BACKGROUND: Systemic contact dermatitis (SCD) is an allergic inflammatory skin disease. We report that 3 family members developed SCD after exposing to laundry detergent containing benzalkonium chloride, which is rare. SCD caused by benzalkonium chloride has been reported. However, Similar symptoms in the whole family caused by it have not been reported yet. In our case, a 36-year-old man was diagnosed as SCD, and his symptoms had not controlled after 7 days treatment, until he stopped dressing the clothes washed by the laundry detergent containing benzalkonium chloride. It was interesting that both his wife and the daughter developed SCD successively, and they have not exposed to any haptens besides the benzalkonium chloride in the laundry detergent.
METHODS: Dermoscopic examination showed bright-red background, focal branching vessels and white scales. HE staining from the lesion revealed hyperkeratosis and parakeratosis, focal subcorneal microabscess, ocal hyperkeratosis, koilocyte in the epidermis, and erythrocyte extravasation, fibroplasia, hyaline degeneration and scattered aggregates of lymphocytes in the dermis. Then path test was performed 1 month after recovery with benzalkonium chloride 0.05% and 0.1% in petrolatum.
RESULTS: Stop the laundry detergent containing benzalkonium chloride. The symptoms had controlled after they stopped the laundry detergent containing benzalkonium chloride.
CONCLUSIONS: The case highlights that benzalkonium chloride with very low concentration and repeated exposure may be an active agent of SCD. It is of the utmost importance to pay close attention to patients presenting with similar symptoms within the family. A thorough examination of the medical history is essential to determine the underlying cause.

BACKGROUND: Nowadays, companion and working dogs hold significant social and economic importance. Dry eye, also known as dry keratoconjunctivitis (KCS), a common disease in ophthalmology, can readily impact a dog\'s working capacity and lead to economic losses. Although there are several medications available for this disease, all of them only improve the symptoms on the surface of the eye, and they are irritating and not easy to use for long periods of time. Adipose-derived mesenchymal stem cells (ADMSC) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of ADMSC. Here, we aimed to use ADMSC overexpressing Secreted Protein Acidic and Rich in Cysteine (SPARC) to treat 0.25% benzalkonium chloride-treated dogs with dry eye to verify its efficacy. For in vitro validation, we induced corneal epithelial cell (HCECs) damage using 1 µg/mL benzalkonium chloride.
METHODS: Fifteen male crossbred dogs were randomly divided into five groups: normal, dry eye self-healing control, cyclosporine-treated, ADMSC-CMV-treated and ADMSC-OESPARC-treated. HCECs were divided into four groups: normal control group, untreated model group, ADMSC-CMV supernatant culture group and ADMSC-OESRARC supernatant culture group.
RESULTS: SPARC-modified ADMSC had the most significant effect on canine ocular surface inflammation, corneal injury, and tear recovery, and the addition of ADMSC-OESPARC cell supernatant also had a salvage effect on HCECs cellular damage, such as cell viability and cell proliferation ability. Moreover, analysis of the co-transcriptome sequencing data showed that SPARC could promote corneal epithelial cell repair by enhancing the in vitro viability, migration and proliferation and immunosuppression of ADMSC.
CONCLUSIONS: The in vitro cell test and in vivo model totally suggest that the combination of SPARC and ADMSC has a promising future in novel dry eye therapy.

UNASSIGNED: Dry eye disease (DED) is a multifactorial ocular surface disease with a rising incidence. Therefore, it is urgent to construct a reliable and efficient drug delivery system for DED treatment.
UNASSIGNED: In this work, we loaded C-dots nanozyme into a thermosensitive in situ gel to create C-dots@Gel, presenting a promising composite ocular drug delivery system to manage DED.
UNASSIGNED: This composite ocular drug delivery system (C-dots@Gel) demonstrated the ability to enhance adherence to the corneal surface and extend the ocular surface retention time, thereby enhancing bioavailability. Furthermore, no discernible ocular surface irritation or systemic toxicity was observed. In the DED mouse model induced by benzalkonium chloride (BAC), it was verified that C-dots@Gel effectively mitigated DED by stabilizing the tear film, prolonging tear secretion, repairing corneal surface damage, and augmenting the population of conjunctival goblet cells.
UNASSIGNED: Compared to conventional dosage forms (C-dots), the C-dots@Gel could prolong exhibited enhanced retention time on the ocular surface and increased bioavailability, resulting in a satisfactory therapeutic outcome for DED.

