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Salicylate preservatives are widely used in consumer products and pharmaceuticals. This study investigates their potential endocrine-disrupting effects on neurosteroidogenesis, focusing on 5α-reductase type 1 (SRD5A1). We evaluated the effects of 13 salicylates on human SRD5A1 using SF126 glioblastoma cell microsomes and rat brain microsomes, examining dihydrotestosterone production in SF126 cells. Results revealed a hierarchy of inhibitory potency against human SRD5A1, with methyl salicylate (IC 50 , 71.93 μM) to menthyl salicylate (2.41 μM), indicating increasing potency. Kinetic analysis indicates their mixed/noncompetitive inhibitions. In SF126 cells, all salicylates at 100 μM significantly reduced dihydrotestosterone production. Rat SRD5A1 showed reduced sensitivity, with menthyl salicylate as the most potent inhibitor (IC 50 , 17.12 μM). Docking analysis suggests salicylates bind to the reduced nicotinamide adenine dinucleotide phosphate site of both human and rat SRD5A1. Bivariate correlation analysis highlights the influence of LogP, molecular weight, carbon number in the alcohol moiety, and p K a on inhibitory potency. 3D-QSAR revealed the importance of hydrophobic aromatic regions in SRD5A1 binding. This study delineates the inhibitory effects of salicylates and binding mechanisms on human and rat SRD5A1, providing insights into their impact on neurosteroid production.

Ginkgolic acid (GA), isolated from the leaves and seed coats of Ginkgo biloba , exerts several biological effects, including antitumor, antibacterial, anti‑HIV and anti‑inflammatory effects. However, the effects of GA on C2C12 myoblasts remain unclear. The present study assessed cell viability with the MTT assay and evaluated colony formation through crystal violet staining. Flow cytometry was used to analyze apoptosis with Annexin V/7‑AAD staining, proliferation with Ki67 staining and cell cycle arrest. Western blotting detected myogenic markers and other relevant proteins. Myotube formation was examined by immunofluorescence, and autophagy was measured using an LC3 antibody‑based kit via flow cytometry. The present study showed that treatment of C2C12 cells with GA significantly inhibited their viability and colony formation capacity but did not trigger apoptosis, as indicated by Annexin V/7‑AAD staining. However, Ki67 staining indicates that GA exerted dose‑dependent antiproliferative effects. Further analysis revealed that GA partially inhibited the growth of C2C12 cells via cell cycle arrest in S phase, highlighting its role in the disruption of cell proliferation. Furthermore, treatment with GA impaired myoblast differentiation, as evidenced by a reduction in the expression of the myogenesis markers, the myosin‑heavy chain, myoblast determination protein 1 and myogenin, and suppressed myotube formation. Notably, during C2C12 cell differentiation, GA promoted apoptosis without affecting cell cycle progression or Ki67 expression. Mechanistically, GA could suppress nuclear extracellular signal‑regulated kinase phosphorylation, suggesting that it modulates cell proliferation pathways. Moreover, GA triggered autophagy in differentiated C2C12 cells, as confirmed by elevated LC3 II levels. These findings highlight the multifaceted effects of GA on C2C12 cells.

The use of salicylates as flavoring agents in food and beverages is common, but their potential to disrupt the endocrine system remains unclear. Human placental 3β-hydroxysteroid dehydrogenase 1 (h3β-HSD1) plays a role in progesterone synthesis and is the potential target. This study evaluated the inhibition of 13 salicylates on h3β-HSD1, structure-activity relationship (SAR) and compared with rat placental homolog r3β-HSD4. Salicylates inhibited h3β-HSD1, depending on carbon chain number in the alcohol moiety and the IC 50 values for hexyl, ethylhexyl, homomenthyl, and menthyl salicylates were 53.27, 15.78, 2.35, and 2.31 μM, as mixed inhibitors, respectively, while methyl to benzyl salicylates were ineffective at 100 μM. Interestingly, only hexyl salicylate inhibited r3β-HSD4 with IC 50 of 31.05 μM. Bivariate analysis revealed a negative correlation between IC 50 and hydrophobicity (LogP), molecular weight, heavy atoms, and carbon number in the alcohol moiety against h3β-HSD1. Docking analysis demonstrated that these salicylates bind to cofactor binding sites or between the steroid and cofactor binding sites. Additionally, 3D-QSAR showed distinct binding via hydrogen bond donors and hydrophobic regions. In conclusion, the inhibition of h3β-HSD1 by salicylates appears to be dependent on factors such as LogP, molecular weight, heavy atoms, and carbon-chain length and there is species-dependent inhibition sensitivity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: The symptoms of herpes simplex viruses type 1 (HSV-1) infections might be severe and persistent in immunocompromised patients in whom they reactivate at a high frequency. The development of Acyclovir (ACV) resistant strains due to long-term treatment with antiviral agents in those patients is not uncommon. The aim of the present study was to assess the virucidal effect of commercially available mouthwashes against ACV-resistant HSV-1 strains., Materials and Methods: Two acyclovir-resistant HSV-1 strains were exposed for 30 s to essential oil-based (Listerine Fresh Burst® and Listerine Zero®), chlorhexidine gluconate 0.2% (Hexidyl®) and povidone-iodine 7.5% (Betadine Gargle®) mouthwashes. Loss of virus infectivity was determined by means of plaque reduction assays in a cell culture system., Results: All 4 of the tested solutions significantly reduced virus infectivity, with the essential oil-based and povidone-iodine mouthwashes being slightly more efficacious, compared to chlorhexidine., Conclusion: The findings of this analysis revealed that the tested oral rinses demonstrated in-vitro antiviral activity against ACV-resistant HSV. Comparative clinical trials are required to establish the clinical effectiveness of daily use of oral rinses in reducing the appearance of oral HSV lesions in immunocompromised patients., (© 2023 Wiley Periodicals LLC.)

This study is focused on the utilization of naturally occurring salicylic acid and nicotinamide (vitamin B 3 ) in the development of novel sustainable Active Pharmaceutical Ingredients (APIs) with significant potential for treating acne vulgaris. The study highlights how the chemical structure of the cation significantly influences surface activity, lipophilicity, and solubility in aqueous media. Furthermore, the new ionic forms of APIs, the synthesis of which was assessed with Green Chemistry metrics, exhibited very good antibacterial properties against common pathogens that contribute to the development of acne, resulting in remarkable enhancement of biological activity ranging from 200 to as much as 2000 times when compared to salicylic acid alone. The molecular docking studies also revealed the excellent anti-inflammatory activity of N -alkylnicotinamide salicylates comparable to commonly used drugs (indomethacin, ibuprofen, and acetylsalicylic acid) and were even characterized by better IC 50 values than common anti-inflammatory drugs in some cases. The derivative, featuring a decyl substituent in the pyridinium ring of nicotinamide, exhibited efficacy against Cutibacterium acnes while displaying favorable water solubility and improved wettability on hydrophobic surfaces, marking it as particularly promising. To investigate the impact of the APIs on the biosphere, the EC 50 parameter was determined against a model representative of crustaceans─ Artemia franciscana . The majority of compounds (with the exception of the salt containing the dodecyl substituent) could be classified as "Relatively Harmless" or "Practically Nontoxic", indicating their potential low environmental impact, which is essential in the context of modern drug development.

In the present study, the drug delivery by albumin protein and antiproliferetaive activity of new transition metal complex i.e., [Pd (phen)(SSA)] (where phen and SSA represent 1, 10 phenanthroline and sulfosalicylic acid, respectively) was investigated. DFT (density functional theory) calculations were conducted at B3LYP level with 6-311G(d,p)/aug-ccpVTZ-PP basis set for the purpose of geometry optimization, frontier molecular orbital (FMO) analysis, molecular electrostatic potential (MEP), and natural bond orbital (NBO) analysis. Experimental tests were conducted to preliminarily assess the lipophilicity and antitumor activity of the metal complex, resulting in promising findings. In-silico prediction was accomplished to assess its toxicity and bioavailability. To evaluate the binding of the newly formed complex with DNA (which results in halting the cell cycle) or serum albumin protein (drug transporter to the tissues), in-silico molecular modeling was employed. Experimental results (spectroscopic and non-spectroscopic) showed that the new compound interacts with each biomolecule via hydrogen bond and van der Waals interactions. Molecular docking demonstrated the binding of this complex to the DNA groove and site I of BSA occurs mainly through hydrogen bonds. Molecular dynamics simulation confirmed the interactions between [Pd (phen)(SSA)] with DNA or BSA through stable hydrogen bonds., (© 2024 John Wiley & Sons Ltd.)

