Lung squamous cell carcinoma (LSCC) is among the most prevalent and deadly malignancies in arsenic‐exposed populations, yet effective targeted therapies remain elusive. Cross-Reactive Material (CRM197), a non‐toxic mutant of diphtheria toxin that binds heparin‐binding EGF‑like growth factor (HB‑EGF), has demonstrated anti‑tumor activity, but its efficacy against arsenic‐induced LSCC has not been characterized. In this study, we assessed CRM197’s effects on proliferation (CCK‑8 and colony‑formation assays), cell‑cycle progression (flow cytometry), comparing its activity to cetuximab and afatinib in arsenic‑transformed BEAS‑2B cells obtained by 6-month treatment on human bronchial epithelial cells BEAS-2B with low-dose sodium arsenite (As‑T) and lung cancer cells(NCI‑H226 and PC‑9). Next, we evaluated in vivo efficacy in nude mice bearing As‑T and NCI‑H226 xenografts treated daily with CRM197 (5 mg/kg) or afatinib. Finally, tandem‑mass‑tag proteomics and network pharmacology identified 179 upregulated proteins in As‑T cells and 11 overlapping CRM197 targets—including AKR1B1, PTPN1, PPARA, and SERPINE1—which were validated by molecular docking and 100‑ns dynamics simulations. CRM197 markedly inhibited cell proliferation, induced G₀/G₁ arrest, and outperformed cetuximab and matched or exceeded afatinib in vitro; in vivo, CRM197 reduced tumor volume and weight more effectively than afatinib, with extensive necrosis. These data establish CRM197 as a potent, multi‑targeted inhibitor of arsenic‑driven LSCC and highlight novel therapeutic targets for further drug development.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-23832-z.

Echinochrome guarding effect against sodium arsenite-induced hepatorenal toxicity in rats.

Characterization of human healthy i3 lower motor neurons exposed to CSF from ALS patients stratified by UNC13A and C9ORF72 genotype.

Modeling of TDP-43 proteinopathy by chronic oxidative stress identifies rapamycin as beneficial in ALS patient-derived 2D and 3D iPSC models

Two prominent cytoplasmic RNA granules, ubiquitous RNA-processing bodies (PB) and inducible stress granules (SG), regulate mRNA translation and are intimately related. In this study, we found that arsenite (ARS)-induced SG formed in a stepwise process is topologically and mechanically linked to PB. Two essential PB components, GW182 and DDX6, are repurposed under stress to play direct but distinguishable roles in SG biogenesis. By providing scaffolding activities, GW182 promotes the aggregation of SG components to form SG bodies. DEAD-box helicase DDX6 is also essential for the proper assembly and separation of PB from SG. DDX6 deficiency results in the formation of irregularly shaped 'hybrid' PB/SG granules with accumulated components of both PB and SG. Wild-type DDX6, but not its helicase mutant E247A, can rescue the separation of PB from SG in DDX6KO cells, indicating a requirement of DDX6 helicase activity for this process. DDX6 activity in biogenesis of both PB and SG in the cells under stress is further modulated by its interaction with two protein partners, CNOT1 and 4E-T, of which knockdown affects the formation of both PB and also SG. Together, these data highlight a new functional paradigm between PB and SG biogenesis during the stress.

Stress granules (SGs) are cytoplasmic aggregates of RNA-protein complexes that form in response to various cellular stresses and are known to restrict viral access to host translational machinery. However, the underlying molecular mechanisms of SGs during viral infections require further exploration. In this study, we evaluated the effect of SG formation on cellular responses to coxsackievirus B3 (CVB3) infection. Sodium arsenite (AS)-mediated SG formation suppressed cell death induced by tumor necrosis factor-alpha (TNF-a)/cycloheximide (CHX) treatment in HeLa cells, during which G3BP1, an essential SG component, contributed to the modulation of apoptosis pathways. SG formation in response to AS treatment blocked CVB3-mediated cell death, possibly via the reduction of mitochondrial reactive oxygen species. Furthermore, we examined whether AS treatment would affect small extracellular vesicle (sEV) formation and secretion during CVB3 infection and modulate human monocytic cell (THP-1) response. CVB3-enriched sEVs isolated from HeLa cells were able to infect and replicate THP-1 cells without causing cytotoxicity. Interestingly, sEVs from AS-treated HeLa cells inhibited CVB3 replication in THP-1 cells. These findings suggest that SG formation during CVB3 infection modulates cellular response by inhibiting the release of CVB3-enriched sEVs.