Benzalkonium chloride (BAC) is a disinfectant with broad-spectrum antibacterial properties, yet despite its widespread use and detection in the environment, the effects of BAC exposure on microorganisms remain poorly documented. Herein, the impacts of BAC on a Pseudomonas aeruginosa strain Jade-X were systematically investigated. The results demonstrated that the minimum inhibitory concentration (MIC) of BAC against strain Jade-X was 64 mg L-1. Exposure to BAC concentrations of 8, 16, 32, and 64 mg L-1 significantly augmented biofilm formation by 2.03-, 2.43-, 2.96-, and 2.56-fold respectively. The swimming and twitching abilities, along with the virulence factor production, were inhibited. Consistently, quantitative reverse transcription PCR assays revealed significant downregulation of genes related to flagellate- and pili-mediated motilities (flgD, flgE, pilB, pilQ, and motB), as well as phzA and phzB genes involved in pyocyanin production. The results of disk diffusion and MIC assays demonstrated that BAC decreased the antibiotic susceptibility of ciprofloxacin, levofloxacin, norfloxacin, and tetracycline. Conversely, an opposite trend was observed for polymyxin B and ceftriaxone. Genomic analysis revealed that strain Jade-X harbored eleven resistance-nodulation-cell division efflux pumps, with mexCD-oprJ exhibiting significant upregulation while mexEF-oprN and mexGHI-opmD were downregulated. In addition, the quorum sensing-related regulators LasR and RhlR were also suppressed, implying that BAC might modulate the physiological and biochemical behaviors of strain Jade-X by attenuating the quorum sensing system. This study enhances our understanding of interactions between BAC and P. aeruginosa, providing valuable insights to guide the regulation and rational use of BAC.

This experiment aimed to investigate the feasibility of cytisine (CYT) in treating eye diseases with ocular topical application. An in vitro cytotoxicity test, a hen\'s egg test-chorioallantoic membrane (HET-CAM), and a mouse eye tolerance test were used to fully reveal the ocular safety profiles of CYT. For the efficacy evaluations, CYT\'s effects on cell wound healing, against H2O2-induced oxidative stress damages on cells, and on benzalkonium chloride (BAC)-induced dry eye disease (DED) in mice were evaluated. Results showed that CYT did not show any cytotoxicities at concentrations no higher than 250 μg/ml, while lipoic acid (α-LA) at 250 μg/ml and BAC at 1.25 μg/ml showed significant cytotoxicities within 48 h incubation. The HET-CAM and mouse eye tolerance test confirmed that 0.5% CYT eye drops demonstrated good safety characteristics. Efficacy evaluations showed that CTY significantly promoted cell migration and wound healing. CYT significantly improved cell survival against H2O2-induced oxidative stress damage by reversing the imbalance between the reactive oxygen species (ROS) and antioxidant defense mechanisms. The animal evaluation of the BAC-induced dry eye model revealed that CYT demonstrated a strong treatment effect, including reversing ocular surface damages, recovering corneal sensitivity, and inhibiting neovascularization; HMGB1/NF-κB signaling was involved in this DED treatment by CTY. In conclusion, CYT had strong experimental treatment efficacy against DED with good ocular safety profiles, and it might be a novel and promising drug for DED.

BACKGROUND: Umbilical cord blood-derived therapeutics, such as serum (UCS) and platelet-rich plasma (UCPRP), are popular treatment options in clinical trials and can potentially be utilized to address a clinically unmet need caused by preservatives, specifically benzalkonium chloride (BAK), present in ophthalmic formulations. As current clinical interventions for secondary injuries caused by BAK are suboptimal, this study will explore the feasibility of utilizing UCS and UCPRP for cornea treatment and investigate the underlying mechanisms associated with this approach.
METHODS: Mice\'s corneas were administered BAK to induce damage. UCS and UCPRP were then utilized to attempt to treat the injuries. Ocular tests were performed on the animals to evaluate recovery, while immunostaining, RNA-seq, and subsequent bioinformatics analysis were conducted to investigate the treatment mechanism.
RESULTS: BAK administration led to widespread inflammatory responses in the cornea. Subsequent treatment with UCS and UCPRP led to the downregulation of immune-related \'interactions between cytokine receptors\' and \'IL-17 signaling\' pathways. Although axonal enhancers such as Ngf, Rac2, Robo2, Srgap1, and Rock2 were found to be present in the injured group, robust axonal regeneration was observed only in the UCS and UCPRP treatment groups. Further analysis revealed that, as compared to normal corneas, inflammation was not restored to pre-injury levels post-treatment. Importantly, Neuropeptide Y (Npy) was also involved in regulating immune responses, indicating neuroimmune axis interactions.
CONCLUSIONS: Cord blood-derived therapeutics are feasible options for overcoming the sustained injuries induced by BAK in the cornea. They also have potential applications in areas where axonal regeneration is required.