Gaultheria trichophylla Royle is a traditional treatment for inflammatory conditions including arthritis. The objective was to evaluate the anti-arthritic activity of the extracts and salicylate-rich fractions through adjuvant-induced arthritis, histopathological analysis, radiological imaging, hematological, biochemical parameters along with using bioinformatic tools. In vivo anti-arthritic efficacy of the extract and SRF (at 100, 200, 300, and 150 mg/kg doses) was assessed using healthy albino rats. Molecular docking of identified compounds along with network pharmacology analysis helped to determine the route of action of drug. Both the extract and SRF showed dose-dependent anti-arthritic activity by decreasing the joint diameter, increase in pain threshold and body weight compared with negative control group. Along with SRF (150 mg/kg), EEGT (300 and 200 mg/kg) shows significant (P < 0.01) anti-arthritic activity by lowering levels of WBC, platelets, serum C-reactive protein (CRP), and rheumatoid factor (RF) and raising levels of RBC and Hb. The modified biochemical measures (AST, ALT, ALP, and total protein level) further supported the anti-arthritic action. Histopathology and radiology study showed that EEGT (300 and 200 mg/kg), SRF (150 mg/kg) and diclofenac (10 mg/kg) inhibited joint destruction. GCMS analysis showed the presence of methyl salicylate, sitosterol, calcifediol, and ergosta-5,22-dien-3-ol, acetate as important bioactive constituents. Moreover, as the significant node in the pharmacology network and docking against TNF-α, a classical therapeutic target in RA showed potential of G. trichophylla in treatment of RA. The results showed that G. trichophylla have effectively reduced the inflammation of the joints., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

This study aimed to investigate the effects of the intravenous administration of lidocaine in the auditory cortex after the systemic administration of salicylate. Healthy male albino Hartley guinea pigs were divided into two groups. The control group received only lidocaine, whereas the experimental group received lidocaine after checking for the effects of salicylate. Extracellular recordings of spikes in the primary auditory cortex and dorsocaudal areas in healthy albino Hartley guinea pigs were continuously documented (pre- and post-lidocaine, pre- and post-salicylate, and post-salicylate after adding lidocaine to post-salicylate). We recorded 160 single units in the primary auditory cortex from five guinea pigs and 155 single units in the dorsocaudal area from another five guinea pigs to confirm the effects of lidocaine on untreated animals. No significant change was detected in either the threshold or Q10dB value after lidocaine administration in the primary auditory cortex and dorsocaudal areas. Spontaneous firing activity significantly decreased after lidocaine administration in the primary auditory cortex and dorsocaudal areas. Next, we recorded 160 single units in the primary auditory cortex from five guinea pigs and 137 single units in the dorsocaudal area from another five guinea pigs to determine the effects of lidocaine on salicylate-treated animals. The threshold was significantly elevated after salicylate administration; however, no additional change was detected after adding lidocaine to the primary auditory cortex and dorsocaudal areas. Regarding the Q10dB value, lidocaine negated the significant changes induced by salicylate in the primary auditory cortex and dorsocaudal areas. Moreover, lidocaine negated the significant changes in spontaneous firing activities induced by salicylate in the primary auditory cortex and dorsocaudal areas. In conclusion, changes in the Q10dB value and spontaneous firing activities induced by salicylate administration are abolished by lidocaine administration, suggesting that these changes are related to the presence of tinnitus., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kenmochi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Depression is a life-threatening neurodegenerative disease lacking a complete cure. Cajaninstilbene acid (CSA), a potent stilbene compound, has demonstrated neuroprotective effects, however, studies on its antidepressant mechanisms are still scarce. This study examined the effects of CSA on lipopolysaccharide (LPS)-induced and chronic unpredictable mild stress (CUMS)-induced depression in mice, investigating its mechanisms related to inflammation and autophagy. Mice were treated with CSA (7.5, 15, and 30 mg/kg) daily for 3 weeks before intraperitoneal LPS injection (0.8 mg/kg). Another cohort underwent the same doses of CSA (7.5-30 mg/kg) daily for 6 weeks in accompany with CUMS stimulation. Behavioral assessments were conducted, and cortical samples were collected for molecular analysis. Findings indicate that CSA ameliorated depressive behaviors induced by both LPS and CUMS. Notably, CSA (15 mg/kg) reversed despair behavior in mice more persistently than amitriptyline, indicating that optimal doses of CSA may effectively decelerate the procession of mood despair and yield a good compliance. CSA countered CUMS-induced activation of TLR4/NF-κB pathway and the reduction in autophagy levels. Furthermore, CSA attenuated the CUMS-induced decline in neuroplasticity. Collectively, these findings suggest that CSA mitigates depression-like behaviors in mice by inhibiting TLR4/NF-κB-mediated neuroinflammation and enhancing autophagy. This research provides further insights into CSA's mechanisms of action in ameliorating depressive behaviors, offering a scientific foundation for developing CSA-based antidepressants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The transcriptional regulator nuclear factor-κB (NF-κB) is a mediator of endothelial dysfunction. Inhibiting NF-κB with salsalate is used to investigate inflammatory mechanisms contributing to accelerated cardiovascular disease risk. However, in the absence of disease, inhibition of NF-κB can impact redox mechanisms, resulting in paradoxically decreased endothelial function. This study aimed to measure microvascular endothelial function during inhibition of the transcriptional regulator NF-κB in reproductive-aged healthy women. In a randomized, single-blind, crossover, placebo-controlled design, nine healthy women were randomly assigned oral salsalate (1,500 mg, twice daily) or placebo treatments for 5 days. Subjects underwent graded perfusion with the endothelium-dependent agonist acetylcholine (ACh, 10 -10 to 10 -1 M, 33°C) alone and in combination with 15 mM N G -nitro-l-arginine methyl ester [l-NAME; nonselective nitric oxide (NO) synthase inhibitor] through intradermal microdialysis. Laser-Doppler flux was measured over each microdialysis site, and cutaneous vascular conductance (CVC) was calculated as flux divided by mean arterial pressure and normalized to site-specific maximum (CVC %max ; 28 mM sodium nitroprusside + 43°C). The l-NAME sensitive component was calculated as the difference between the areas under the dose-response curves. During the placebo and salsalate treatments, the l-NAME sites were reduced compared with the control sites (both P < 0.0001). Across treatments, there was a significant difference between the control and l-NAME sites, where both sites shifted upward following salsalate treatment (both P < 0.0001), whereas the l-NAME-sensitive component was not different ( P = 0.94). These data demonstrate that inhibition of the transcriptional regulator NF-κB improves cutaneous microvascular function in reproductive-aged healthy women through non-NO-dependent mechanisms. NEW & NOTEWORTHY The transcription factor nuclear factor-κB (NF-κB) regulates multiple aspects of innate and adaptive immunity by encoding for genes that participate in inflammation and impact endothelial function following NF-κB inhibition with salsalate treatment. Our results show that cutaneous microvascular function is increased through non-nitric oxide (NO)-dependent mechanisms following salsalate treatment in reproductive-aged healthy women.

Wounds that occur in adults form scars due to fibrosis, whereas those in embryos regenerate. If wound healing in embryos is mimicked in adults, scarring can be reduced. We found that mouse fetuses could regenerate tissues up to embryonic day (E) 13, but visible scars remained thereafter. This regeneration pattern requires actin cable formation at the epithelial wound margin via activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK). Here, we investigated whether the AMPK-activating effect of salicylate, an anti-inflammatory drug, promotes regenerative wound healing. Salicylate administration resulted in actin cable formation and complete wound regeneration in E14 fetuses, in which scarring should have normally occurred, and promoted contraction of the panniculus carnosus muscle, resulting in complete wound regeneration. In vitro, salicylate further induced actin remodeling in mouse epidermal keratinocytes in a manner dependent on cell and substrate target-specific AMPK activation and subsequent regulation of Rac1 signaling. Furthermore, salicylate promoted epithelialization, enhanced panniculus carnosus muscle contraction, and inhibited scar formation in adult mice. Administration of salicylates to wounds immediately after injury may be a novel method for preventing scarring by promoting a wound healing pattern similar to that of embryonic wounds., (© 2024. The Author(s).)