Mitochondrial stress is involved in many pathological conditions and triggers the integrated stress response (ISR). The ISR is initiated by phosphorylation of the eukaryotic translation initiation factor (eIF) 2α and results in global inhibition of protein synthesis, while the production of specific proteins important for the stress response and recovery is favored. The stalled translation preinitiation complexes phase-separate together with local RNA binding proteins into cytoplasmic stress granules (SG), which are important for regulation of cell signaling and survival under stress conditions. Here we found that mitochondrial inhibition by sodium azide (NaN3) in mammalian cells leads to translational inhibition and formation of SGs, as previously shown in yeast. Although mammalian NaN3-induced SGs are very small, they still contain the canonical SG proteins Caprin 1, eIF4A, eIF4E, eIF4G and eIF3B. Similar to FCCP and oligomycine, other mitochodrial stressors that cause SG formation, NaN3-induced SGs are formed by an eIF2α phosphorylation-independent mechanisms. Finally, we discovered that as shown for arsenite (ASN), but unlike FCCP or heatshock stress, Thioredoxin 1 (Trx1) is required for formation of NaN3-induced SGs.

Thioredoxin 1 is required for stress granule assembly upon arsenite-induced oxidative stress

The nephro-protective effect of Clerodendrum infortunatum Linn ( C. infortunatum ) in arsenic induced sub-acute toxicity (28 days) was evaluated in albino rats. 18 albino rats were divided into 3 groups representing control, sodium arsenite alone and in combination with hydro-methanolic extract of C. infortunatum leaves representing Group I, Group II and Group III respectively. Sodium arsenite (3 mg/kg b.wt.) and C. infortunatum extracts (100 mg/kg b.wt.) were administered orally once daily over a period of 28 days. At the end of treatment period (29th day), rats were sacrificed. The blood samples for hematological parameters and kidney tissues for oxidative stress indices were collected. The kidney weight was also measured. The preliminary phytochemical screening of the above plant was done to know the different phyto-constituents present. Significant reduction were observed in kidney wt., TEC, Hb% and SOD levels where as creatinine, BUN, TLC and MDA levels (P < 0.001) were significantly increased on arsenic exposure. Treatment with extract of C. infortunatum @ 100 mg/kg b.wt for 28 days, significantly reduced the creatinine, BUN, TLC and MDA levels and significantly increased the kidney wt., TEC, Hb% and SOD level (P ≤ 0.001) as compared to arsenic intoxicated group. The major phyto-constituents were present in the leaves i.e. alkaloids, flavonoids, saponins, sterols and terpenes. On the above findings, it can be concluded that treatment with C. infortunatum in sodium arsenite intoxication has significant role in protecting the animals from nephrotoxicity by modulating hemato-biochemical parameters and oxidative stress level.

Статья посвящена отношению патриарха свт. Афанасия I Константинопольского (1289-1293; 1303-1309) к соглашению 1310 г., завершившему собой арсенитский раскол (1265-1310). Рассматриваются взгляды патриарха Афанасия на способы примирения, выраженные им до своего второго отречения от патриаршества (1309 г.), главной идеей которых является истинное покаяние раскольников, выражающееся, в частности, в отказе от личных выгод. Возможно, что патриарх Афанасий узнал о планах императора Андроника II пойти на компромисс с арсенитами и написал ему два письма об этом, в которых он пытается переубедить императора. Для понимания причин неприятия мира предлагается обратиться к понятию φρόνημα (мудрование) на основании сопоставления употребления этого понятия у свт. Афанасия и в антиарсенитских проповедях свт. Феолипта Филадельфийского. Одним из возможных мотивов неприятия мира 1310 г. этими двумя иерархами могло стать нарушение формулы свт. Феолипта «Одна вера - одно мудрование (φρόνημα) - одна Церковь». In this article, the A. studies the attitude of Patriarch St. Athanasius I of Constantinople (1289-1293; 1303-1309) to the agreement of 1310, which ended the Arsenite schism (1265-1310). The A. treats the views of Patriarch Athanasius on ways of reconciliation, expressed by him before his second renunciation of the patriarchate (1309), whose main idea is the true repentance of schismatics, expressed, in particular, in the rejection of personal benefits. It is possible that Patriarch Athanasius found out about the plans of Emperor Andronicus II to compromise with the Arsenites and wrote him two letters about this, in which he tries to over-persuade the Emperor. To understand the reasons for the rejection of the reconciliation, the A. propose to refer to the concept of φρόνημα («way of thinking») on the basis of a comparison of the use of this concept by St. Athanasius and in the anti-Arsenite sermons of St. Theoleptos of Philadelphia. One of the possible reasons for the rejection of the reconciliation of 1310 by these two hierarchs could be a violation of the formula of St. Theoleptos «One Faith - One way of thinking (φρόνημα) - One Church».