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BACKGROUND: Although food-grade disinfectants are extensively used worldwide, it has been reported that the long-term exposure of bacteria to these compounds may represent a selective force inducing evolution including the emergence of antibiotic resistance. However, the mechanism underlying this correlation has not been elucidated. This study aims to investigate the genomic evolution caused by long-term disinfectant exposure in terms of antibiotic resistance in Salmonella enterica Typhimurium.
METHODS: S. Typhimurium isolates were exposed to increasing concentrations of benzalkonium chloride (BAC) and variations of their antibiotic susceptibilities were monitored. Strains that survived BAC exposure were analyzed at whole genome perspective using comparative genomics, and Sanger sequencing-confirmed mutations in ramR gene were identified. Next, the efflux activity in ramR-mutated strains shown as bisbenzimide accumulation and expression of genes involved in AcrAB-TolC efflux pump using quantitative reverse transcriptase PCR were determined.
RESULTS: Mutation rates of evolved strains varied from 5.82 × 10-9 to 5.56 × 10-8, with fold increase from 18.55 to 1.20 when compared with strains evolved without BAC. Mutations in ramR gene were found in evolved strains. Upregulated expression and increased activity of AcrAB-TolC was observed in evolved strains, which may contribute to their increased resistance to clinically relevant antibiotics. In addition, several indels and point mutations in ramR were identified, including L158P, A37V, G42E, F45L, and R46H which have not yet been linked to antimicrobial resistance. Resistance and mutations were stable after seven consecutive cultivations without BAC exposure. These results suggest that strains with sequence type (ST) ST34 were the most prone to mutations in ramR among the three STs tested (ST34, ST19, ST36).
CONCLUSIONS: This work demonstrated that disinfectants, specifically BAC forces S. Typhimurium to enter a specific evolutionary trajectory towards antibiotic resistance illustrating the side effects of long-term exposure to BAC and probably also to other disinfectants. Most significantly, this study provides new insights in understanding the emergence of antibiotic resistance in modern society.

An unprecedented increase in the use of disinfection products triggered by the coronavirus disease 2019 (COVID-19) pandemic is resulting in aggravating environmental loads of disinfectants as emerging contaminants, which has been considered a cause for worldwide secondary disasters. This review analyzed the literature published in the last decade about occurrence, bioaccumulation, and possible environmental risks of benzalkonium chlorides (BKCs) as emerging contaminants. Results indicated that BKCs globally occurred in municipal wastewater, surface water, groundwater, reclaimed water, sludge, sediment, soil, roof runoff, and residential dust samples across 13 countries. The maximum residual levels of 30 mg/L and 421 μg/g were reported in water and solid environmental samples, respectively. Emerging evidences suggested possible bioaccumulation of BKCs in plants, even perhaps humans. Environmentally relevant concentrations of BKCs exert potential adverse impacts on aquatic and terrestrial species, including genotoxicity, respiratory toxicity, behavioural effects and neurotoxicity, endocrine disruption and reproductive impairment, phytotoxicity, etc. Given the intrinsic biocidal and preservative properties of disinfectants, the inductive effects of residual BKCs in environment in terms of resistance and imbalance of microorganisms have been paid special attention. Considering the similarities of disinfectants to pharmaceuticals, from the perspective of ecopharmacovigilance (EPV), a well-established strategy for pharmaceutical emerging contaminants, we use the control of BKC pollution as a case, and provide some recommendations for employing the EPV measures to manage environmental risks posed by disinfectant emerging contaminants.

By intercalating montmorillonite (MMT) with Cu2+ and benzalkonium chloride (BAC), the present work constructed a synergistic promotion system (Cu2+/BAC/MMT). MMT not only enhances the thermal stability of Cu2+ and BAC but also facilitates the controlled release of Cu2+ and BAC. Concurrently, the introduction of BAC improves the material\'s organic compatibility. In vitro assays show that the \"MIC+\" of Cu2+/BAC/MMT against Staphylococcus aureus is merely 7.32 mg/L and 55.56 mg/L against Escherichia coli. At concentrations of 10 and 25 mg/L, Cu2+/BAC/MMT inactivates 100% of S. aureus and E. coli within 2 h, respectively. Furthermore, it is confirmed that the prepared Cu2+/BAC/MMT exhibits a long-term antibacterial ability through antibacterial experiments and release tests. Also, the biosafety of this material was also substantiated by in vitro cytotoxicity tests. These comprehensive findings indisputably portend that Cu2+/BAC/MMT holds promise to supplant antibiotics as an efficacious treatment modality for bacterial infections.