Ginkgo biloba leaves (GBLs) contain high phytoconstituents, but ginkgolic acids (GAs, the main toxic compound in GBLs) have limited its applications. Processing Ginkgo biloba dark tea (GBDT) using fixation technology could decrease the toxic compounds; retain flavonoids, ginkgolides, and bilobalide; and improve the product quality. For the first time, various thermal fixations (hot air fixation [HAF], iron pot fixation [IPF], and boiled water fixation [BWF]) followed by rolling, fermentation, and drying were applied to produce GBDT. A comprehensive analysis of the toxicants (GAs), main bioactive compounds (ginkgolides and bilobalide, flavonoids, antioxidants, and phenolic profiles), and product qualities (moisture content, reducing sugar [RS], free amino acids [FAAs], enzyme activity, color properties, antioxidant capacity, etc.) were evaluated. The results revealed that thermal fixations BWF and HAF significantly reduced the GA contents (41.1%-34.6%). Most terpene lactones showed significant differences in control, IPF, and HAF. The HAF had lower total flavonoid content (TFC) than BWF and IPF. The control group (unfixated) had the highest toxic components (GA), terpene trilactones, and TFC compared with various fixations. Adding different fixations to rolling, fermentation, and drying had various impacts on GBDT, and principal component analysis supported the results. Among four thermal fixations, HAF yielded the best results in RS, FAA, total phenolic content, and antioxidant activities, while IPF had the highest TFC. BWF had the lowest content for GA. In conclusion, HAF (6) was chosen as the best technique for producing GBDT since it preserved GBDT's bioactive components while lowering its toxic components., (© 2024 Institute of Food Technologists.)

Introduction. Listerine Ò is a bactericidal mouthwash widely used to prevent oral health problems such as dental plaque and gingivitis. However, whether it promotes or undermines a healthy oral microbiome is unclear. Hypothesis/Gap Statement. We hypothesized that the daily use of Listerine Cool Mint would have a significant impact on the oropharyngeal microbiome. Aim. We aimed to assess if daily usage of Listerine Cool Mint influenced the composition of the pharyngeal microbiome. Methodology. The current microbiome substudy is part of the Preventing Resistance in Gonorrhoea trial. This was a double-blind single-centre, crossover, randomized controlled trial of antibacterial versus placebo mouthwash to reduce the incidence of gonorrhoea/chlamydia/syphilis in men who have sex with men (MSM) taking HIV pre-exposure prophylaxis (PrEP). Fifty-nine MSM taking HIV PrEP were enrolled. In this crossover trial, participants received 3 months of daily Listerine followed by 3 months of placebo mouthwash or vice versa. Oropharyngeal swabs were taken at baseline and after 3 months use of each mouthwash. DNA was extracted for shotgun metagenomic sequencing (Illumina Inc.). Non-host reads were taxonomically classified with MiniKraken and Bracken. The alpha and beta diversity indices were compared between baseline and after each mouthwash use. Differentially abundant bacterial taxa were identified using ANOVA-like differential expression analysis. Results. Streptococcus was the most abundant genus in most samples ( n = 103, 61.7 %) with a median relative abundance of 31.5% (IQR 20.6-44.8), followed by Prevotella [13.5% (IQR 4.8-22.6)] and Veillonella [10.0% (IQR 4.0-16.8)]. Compared to baseline, the composition of the oral microbiome at the genus level (beta diversity) was significantly different after 3 months of Listerine ( P = 0.006, pseudo- F = 2.29) or placebo ( P = 0.003, pseudo- F = 2.49, permutational multivariate analysis of variance) use. Fusobacterium nucleatum and Streptococcus anginosus were significantly more abundant after Listerine use compared to baseline. Conclusion. Listerine use was associated with an increased abundance of common oral opportunistic bacteria previously reported to be enriched in periodontal diseases, oesophageal and colorectal cancer, and systemic diseases. These findings suggest that the regular use of Listerine mouthwash should be carefully considered.

The production of herbivore-induced plant volatiles (HIPVs) is a type of indirect defense used by plants to attract natural enemies and reduce herbivory by insect pests. In many crops little is known about genotypic variation in HIPV production or how this may affect natural enemy attraction. In this study, we identified and quantified HIPVs produced by 10 sorghum (Sorghum bicolor) cultivars infested with a prominent aphid pest, the sorghum aphid (Melanaphis sorghi Theobald). Volatiles were collected using dynamic headspace sampling techniques and identified and quantified using GC-MS. The total amounts of volatiles induced by the aphids did not differ among the 10 cultivars, but overall blends of volatiles differed significantly in composition. Most notably, aphid herbivory induced higher levels of methyl salicylate (MeSA) emission in two cultivars, whereas in four cultivars, the volatile emissions did not change in response to aphid infestation. Dual-choice olfactometer assays were used to determine preference of the aphid parasitoid, Aphelinus nigritus, and predator, Chrysoperla rufilabris, between plants of the same cultivar that were un-infested or infested with aphids. Two aphid-infested cultivars were preferred by natural enemies, while four other cultivars were more attractive to natural enemies when they were free of aphids. The remaining four cultivars elicited no response from parasitoids. Our work suggests that genetic variation in HIPV emissions greatly affects parasitoid and predator attraction to aphid-infested sorghum and that screening crop cultivars for specific predator and parasitoid attractants has the potential to improve the efficacy of biological control., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Yellow pitahaya is a tropical fruit that has gained popularity in recent years. Natural elicitors are compounds that can stimulate the resistance and quality of fruits. The objective of this study was to evaluate the effects of natural elicitors, methyl salicylate (MeSa), methyl jasmonate (JaMe), salicylic acid (SA) and oxalic acid (OA) at concentrations of 0.1 mM (MeSa and JaMe) and 5 mM (SA and OA), applied to the yellow pitahaya fruits under greenhouse conditions. After full blossom, four applications were made with a frequency of 15 days. At the time of harvest and after storage, the following variables were evaluated: firmness (whole fruit), total soluble solids (TSS), total acidity (TA), phenolics and carotenoids (in the pulp), while phenolics, carotenoids, macronutrients and micronutrients were determined in the peel. The results showed MeSa advanced the fruit maturation, according to higher TSS, lower TA and firmness than MeJa-treated fruits, for which a delayed ripening process was shown. All treatments induced a higher polyphenolic concentration during storage. Regarding the alternative use of the peel as a by-product, the application of natural elicitors significantly increased the content of polyphenols, carotenoids, macronutrients and micronutrients in the peel, especially MeSa, which can be used as a bioactive compound in the food industry. In conclusion, the results indicate that natural elicitors can be an alternative to improve the quality and shelf life of yellow pitahaya fruits.