В статье осуществлён полный обзор историографии и источников по арсенитскому расколу (1265-1310). Источники оцениваются с точки зрения их подлинности, достоверности, информативности и объективности. Они разделены на 5 групп: исторические, проарсенитские, антиарсенитские, документы о мире 1310 г. и другие источники. В первой группе наибольшую важность представляют «Истории» Пахимера и Григоры. Среди проарсенитских источников наиболее значимы «Завещание» патриарха Арсения, подлинность которого, однако, сомнительна, анонимное «Слово» в защиту отделяющихся и письмо Макария Писидийского Мануилу Дисипату, являющееся образцом арсенитской пропаганды. Полемические трактаты монаха Мефодия и Иоанна Хилы, две проповеди Феолипта Филадельфийского и ряд творений патриарха Афанасия I Константинопольского составляют наиболее важные памятники борьбы с расколом. Источники о мире 1310 г. позволяют достаточно подробно восстановить картину воссоединения арсенитов, а корреспонденция Мануила (Матфея) Гавалы проливает свет на некоторые последствия этого воссоединения. Отдельное внимание в статье уделено отражению арсенитского раскола в русской историографии, рассмотрена модель борьбы партий («зилотов» и «политиков») и её влияние на подходы к рассматриваемому вопросу. Отмечено, что распространённый взгляд на противостояние арсенитов и иерархии как борьбу носителей принципов акривии и икономии (разработанный И. Е. Троицким, А. П. Лебедевым и И. И. Соколовым) является не вполне методологически и терминологически оправданным, а также неадекватно отражает сложную картину общественных отношений в поздней Византии. In this article, the A. makes a full overview of the historiography and the sources on the Arsenite schism (1265-1310). Sources are evaluated on the degree of their authenticity, reliability, informativeness and objectivity. They are divided 5 groups: historical, pro-Arsenite, anti-Arsenite, documents on the reconciliation of 1310 and other sources. In the first group, the «Histories» of Pachymeres and Gregoras are the most important. Among the pro-Arsenite sources, the most significant are the «Testament» of Patriarch Arsenius, whose authenticity is, however, questionable, the anonymous «Word» in defense of those who separate and the letter of Macarius of Pisidia to Manuel Disipatus, which is an example of arsenite propaganda. The polemical treatises of the monk Methodius and Joannes Cheilas, the two sermons of Theoleptus of Philadelphia and several works of Patriarch Athanasius I of Constantinople are the most important monuments of the struggle against the schism. Sources on the reconciliation of 1310 make it possible to restore in sufficient detail the picture of the reunion of the Arsenites, while the correspondence of Manuel (Matthew) Gavala sheds light on some of the consequences of this reunion. The A. pays special attention to the reflection of the Arsenite schism in Russian historiography, to the model of the struggle of the parties («zealots» and «politicians») and its influence on the approaches to the issue under consideration. The A. notes that the widespread view of the confrontation of the Arsenites and the Hierarchy as a struggle of the carriers of the principles of acrybeia and oikonomia (developed by I. Ye. Troitsky, A. P. Lebedev, and I. I. Sokolov) is not quite methodologically and terminologically justified, and also inadequately reflects the complex picture of public relations in the late Byzantium.

