of key metabolites containing four and two aromatic rings possibly resulting from aromatic ring-opening oxygenases, not known until now in microalgae; iii) HPLC-FD analysis that confirmed the individual BkF and BbF degradation occurring in extra- and intra-cellular extracts, indicating that an oxygenase enzyme complex is released by microalgae cells to the external environment to perform HMW PAHs biodegradation. So, this work presents new insights into the metabolic pathways of BkF and BbF biodegradation by S. capricornutum; likewise, the intra- and extra-cellular extracts of this microalgae have great potential to be applied in environmental procedures.