Background: In our previous study, Cu(sal)phen was found to have anti-tumor effects, yet its precise mechanism remains unknown. Research has shown that dying tumor cells release damage-associated molecular patterns (DAMPs) to promote anti-tumor immune response. Therefore, we have further explored the effects and potential molecular mechanisms of Cu(sal)phen-induced immunogenic cell death (ICD) in colorectal cancer (CRC)., Methods: ELISA and flow cytometry were used to detect the effects of Cu(sal)phen treatment on ICD markers. The molecular mechanisms of Cu(sal)phen-induced ICD were investigated through the detection of endoplasmic reticulum stress (ERS) and reactive oxygen species (ROS) in vitro using Western blot and flow cytometry. Additionally, a mouse model was constructed to study the effects of Cu(sal)phen on immune cells and anti-tumor-related cytokines in vivo., Results: Cu(sal)phen induced the release of calreticulin (CRT), adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1), the main molecular markers of ICD, by promoting the accumulation of ROS and inducing ERS. Furthermore, Cu(sal)phen promoted the maturation of dendritic cells (DCs) and activation of CD8 + T cells, as well as the secretion of interleukin-12 (IL-12) and interferon-γ (IFN-γ), while downregulating transforming growth factor-β (TGF-β) levels, thereby activating the anti-tumor immune response., Conclusion: Cu(sal)phen has the potential to induce ICD in tumors and activate the adaptive immune response to achieve anti-tumor effects. This makes Cu(sal)phen a promising candidate for the treatment of CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Identification of new mechanisms mediating insulin sensitivity is important to allow validation of corresponding therapeutic targets. In this study, we first used a cellular model of skeletal muscle cell iron overload and found that endoplasmic reticulum (ER) stress and insulin resistance occurred after iron treatment. Insulin sensitivity was assessed using cells engineered to express an Akt biosensor, based on nuclear FoxO localization, as well as western blotting for insulin signaling proteins. Use of salubrinal to elevate eIF2α phosphorylation and promote the unfolded protein response (UPR) attenuated iron-induced insulin resistance. Salubrinal induced autophagy flux and its beneficial effects on insulin sensitivity were not observed in autophagy-deficient cells generated by overexpressing a dominant-negative ATG5 mutant or via knockout of ATG7. This indicated the beneficial effect of salubrinal-induced UPR activation was autophagy-dependent. We translated these observations to an animal model of systemic iron overload-induced skeletal muscle insulin resistance where administration of salubrinal as pretreatment promoted eIF2α phosphorylation, enhanced autophagic flux in skeletal muscle and improved insulin responsiveness. Together, our results show that salubrinal elicited an eIF2α-autophagy axis leading to improved skeletal muscle insulin sensitivity both in vitro and in mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Introduction: Tinnitus is the most common symptom of auditory system disorders. It affects the quality of life of millions of people, but it is still incurable in most cases. Vagus nerve stimulation (VNS) therapy is a potential new treatment for subjective tinnitus. In this study, transcutaneous vagus nerve stimulation (tVNS) combined with tones was utilized to treat salicylate-induced tinnitus since salicylate is a reliable and convenient approach for rapidly inducing tinnitus., Methods: Wistar rats were divided into acoustic stimulation alone (AS, n = 6), tVNS alone (n = 6), and tVNS with AS (n = 6) groups for behavioral and electrophysiological tests. They were assessed by auditory brainstem response (ABR), prepulse inhibition (PPI), gap prepulse inhibition of the acoustic startle (GPIAS), social interactions, and aggressive behavior tests at baseline and seven days' post-salicylate (175 mg/kg, twice a day) injection., Results: The inhibition percentage of the GPIAS test was significantly reduced post-salicylate injection in the tVNS and AS alone groups, while it was not significant in the tVNS with AS group. There was no significant difference in the mean percentage of the GPIAS test between the tVNS groups (with or without AS) after salicylate injections. Social interactions were significantly different in the AS alone group pre- and post-salicylate injections, but they were not significant in other groups. Moreover, the results of aggressive behavior tests showed significantly increased post-salicylate injections in the AS alone group, while they were not significant in the tVNS groups (with or without AS)., Conclusions: The current study revealed that the application of tVNS alone produced improved social interaction and mood and alleviated salicylate-induced tinnitus severity. Moreover, combining tVNS with acoustic stimulation can prevent salicylate-induced tinnitus., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Blocking iron uptake and metabolism has been emerging as a promising therapeutic strategy for the development of novel antimicrobial compounds. Like all mycobacteria, M. abscessus (Mab) has evolved several countermeasures to scavenge iron from host carrier proteins, including the production of siderophores, which play a crucial role in these processes. In this study, we solved, for the first time, the crystal structure of Mab-SaS, the first enzyme involved in the biosynthesis of siderophores. Moreover, we screened a small, focused library and identified a compound exhibiting a potent inhibitory effect against Mab-SaS (IC 50  ≈ 2 μM). Its binding mode was investigated by means of Induced Fit Docking simulations, performed on the crystal structure presented herein. Furthermore, cytotoxicity data and pharmacokinetic predictions revealed the safety and drug-likeness of this class of compounds. Finally, the crystallographic data were used to optimize the model for future virtual screening campaigns. Taken together, the findings of our study pave the way for the identification of potent Mab-SaS inhibitors, based on both established and unexplored chemotypes., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laurent R. Chiarelli reports financial support was provided by Italian Cystic Fibrosis Research Foundation (FFC Ricerca). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Antipsychotic medications are used in the management of schizophrenia and a growing number of off-label conditions. While effective at reducing psychoses, these drugs possess noted metabolic side effects including weight gain, liver lipid accumulation and disturbances in glucose and lipid metabolism. To counter the side effects of antipsychotics standard of care has typically included metformin. Unfortunately, metformin does not protect against antipsychotic induced metabolic disturbances in all patients and thus additional treatment approaches are needed. One potential candidate could be salsalate, the prodrug of salicylate, which acts synergistically with metformin to improve indices of glucose and lipid metabolism in obese mice. The purpose of the current investigation was to compare the effects of salsalate, metformin and a combination of both drugs, on weight gain and indices of metabolic health in female mice treated with the antipsychotic, olanzapine. Herein we demonstrate that salsalate was equally as effective as metformin in protecting against olanzapine induced weight gain and liver lipid accumulation with no additional benefit of combining both drugs. Conversely, metformin treatment, either alone or in combination with salsalate, improved indices of glucose metabolism and increased energy expenditure in olanzapine treated mice. Collectively, our findings provide evidence that dual therapy with both metformin and salsalate could be an efficacious approach with which to dampen the metabolic consequences of antipsychotic medications., Competing Interests: Declaration of Competing Interest MKH has received consultant fees from Alkermes. All other authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

An LC-MS/MS-guided analysis of the aerial parts of Glycyrrhiza foetida afforded new phenethyl (amorfrutin)- and alkyl (cannabis)-type phytocannabinoids (six and four compounds, respectively). The structural diversity of the new amorfrutins was complemented by the isolation of six known members and the synthesis of analogues modified on the aralkyl moiety. All of the compounds so obtained were assayed for agonist activity on PPARα and PPARγ nuclear receptors. Amorfrutin A ( 1 ) showed the highest agonist activity on PPARγ, amorfrutin H ( 7 ) selectively targeted PPARα, and amorfrutin E ( 4 ) behaved as a dual agonist, with the pentyl analogue of amorfrutin A ( 11 ) being inactive. Decarboxyamorfrutin A ( 2 ) was cytotoxic, and modifying its phenethyl moiety to a styryl or a phenylethynyl group retained this trait, suggesting an alternative biological scenario for these compounds. The putative binding modes of amorfrutins toward PPARα and PPARγ were obtained by a combined approach of molecular docking and molecular dynamics simulations, which provided insights on the structure-activity relationships of this class of compounds.

We assumed that miRNAs might regulate the physiological and biochemical processes in plants through their effects on the redox system and phytohormones. To check this hypothesis, the transcriptome profile of wild-type Arabidopsis and lines with decreased ascorbate (Asc), glutathione (GSH), or salicylate (Sal) levels were compared. GSH deficiency did not influence the miRNA expression, whereas lower levels of Asc and Sal reduced the accumulation of 9 and 44 miRNAs, respectively, but only four miRNAs were upregulated. Bioinformatics analysis revealed that their over-represented target genes are associated with the synthesis of nitrogen-containing and aromatic compounds, nucleic acids, and sulphate assimilation. Among them, the sulphate reduction-related miR395 - ATP-sulfurylase couple was selected to check the assumed modulating role of the light spectrum. A greater induction of the Asc- and Sal-responsive miR395 was observed under sulphur starvation in far-red light compared to white and blue light in wild-type and GSH-deficient Arabidopsis lines. Sal deficiency inhibited the induction of miR395 by sulphur starvation in blue light, whereas Asc deficiency greatly reduced it independently of the spectrum. Interestingly, sulphur starvation decreased only the level of ATP sulfurylase 4 among the miR395 target genes in far-red light. The expression level of ATP sulfurylase 3 was higher in far-red light than in blue light in wild-type and Asc-deficient lines. The results indicate the coordinated control of miRNAs by the redox and hormonal system since 11 miRNAs were affected by both Asc and Sal deficiency. This process can be modulated by light spectrum, as shown for miR395., (© 2023 Scandinavian Plant Physiology Society.)

Aspirin and its active metabolite salicylate have emerged as promising agents for the chemoprevention of colorectal cancer (CRC). Moreover, aspirin suppresses the progression of established CRCs. However, the underlying molecular mechanisms are not completely understood. Here we found that salicylate induces the expression of the miR-34a and miR-34b/c genes, which encode tumor suppressive microRNAs, in a p53-independent manner. Salicylate activated AMPK, thereby activating NRF2, which directly induced miR-34a/b/c expression via ARE motifs. In addition, salicylate suppressed c-MYC, a known repressor of NRF2-mediated transactivation, via activating AMPK. The suppression of c-MYC by salicylate was necessary for NRF2-mediated activation of miR-34a/b/c. Inactivation of miR-34a/b/c largely abrogated the inhibitory effects of salicylate on migration, invasion and metastasis formation by CRC cells. In the future, aspirin and its derivates may be used therapeutically to activate miR-34a and miR-34b/c in tumors that have lost p53., (© 2023. The Author(s).)

Streptococcus agalactiae is the major cause of invasive neonatal infections and is a recognized pathogen associated with various diseases in nonpregnant adults. The emergence and spread of antibiotic-resistant S. agalactiae necessitate the development of a novel antibacterial agent. Here, the potential antibacterial activities and mechanisms of ginkgolic acid C15:1 (GA (15:1)) from Ginkgo biloba against clinical S. agalactiae are characterized. The MIC 50 and MIC 90 values for GA (15:1) against 72 clinical S. agalactiae isolates were 6.25 and 12.5 μM, respectively. GA (15:1) showed a strong bactericidal effect against both planktonic bacteria and bacteria embedded in biofilms as well as significant effectiveness in suppressing the growth of S. agalactiae biofilms. Moreover, GA (15:1) possesses intracellular antibacterial activity and could significantly decrease the bacterial burden in the intraperitoneal infection model of S. agalactiae . Mechanistic studies showed that GA (15:1) triggers membrane damage of S. agalactiae through a unique dual-targeting mechanism of action (MoA). First, GA (15:1) targets phospholipids in the bacterial cytoplasmic membrane. Second, by using mass-spectrometry-based drug affinity responsive target stability (DARTS) and molecular docking, lipoprotein signaling peptidase II (lspA) was identified as a target protein of GA (15:1), whose role is crucial for maintaining bacterial membrane depolarization and permeabilization. Our findings suggest a potential therapeutic strategy for developing GA (15:1) to combat S. agalactiae infections.