The arsenic is a toxic element for the human and other organisms´ health, it may affect the exploitation of water, the agriculture development and the sustainable rational use of soil, the result is reflected within the socioeconomic growth lag in the affected area. Arsenic is mobilized in the environment by a combination of several natural processes, such as weathering reactions, biological activities and volcanic emissions, as well as by a group of anthropogenic activities. Microorganisms interact with the arsenic through a different mechanism such as adsorption, redox, precipitation, etc. On the other hand, the rate of arsenic releasing in geochemical environments is controlled mainly by microorganisms. In the environment, the major arsenic transformations include microbial oxidation, reduction, methylation and demethylation, those reactions have an enormous impact in the arsenic behavior that depends on its redox state that exhibits differences in its mobility and toxicity. Normally, the arsenic resistance comes through the production of genes within operon ars, their location is usually plasmid or chromosomic. In this study, it was achieved the isolation of 11 strains from which 2 have been reported as an arsenic resistant in this work. The samples were collected from water, sediment and biofilm of Xichu River, which has been impacted by mining activity, exhibiting a high arsenic concentration (98 µg/l). All the strains were tested by several methods as arsenic resistance, colorimetric test for arsenate reduction, pDNA extraction as well as ars and aox genes amplification, which are the genes involved in arsenic transformation. It was obtained a great microbial diversity with different skills in arsenic transformation. One of the isolated strains Rodoccoccus gordoniae, did not show the presence of any gen but it was the most likely microorganisms to grow in the presence of arsenic. Almost all the microorganisms showed arsenic resistant until 20 mM of arsenite and arsenate. The main contribution of this study is the development of knowledge to understand much better the arsenic biogeochemistry, as well as the development of new bio-technologies for water treatment in rural communities impacted by mining activity.

Poultry and meat products contaminated with Salmonella enterica are a major cause of foodborne illness in the United States. The food industries use a wide variety of antimicrobial interventions to reduce bacterial contamination. However, little is known about Salmonella susceptibility to these compounds and some studies have shown a concerning link between biocide resistance and antibiotic resistance. To investigate this, a 96 well panel of 17 common household and commercially used biocides was designed to determine the minimum inhibitory concentrations (MIC) of these compounds for Salmonella. The panel contained two-fold serial dilutions of chemicals including Dodecyltrimethylammonium chloride (DC), Benzalkonium chloride (BKC), Cetylpyridinium chloride (CPC), Hexadecyltrimethylammonium bromide (HB), Hexadecyltrimethylammonium chloride (HC), Acetic acid (AA), Lactic acid (LA), Citric acid (CA), Peroxyacetic acid (PXA), Acidified sodium chlorite (ASC), Sodium hypochlorite (SHB), 1,3 dibromo, 5,5 dimethylhydantoin (DBH), Chlorhexidine (CHX), Sodium metasilicate (SM), Trisodium phosphate (TSP), Arsenite (ARI), and Arsenate (ARA). The assay was used to test the susceptibility of 88 multidrug resistant (MDR) Salmonella isolates from animal sources. Bacteria are defined as multidrug resistant (MDR) if it exhibited non-susceptibility to at least one agent in three or more antimicrobial categories. The concentration of biocide at which ≥50% of the isolates could not grow was designated as the minimum inhibitory concentration or MIC50 and was used as the breakpoint in this study. The MIC50 (μg ml-1) for the tested MDR Salmonella was 256 for DC, 40 for BKC, 80 for CPC. HB and HC, 1,640 for AA, 5664 for LA, 3,156 for CA, 880 for PXA, 320 for ASC, 3.0 for CHX, 1,248 for DBH, 3,152 (6%) for SHB, 60,320 for SM, 37,712 for TSP, 56 for ARI and 832 for ARA. A few isolates were not susceptible at the MIC50 breakpoint to some chemicals indicating possible resistance. Isolates with MICs of two 2-fold dilutions above the MIC50 were considered resistant. Biocides for which resistant isolates were detected included CPC (n = 1 isolate), HB (1), CA (18), ASC (7), CHX (22), ARA (16), and ARI (4). There was no correlation detected between the biocide susceptibility of Salmonella isolates and antibiotic resistance. This assay can determine the MICs of bacteria to 17 biocides in a single test and will be useful in evaluating the efficacy of biocides and to detect the development of resistance to them.

[This corrects the article DOI: 10.1155/2017/2597256.].