Fungicides or insecticides are popular means of controlling a variety of pathogens and insect pests; however, they can cause harmful effects on both human health and the environment. Different researchers have suggested using plant extracts, which have shown promise in managing fungi and insects. The purpose of this investigation was to explore the antifungal activities of an acetone extract made from the leaves of Indian Hawthorn (HAL) against phytopathogens that are known to harm maize crops, Fusarium verticillioides (OQ820154) and Rhizoctonia solani (OQ820155), and to evaluate the insecticidal property against Aphis gossypii Glover aphid. The HAL extract demonstrated significant antifungal activity against the two fungal pathogens tested, especially at the high dose of 2000 µg/mL. Laboratory tests on the LC 20 of HAL extract (61.08 mg/L) versus buprofezin 25% WP (0.0051 mg/L) were achieved on A. gossypii Glover. HAL extract diminished the nymph's production over 72 h and their total reproductive rate. This extract was like buprofezin 25% WP in decreasing the daily reproductive rate, reproductive period, and mean survival percentage. Nevertheless, the newly-born nymphs of treated females with HAL extract attained the highest reduction in survival percentage at 46.00%. Equalized prolongations on the longevity of nymphs to 9.33, 8.33, and 7 days and the total life cycle to 15.00, 14.00, and 12.67 days were realized by HAL extract, buprofezin 25% WP, and the control, respectively. The olfactory choice test on the aphids showed the minimum attraction rate to HAL extract. The HPLC of HAL extract comprised an abundance of phenolic compounds (ferulic acid, gallic acid, 4-hydroxybenzoic acid, salicylic acid, ellagic acid, and pyrogallol), and the concentrations of these compounds vary widely, with salicylic acid being the most concentrated at 25.14 mg/mL. Among the flavonoids, epicatechin has the highest concentration at 11.69 mg/mL. The HAL extract GC-MS consists of various organic compounds, including sesquiterpenes, cyclopropenes, fatty acids, steroids, alcohols, ketones, esters, bufadienolides, opioids, and other organic compounds. The most abundant compounds in the sample are n-hexadecanoic acid (12.17%), followed by 5α, 7αH, 10α-eudesm-11-en-1α-ol (9.43%), and cis-13-octadecenoic acid (5.87%). Based on the findings, it can be inferred that the HAL extract may be a viable option for plants to combat both fungal and insect infestations. This presents an encouraging prospect for utilizing a natural and sustainable approach toward long-term pest management in plants., (© 2023. Springer Nature Limited.)

Plant secondary metabolites (PSMs) can potentially reduce ruminal methane formation. However, related to differences in their molecular structures, it is not yet clear what causes an anti-methanogenic effect. In an in vitro system simulating rumen fermentation, we investigated the impact of eight compounds with distinct chemical characteristics (gallic and salicylic acids, tannic acid, catechin, epicatechin, quercetin, rutin, and salicin) when added to a basal feed (maize silage) at a concentration of 12% of the feed dry matter. After 48 h of incubation in buffered rumen fluid, methane production was significantly lowered by quercetin (43%), tannic acid (39%) and salicylic acid (34%) compared to the control (maize silage alone) and without changes in total volatile fatty acid production during fermentation. No other PSM reduced methane formation as compared to control but induced significant differences on total volatile fatty acid production. The observed differences were related to lipophilicity, the presence of double bond and carbonyl group, sugar moieties, and polymerization of the compounds. Our results indicate the importance of distinct molecular structures of PSMs and chemical characteristics for methane lowering properties and volatile fatty acid formation. Further systematic screening studies to establish the structure-function relationship between PSMs and methane reduction are warranted., (© 2023. Springer Nature Limited.)

Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. In this study, the antiproliferative activity on six different solid tumor cell lines was evaluated with a series of lipophilic thioether modified salirasib analogues, including those with or without a 1,2,3-triazole linker. A combination of bioassay, cheminformatics, docking, and in silico ADME-Tox was also performed. SAR analysis that analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, three compounds display superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behavior of the collection on migration and invasion, a key process in tumor metastasis, was also studied. Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Oxaliplatin (Oxa) is one of the most effective chemotherapeutic drugs used in the treatment of colorectal cancer (CRC). However, the use of this drug is associated with severe side‑effects and patients eventually develop resistance to Oxa. In recent years, copper complexes have been extensively investigated as substitutes for platinum‑based drugs. Therefore, a number of copper complexes have also been developed for cancer therapy, such as copper (II) complex of salicylate phenanthroline [Cu(sal)(phen)]. In the present study, the antitumor activity and the related molecular mechanisms of Cu(sal)(phen) were examined in CRC cells. As compared with the chemotherapeutic drug, Oxa, Cu(sal)(phen) was more effective in inducing apoptosis and reactive oxygen species (ROS) production, and in decreasing mitochondrial membrane potential in the CRC cell lines, HCT116 and SW480. In addition, the expression of the apoptosis‑related proteins, Bcl‑2 and survivin, and those of the upstream regulators, p‑JAK2 and p‑STAT5, were significantly decreased in the two cell lines following treatment with Cu(sal)(phen). Furthermore, the efficacy of the complex against CRC was found to be excellent in an animal model. The results of immunohistochemical analysis revealed that the expression levels of Bcl‑2, survivin and Ki‑67 in tumor tissues were decreased following Cu(sal)(phen) treatment. The antitumor mechanisms underlying Cu(Sal)(phen) treatment were the induction of ROS generation, the inhibition of the JAK2/STAT5 signaling pathway and the downregulation of the expression of anti‑apoptotic proteins, such as Bcl‑2 and survivin. On the whole, the findings of the present study indicated that Cu(sal)(phen) effectively inhibited the viability and proliferation of HCT116 and SW480 CRC cells; in the future, the authors aim to conduct further experiments in future studies to provide more evidence that supports the development of Cu(sal)(phen) as a therapeutic agent for CRC.

Ethylhexyl salicylate (EHS) is an organic UV filter commonly used in sunscreens to protect people from the UV radiation. The widespread use of EHS will enter the aquatic environment along with human activities. EHS readily accumulates in adipose tissue as a lipophilic compound, but its toxic effects on lipid metabolism and cardiovascular system of aquatic organisms have not been studied. This study investigated the effects of EHS on lipid metabolism and cardiovascular development during zebrafish embryogenesis. The results showed that EHS caused defects such as pericardial edema, cardiovascular dysplasia, lipid deposition, ischemia, and apoptosis in zebrafish embryos. In addition, qPCR and whole-mount in situ hybridization (WISH) results indicated that EHS treatment significantly altered the expression of genes related to cardiovascular development, lipid metabolism, erythropoiesis, and apoptosis. The hypolipidemic drug rosiglitazone was able to alleviate the cardiovascular defects caused by EHS, indicating that EHS affected cardiovascular development by disrupting lipid metabolism. In addition, severe ischemia caused by cardiovascular abnormalities and apoptosis were observed in the EHS-treated embryos, which was likely to be the main cause of embryonic mortality. In conclusion, this study shows that EHS has toxic effects on lipid metabolism and cardiovascular formation. Our findings provide new evidence for assessing UV filter EHS toxicity and contribute to raising awareness of the safety risks of EHS., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

In the present study, we investigated the antitumor effect and associated molecular mechanisms of the copper (II) complex of salicylate phenanthroline [Cu(sal)(phen)] against hepatocellular carcinoma (HCC). Cu(sal)(phen) inhibited the proliferation of HCC cells (HepG2 and HCC-LM9) and induced apoptosis of HCC cells in a dose-dependent manner by upregulating mitochondrial reactive oxygen species (ROS) production. The expression of the antiapoptotic proteins survivin and Bcl-2 was decreased, while the expression of the DNA damage marker γ-H 2 AX and the apoptotic marker cleaved PARP was upregulated with Cu(sal)(phen) treatment. In vivo, the growth of HepG2 subcutaneous xenograft tumors was greatly attenuated by Cu(sal)(phen) treatment. Immunohistochemistry staining showed that the expression of survivin, Bcl-2, and Ki67 in the tumor was downregulated by Cu(sal)(phen). Toxicity experiments with BALB/c mice revealed that Cu(sal)(phen) is a relatively safe drug. Our results indicate that Cu(sal)(phen) possesses great potential as a therapeutic drug for HCC., (© 2023 Wiley Periodicals LLC.)

Echinococcosis is a zoonotic disease caused by larval stages of the Echinococcus genus (metastasis). In this study, salicylate-coated Zinc oxide nanoparticles (SA-ZnO-NPs) were fabricated and characterized by SEM, FTIR and XRD analytical techniques. After that, different doses of SA-ZnO-NPs, SA and ZnO-NPs were taken to assess scolicidal potency. Scanning electron microscopy (SEM) micrographs were also used to evaluate the morphological deformities of treated protoscoleces. Furthermore, Caspase-3&7 inductions were examined in protoscoleces cysts treated with all formulations. Based on SEM and DLS analyses, the size of SA-ZnO-NPs was between 30 and 40 nm, with a spherical shape. The FTIR spectrum verified the presence of SA functional groups on the ZnO coating. At 20 min, SA-ZnO-NPs at 2000 μg/ml exhibited the greatest activity on protoscolices with 100% mortality, followed by ZnO-NPs at 1500 μg/ml at 10 min and SA alone at 2000 μg/ml at 30 min. The activation of Caspase-3&7 apoptotic enzyme was determined for 2000 μg/ml of SA-ZnO-NPs, ZnO-NPs and SA to be 16.4, 31.4, and 35.7%, respectively. The SEM image revealed apoptogenic alterations and the induction of tegument surface wrinkles, as well as abnormalities in rostellum protoscolices. According to the current study, SA-ZnO-NPs have a high mortality rate against hydatid cyst protoscolices. As a result, further studies on the qualitative assessment of these nanoformulations in vivo and preclinical animal trials seem to be required. Furthermore, the adoption of nano-drugs potentially offers alternative therapeutic approaches to combat hydatid cysts., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Aphids have been mainly controlled by traditional chemical insecticides, resulting in unamiable risk to the environment over the last decades. Push-pull strategy is regarded as a promising eco-friendly approach for aphid management through repelling aphid away and attracting their natural enemy. Methyl salicylate (MeSA), one of typical HIPVs (herbivore-induced plant volatiles), can repel aphids and attract ladybugs. Our previous studies discovered a new lead compound 3e, a salicylate-substituted carboxyl (E)-β-farnesene derivative that had effective aphid-repellent activity. However, whether 3e has attractive activity to ladybug like MeSA is unknown. Meanwhile, to discover a new derivative for both deterring aphid and recruiting ladybug is meaningful for green control of aphids., Results: Through the structural optimization of 3e, 14 new derivatives were designed and synthesized. Among them, compounds 4e and 4i had good aphid (Acyrthosiphon pisum) repellent activity, and compounds 3e, 4e and 4i had significant ladybug (Harmonia axyridis) attractive activity to males. Particularly, 4i exhibited manifest attractive effect on the females as well. Binding mechanism showed that 4i not only bound effectively with the aphid (Acyrthosiphon pisum) target ApisOBP9 thanks to its multiple hydrophobic interactions and hydrogen-bond, but also had strong binding affinity with ladybug target HaxyOBP15 due to the suitable steric space. Additionally, 4i displayed low toxicity to bee Apis mellifera., Conclusion: Compound 3e does exhibit attractive activity to male ladybug as MeSA. However, the new derivative 4i, with both pleasant aphid-repellent and ladybug-attraction activities, can be considered as a novel potential push-pull candidate for aphid control in sustainable agriculture. © 2022 Society of Chemical Industry., (© 2022 Society of Chemical Industry.)

Ethnopharmacological Relevance: Medicinal properties of Gaultheria have been used in traditional medicine to treat pain and inflammation., Aim of the Study: Hence, the purpose of this study was to evaluate the analgesic, antipyretic, and anti-inflammatory properties of Gaultheria trichophylla Royle extract and salicylate-rich fraction in vivo, in vitro, and in silico., Materials and Methods: In vivo analgesic, antipyretic, and anti-inflammatory of extract and a salicylate-rich fraction (at doses of 100, 200, 300, and 150 mg/kg) were assessed using healthy albino mice employing acetic acid-induced writhing, tail immersion test, carrageenan-induced inflammation, and croton oil-induced edema. For in vitro testing of extracts COX and LOX enzyme inhibition assays were used. Molecular docking studies were conducted for in silico testing of the inhibitory activity of the dominant compound Gaultherin against COX and LOX., Results: G-EXT 200 and 300 and G-SAL 150 mg/kg reduced pyrexia significantly (P < 0.05 and P < 0.01). G-EXT-200, 300, and G-SAL 150 reduce the writing to a significant level (p > 0.05, p < 0.01). G-EXT 200 and 300 and G-SAL 150 mg/kg doses the analgesic effect was significant (p > 0.05, p > 0.01) and was comparable to tramadol. G-EXT 100 200, 300 mg/kg showed 43.8%, 47.94% and 56% respectively. G-SAL 150 mg, rich in salicylates, showed maximum inhibition of 65.75% next to standard drug diclofenac with 76.7% inhibition. G-EXT 100 and 200 mg/kg dose showed significant (p < 0.05) reduction in ear edema. With 300 mg/kg dose the effect was more (61.89%, p < 0.01). The salicylate-rich fraction G-SAL and Celecoxib showed an almost similar effect (p < 0.01). Significance inhibition was shown in the COX-2 test (G-EXT 39.70 and G-SAL 77.20 IC50 μg/ml) and in the 5-LOX test (G-EXT 28.3 and G-SAL 39.70 IC50 μg/ml). The preliminary in silico results suggest that the investigated compound showed excellent inhibitory activity against COX and LOX enzymes as evident from the free binding energy. Molecular docking revealed that Gaultherin binds well in the COX and LOX enzyme catalytic region., Conclusion: The extract and salicylate-rich fraction obtained from G. trichophylla showed significant analgesic, anti-inflammatory, and antipyretic effects in vivo, in vitro, and in silico assays that support its use in traditional medicine., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

As a worldwide health issue, obesity is associated with the infiltration of monocytes/macrophages into the adipose tissue causing unresolved inflammation. Monocyte chemoattractant protein-1 (MCP-1) exerts a crucial effect on obesity-related monocytes/macrophages infiltration. Clinically, aspirin and salsalate are beneficial for the treatment of metabolic diseases in which adipose tissue inflammation plays an essential role. Herein, we investigated the effect and precise mechanism of their active metabolite salicylate on TNF-α-elevated MCP-1 in adipocytes. The results indicated that salicylate sodium (SAS) could lower the level of MCP-1 in TNF-α-stimulated adipocytes, which resulted from a previously unrecognized target phosphodiesterase (PDE), 3B (PDE3B), rather than its known targets IKKβ and AMPK. The SAS directly bound to the PDE3B to inactivate it, thus elevating the intracellular cAMP level and activating PKA. Subsequently, the expression of MKP-1 was increased, which led to the decrease in p-EKR and p-p38. Both PDE3B silencing and the pharmacological inhibition of cAMP/PKA compromised the suppressive effect of SAS on MCP-1. In addition to PDE3B, the PDE3A and PDE4B activity was also inhibited by SAS. Our findings identify a previously unrecognized pathway through which SAS is capable of attenuating the inflammation of adipocytes.

We report the synthesis, characterisation, and anti-osteosarcoma properties of a gallium(III) complex (1) comprising of two 1,10-phenanthroline ligands and salicylate, a non-steroidal anti-inflammatory drug. The gallium(III) complex 1 displays micromolar potency towards bulk osteosarcoma cells and osteosarcoma stem cells (OSCs). Notably, the gallium(III) complex 1 exhibits significantly higher toxicity towards OSCs grown in monolayer and three-dimensional cultures than cisplatin, a frontline anti-osteosarcoma drug. Nuclei isolation and immunoblotting studies show that the gallium(III) complex 1 enters osteosarcoma cell nuclei and induces DNA damage. Flow cytometry and cytotoxicity studies (in the presence of prostaglandin E2) indicate that the gallium(III) complex 1 downregulates cyclooxygenase-2 (COX-2) expression and kills osteosarcoma cells in a COX-2-dependent manner. Further, the mode of osteosarcoma cell death evoked by the gallium(III) complex 1 is characterised as caspase-dependent apoptosis., (© 2022 The Authors. ChemBioChem published by Wiley-VCH GmbH.)