Trivalent arsenic (arsenite) is a natural component of the earth's crust and is often found in drinking water in areas where the composition is high. The compound may circulate through natural or manmade means, including pollution from factories or businesses (Fig. 1). While some studies suggest that arsenite exposure is not as harmful as we once thought, other research proposes that arsenite is toxic to individuals who are both acutely and chronically exposed through drinking water, characterized by an increase in inflammatory cytokine release at nanomolar concentrations of arsenite exposure.6 Inflammatory molecules are small molecules released by cells to communicate with neighboring cells to produce an overall effect of inflammation. Nanomolar concentrations are usually considered very low and often undetectable by humans. Chronic arsenite exposure is especially associated with inflammatory vascular diseases including ischemic heart disease and atherosclerosis.3

English

Introduction: In our earlier studies, we reported that arsenic-induced enhanced oxidative stress, apoptosis, immunotoxicity and inflammation in the spleen and thymus of mice and hepatotoxicity have been protected through treatment with Emblica officinalis (amla). The present study is focused on to the efficacy of amla in mitigation of arsenic-induced dyslipidemia and alterations in inflammatory biomarkers in the blood of mice. Materials and Methods: Mice were randomly divided into four groups and treated with sodium arsenite (3 mg/kg b.w., per os), amla (500 mg/kg b.w., per os) and simultaneously with arsenic and amla daily for 30 days. Results: Arsenic treatment altered the hematological and lipid profile by increasing total cholesterol (TC), triglyceride (TG), phospholipid (PL) and low-density lipoprotein (LDL) levels and decreasing high-density lipoprotein (HDL) levels as compared to controls. Treatment with arsenic also disturbed the levels of inflammatory biomarkers. Concurrent treatment with arsenic and amla significantly restored serum TC level (0.83-fold), TG level (0.92-fold), LDL level (0.72-fold), PL level (1.29-fold), and increased HDL level (1.4-fold). Inflammatory cytokine levels were also corrected significantly as serum interleukin-8 level (0.6-fold) and C-reactive protein level decreased (0.7-fold) respectively, while interleukin-10 level was increased (1.5-fold) as compared to those treated with arsenic alone. The alterations in hematological parameters were also found to be normalized by treatment of amla. Conclusion: The results of the present study strengthen the fact that nutritional supplement of amla in arsenic affected areas might improve the adverse effects of arsenic on lipid profile.

Творения патриарха свт. Афанасия I Константинопольского, касающиеся арсенитского раскола

돼지정자의 운동성, 원형질막 온전성, 미토콘드리아 기능성 및 원형질막 지질과산화에 미치는 arsenite 및 항산화제의 영향

TLQP peptides (TLQPp) act on synaptic strengthening or against neuronal apoptosis but their involvement in Amyotrophic Lateral Sclerosis (ALS) is not well known. We used an ALS animal model (SOD1-G93A) and human tissues (plasma and fibroblasts from both patients and controls), to address the TLQPp expression and their modulation in ALS mechanisms. Mouse motor neuronal cells (NSC-34), were used to study the neuroprotective role of the TLQP-21 against oxidative stress induced by Sodium Arsenite. TLQPp were immunoquantified by ELISA, their cell expression studied by immunofluorescence while cell viability was addressed by MTT assay. In the NSC-34 naive cells, TLQPp were found within the cytoplasm, axons and growth cones. Upon stress, they appeared immunolocalized exclusively within a cytoplasmatic area, close to the nucleus, (probably the Golgi). Moreover, under stress, TLQPp levels were reduced (42%, p=3.1x10-6), while the exogenous increase of TLQP-21 improved cell viability (13%, p= 0.018). In naive fibroblasts, TLQPp were also similarly localized in an area, likely the Golgi, of patients and controls while their reduction (31%, p=0.03) was observed in cells with TARDBP-A382T mutation. Stress granules only appeared after SA treatment, and did not contain TLQPp. In plasma, a reduced release of TLQPp was associated with the beginning of the clinical motor symptoms in patients (12%, p=0.026), and with a pre-symptomatic stage in mutant mice (26.3%, p=0.048). Finally, in mouse spinal cord we identified by vescicular acetylcholine transporter (VAChT) antibody, a specific localization of the TLQPp in the motor neurons with a reduction in the pre-symptomatic stage of mutant mice. In conclusion, TLQPp are reduced in the stressed NSC-34 cells, mutant mouse motor neurons as well as in fibroblasts with TARDBP-A382T mutation that also induces production of reactive oxygen specie. Hence, we suggest that their reduction may occur in response to oxidative stress. They could be also considered as early biomarkers, while TLQP-21 acts as neuroprotective factor.