Objective: Pendrin is a transmembrane protein encoded by the SLC26A4 gene that functions in maintaining ion concentrations in the endolymph of the inner ear, most likely by acting as a chloride/bicarbonate transporter. Variants in the SLC26A4 gene are responsible for sensorineural hearing loss. Although pendrin localizes to the plasma membrane, we previously identified that 8 missense allele products of SLC26A4 were retained in the intracellular region and lost their anion exchange function. We also found that 10 mM salicylate induced the translocation of 4 out of 8 allele products from the intracellular region to the plasma membrane and restored their anion exchanger activity. However, since 10 mM salicylate exhibits cytotoxicity, the use of chemical compounds with less cell toxicity is needed. In the present study, therefore, salicylate derivatives were used as the chemical compounds and their effects on the p.H723R allele products of SLC26A4 were investigated., Methods: HEK293 cells were transfected with the cDNA of p.H723R. Cell proliferation, viability and toxicity assays were performed to investigate the response and health of cells in culture after treatment with four types of salicylate derivatives, i.e., 2-hydroxybenzyl alcohol, 2,3-dihydroxybenzoic acid, 2'-hydroxyacetophenone and methyl salicylate. The effects of these salicylate derivatives on the localization of the p.H723R were investigated by immunofluorescence microscopy., Results: The application of 10 mM salicylate showed an increase in cell toxicity and decrease in cell viability, leading to a significant decrease in cell proliferation. In contrast, the application of 1 mM salicylate derivatives did not show any significant increase in cell toxicity and decrease in cell viability, corresponding to a logarithmic increase in cell concentration with an increase in culture time. Immunofluorescence experiments showed that the p.H723R retained in the endoplasmic reticulum (ER). Among the salicylate derivatives applied, 2-hydroxybenzyl alcohol induced the translocation of p.H723R from the ER to the plasma membrane 3 h after its application., Conclusion: The results obtained showed that 2-hydroxybenzyl alcohol restored the localization of the p.H723R allele products of SLC26A4 from the ER to the plasma membrane at a concentration of 1 mM by 3 h after its administration with less cytotoxicity than 10 mM salicylate., (Copyright © 2022. Published by Elsevier B.V.)

To date, the effect of resveratrol on tinnitus has not been reported. The attenuative effects of resveratrol (RSV) on a salicylate-induced tinnitus model were evaluated by in vitro and in vivo experiments. The gene expression of the activity-regulated cytoskeleton-associated protein ( ARC ), tumor necrosis factor-alpha ( TNFα ), and NMDA receptor subunit 2B ( NR2B ) in SH-SY5Y cells was examined using qPCR. Phosphorylated cAMP response element-binding protein (p-CREB), apoptosis markers, and reactive oxygen species (ROS) were evaluated by in vitro experiments. The in vivo experiment evaluated the gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and auditory brainstem response (ABR) level. The NR2B expression in the auditory cortex (AC) was determined by immunohistochemistry. RSV significantly reduced the salicylate-induced expression of NR2B , ARC , and TNFα in neuronal cells; the GPIAS and ABR thresholds altered by salicylate in rats were recovered close to their normal range. RSV also reduced the salicylate-induced NR2B overexpression of the AC. These results confirmed that resveratrol exerted an attenuative effect on salicylate-induced tinnitus and may have a therapeutic potential.

Melatonin was discovered in plants in the late nineties, but its role, signaling, and crosstalk with other phytohormones remain unknown. Research on melatonin in plants has risen dramatically in recent years and the role of this putative plant hormone under biotic and abiotic stress conditions has been reported. In the present review, we discuss the main functions of melatonin in the growth and development of plants, its role under abiotic stresses, such as water stress (waterlogging and drought), extreme temperature (low and high), salinity, heavy metal, and light-induced stress. Similarly, we also discuss the role of melatonin under biotic stresses (antiviral, antibacterial, and antifungal effects). Moreover, the present review meticulously discusses the crosstalk of melatonin with other phytohormones such as auxins, gibberellic acids, cytokinins, ethylene, and salicylic acid under normal and stressful conditions and reports melatonin receptors and signaling in plants. All these aspects of melatonin suggest that phytomelatonin is a key player in crop improvement and biotic and abiotic stress regulation.

The cytoprotective effects of a novel hydroalcoholic extract (0.01-5 mg/mL) from Lens culinaria (Terre di Altamura Srl) were investigated within murine native skeletal muscle fibers, bone marrow cells, and osteoblasts, and in cell lines treated with the apoptotic agent staurosporine (2.14 × 10 -6 M), the alkylating drug cisplatin (10 -4 M), the topoisomerase I inhibitor irinotecan (10 -4 M), the antimitotic pro-oxidant doxorubicin (10 -6 M), and the immunosuppressant dexamethasone (2 × 10 -6 M). An amount of 10g of plant material was used to obtain a 70% ethanol/water product, following two-step extraction, evaporation, lyophilization, and storage at -20 °C. For the murine osteoblasts, doxorubicin reduced survival by -65%, dexamethasone by -32% and -60% after 24 and 48 h of incubation time, respectively. The extract was effective in preventing the osteoblast count-reduction induced by dexamethasone; it was also effective at preventing the inhibition of mineralization induced by dexamethasone. Doxorubicin and cisplatin caused a significant reduction in cell growth by -77% for bone marrow cells, -43% for irinotecan, and -60% for dexamethasone, but there was no evidence for the cytoprotective effects of the extract in these cells. Staurosporine and doxorubicin caused a fiber death rate of >-40% after 18 and 24 h of incubation, yet the extract was not effective at preventing these effects. The extract was effective in preventing the staurosporine-induced reduction of HEK293 proliferation and colony formation in the crystal violet DNA staining and the clonogenic assays. It was also effective for the cisplatin-induced reduction in HEK293 cell proliferation. The extract, however, failed to protect the SHSY5Y neurons against cisplatin and irinotecan-induced cytotoxicity. A UV/VIS spectroscopy analysis showed three peaks at the wavelengths of 350, 260, and 190 nm, which correspond to flavonoids, proanthocyanins, salicylates, and AA, constituting the extract. These data suggest the possible development of this extract for use against dexamethasone-induced bone loss and renal chemotherapy-induced damage.

High doses of salicylate induce tinnitus in humans and experimental animals. The Dorsal Cochlear Nucleus is implicated with the genesis of tinnitus, and increased activity in this nucleus is seen in animal models of tinnitus. Incubation of brainstem slices containing the DCN with millimolar salicylate reduces the spontaneous firing of glycinergic cartwheel neurons and glycinergic neurotransmission on fusiform neurons, the principal neuron of this nucleus. However, the mechanism of salicylate mediating this effect is not known. Recently, we have shown that K ATP channels strongly modulate the spontaneous firing of cartwheel neurons. We tested if K ATP channels could mediate the effects of salicylate on cartwheel neurons. Perfusion of 1.4 mM salicylate hyperpolarizes the membrane of cartwheel neurons and stops firing. Salicylate produces an outward current similar to the K ATP current seen in quiet cartwheel neurons. Activation of this current is occluded by the K ATP agonist diazoxide, which is produced by the opening of K ATP channels. The antagonist of AMP-kinase (AMPK), dorsomorphim, inhibited salicylate effects, suggesting that they could be mediated by activation of this kinase. Still, the AMPK agonist, AICAR, did not reproduce salicylate effects but occluded them. Additionally, inhibiting mitochondrial ATP synthesis with the protonophore CCCP reproduced, albeit with less efficacy, and inhibited the effects of salicylate. We concluded that salicylate in millimolar concentrations opens K ATP channels in DCN cartwheel neurons, inhibiting spontaneous firing of these neurons, probably by activating AMPK and reducing mitochondrial ATP synthesis., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Tetramethrin (Tm) is a commonly used pesticide that has been reported to exert estrogen-antagonistic effects selectively on female rats. The present study was undertaken to assess the protective role of lobaric acid (La) on estrous cycle in Tm-treated female Wistar rats. Female rats were exposed to Tm (50 mg/kg b.w/day) only or in combination with La at low (50 mg/kg b.w/day) or high (100 mg/kg b.w/day) dose for 30 days. The results showed that Tm altered the estrous cycle of female rats by decreasing the levels of luteinizing hormone, follicular-stimulating hormone, progesterone, estrone, and estradiol while increasing testosterone level. The morphology of vaginal smears of Tm-treated female rats showed the presence of abnormal cells and/or structures at different phases of estrus cycle. Strikingly, in (Tm + La)-treated rats, all the observed adverse effects of Tm on the hormonal parameters, cell morphology, and the length of each phase of estrous cycle were significantly diminished in a dose-dependent manner. The docking results showed that La competes with Tm for Gonadotropin-Releasing Hormone (GnRH) receptor, thereby reducing the toxicity of Tm but did not cancel the response of GnRH receptor completely. In conclusion, our results designated that La could be used as a potential candidate in the management of insecticide-induced alterations of the reproductive cycle of rodents., Competing Interests: The authors have declared that no competing interests exist.

The leaves of Gaultheria procumbens are polyphenol-rich traditional medicines used to treat inflammation-related diseases. The present study aimed to optimise the solvent for the effective recovery of active leaf components through simple direct extraction and verify the biological effects of the selected extract in a model of human neutrophils ex vivo. The extracts were comprehensively standardised, and forty-one individual polyphenols, representing salicylates, catechins, procyanidins, phenolic acids, and flavonoids, were identified by UHPLC-PDA-ESI-MS 3 . The chosen methanol-water (75:25, v / v ) extract (ME) was obtained with the highest extraction yield and total phenolic levels (397.9 mg/g extract's dw), including 98.9 mg/g salicylates and 299.0 mg/g non-salicylate polyphenols. In biological tests, ME revealed a significant and dose-dependent ability to modulate pro-oxidant and pro-inflammatory functions of human neutrophils: it strongly reduced the ROS level and downregulated the release of pro-inflammatory cytokines and tissue remodelling enzymes, especially IL-1β and elastase 2, in cells stimulated by f MLP, LPS, or f MLP + cytochalasin B. The extracts were also potent direct scavengers of in vivo relevant oxidants (O 2 •- , • OH, and H 2 O 2 ) and inhibitors of pro-inflammatory enzymes (cyclooxygenase-2, hyaluronidase, and lipoxygenase). The statistically significant correlations between the tested variables revealed the synergic contribution of individual polyphenols to the observed effects and indicated them as useful active markers for the standardisation of the extract/plant material. Moreover, the safety of ME was confirmed in cytotoxicity tests. The obtained results might partially explain the ethnomedicinal application of G. procumbens leaves and support the usage of the standardised leaf extract in the adjuvant treatment of oxidative stress and inflammation-related chronic diseases.

Reactive oxygen species (ROS)-mediated reductions in nitric oxide (NO)-dependent dilation are evident in adults with major depressive disorder (MDD); however, the upstream mechanisms remain unclear. Here, we hypothesized that nuclear factor-κB (NF-κB) activation-induced ROS production contributes to microvascular endothelial dysfunction in MDD. Thirteen treatment-naive adults with MDD (6 women; 19-23 yr) and 10 healthy nondepressed adults (HAs; 5 women; 20-25 yr) were tested before and after (open-label design) systemic NF-κB knockdown (nonacetylated salicylate; 3,000-4,500 mg/day × 4 days). Red cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium-dependent agonist acetylcholine (ACh), alone and in combination with NO synthase inhibition [ N G -nitro-l-arginine methyl ester (l-NAME)] or ROS scavenging (apocynin). Serum salicylate concentrations following treatment were not different between groups (22.8 ± 7.4 HAs vs. 20.8 ± 4.3 mg/dL MDD; P = 0.46). When compared with HAs, the NO-dependent component of ACh-induced dilation was blunted in adults with MDD before ( P = 0.023), but not after ( P = 0.27), salsalate treatment. In adults with MDD, the magnitude of improvement in endothelium-dependent dilation following salsalate treatment was inversely related to the degree of functional impairment at baseline ( R 2 = 0.43; P = 0.025). Localized ROS scavenging improved NO-dependent dilation before ( P < 0.01), but not after ( P > 0.05), salsalate treatment. Salsalate did not alter systemic concentrations of pro- or anti-inflammatory cytokines (all P > 0.05). These data suggest that NF-κB activation, via increased vascular ROS production, contributes to blunted NO-dependent dilation in young adults with MDD but otherwise free of clinical disease. These data provide the first direct evidence for a mechanistic role of vascular inflammation-associated endothelial dysfunction in human depression. NEW & NOTEWORTHY Our data indicate that short-term treatment with therapeutic doses of the nuclear factor-κB (NF-κB) inhibitor salsalate improved nitric oxide (NO)-mediated endothelium-dependent dilation in adults with major depressive disorder (MDD). In adults with MDD, acute localized scavenging of reactive oxygen species (ROS) with apocynin improved NO-dependent dilation before, but not after, salsalate administration. These data suggest that activation of NF-κB, in part via stimulation of vascular ROS production, contributes to blunted NO-mediated endothelium-dependent dilation in young adults with MDD.

Lichen extracts containing, among other compounds, depsides such as evernic acid, atranorin, and lecanoric acid possess anti-proliferative effects. We aimed to identify lichen metabolites that are responsible for the observed anti-proliferative effects. We performed cytotoxicity, cell colony, cell cycle and apoptosis assays in various cell lines or primary immune cells. We analyzed several cell cycle proteins and apoptosis-related proteins to gain insights into the underlying mechanism. All depsides reduced the viability of the tested cell lines (HCT-116, HEK293T, HeLa, NIH3T3, RAW246.7) in a cell line-dependent manner with lecanoric acid being the most effective. Atranorin did not influence the cell cycle or colony formation in HCT-116 cells, but induced apoptosis in HCT-116 cells. Evernic acid showed no anti-proliferative effects. Lecanoric acid inhibited cell colony formation already at 0.03 µg/ml in HCT-116 cells and induced a G2 cell cycle block in several cell lines. Moreover, lecanoric acid arrested the cell cycle, presumably in the M phase, since expression of cyclin B1 and phosphorylated histone H3 was upregulated, whereas the inactive cyclin-dependent kinase 1 (CDK1) was reduced in HCT-116 cells. Most importantly, cell death induced by lecanoric acid was more prominent in cancer cells than in primary human immune and endothelial cells. In conclusion, lecanoric acid seems to mediate its anti-proliferative effects via arrest of cells in the M phase. Our data suggest lecanoric acid may be a potential new candidate for anti-cancer therapy, because it has anti-proliferative effects on cancer cell lines, and does not affect primary immune cells., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The zinc complex of 3,5-di-tert-butyl salicylate (Zn{[CH 3 ) 3 C] 2 Sal} 2 2- ) is a zinc ion chelate of salicylate. In this study, we found that this compound inhibits viability, invasion, and migration and induces apoptosis in triple-negative breast cancer 4T1 cells. RNA-seq showed that the expression of 17 genes was upregulated and 26 genes were downregulated significantly by Zn{[CH 3 ) 3 C] 2 Sal} 2 2- treatment. Further GO and KEGG analysis showed that the activity of Zn{[CH 3 ) 3 C] 2 Sal} 2 2- against triple-negative breast cancer cells may be involved in the JAK-STAT3, HIF-1, and TNF signaling pathways. The expression of key genes was verified by RT-PCR. The phosphorylation of STAT3 and its upstream SRC decreased drastically upon Zn{[CH 3 ) 3 C] 2 Sal} 2 2- treatment, as demonstrated by western blot. Our results indicate that Zn{[CH 3 ) 3 C] 2 Sal} 2 2- inhibits the activity of TNBC cells by downregulating the STAT3 signaling through the SRC pathway., (© 2022. The Author(s).)

Women who have had preeclampsia demonstrate microvascular endothelial-dysfunction, mediated in part by reduced nitric oxide (NO)-dependent dilation. Preeclamptic pregnancies are associated with elevated inflammation, and inhibition of inflammation attenuates endothelial damage in animal models of preeclampsia. However, it is unclear if inhibition of vascular inflammation improves endothelial function in women after a preeclamptic pregnancy. Using the cutaneous microcirculation as a model, we hypothesized that acute systemic inhibition of vascular inflammation (oral salsalate; 1500 mg/twice daily, 4 days) would improve endothelium- and NO-dependent vasodilation in women with a history of preeclampsia (PE) but not in women with a history of uncomplicated pregnancy (HC). Twelve HC (30 ± 1yrs, 10 ± 2 months postpartum) and 10 PE (30 ± 2yrs, 8 ± 2 months postpartum) participated in a double-blind placebo-controlled study. Following each treatment, 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusion of acetylcholine (Ach, 10 -7 -10 2 mM) or Ach + 15 mM L-NAME (NO synthase antagonist). Red blood cell flux was measured over each site by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC = LDF/mean arterial pressure) and normalized to maximum (%CVC max ; 28 mM SNP + local heat 43 °C). ACh-induced (77 ± 3 vs. 92 ± 3%CVC max ; p = 0.01) and NO-dependent (20 ± 6 vs. 33 ± 4%; p = 0.02) vasodilation were attenuated in PE compared to HC. Salsalate augmented ACh-induced (95 ± 2%CVC max ; p = 0.002) and NO-dependent (39 ± 3%; p = 0.009) dilation in PE compared to placebo but had no effect in HC (all p > 0.05). Salsalate treatment augmented endothelium-dependent vasodilation via NO-mediated pathways in women who have had preeclampsia, suggesting that inflammatory signaling mediates persistent endothelial dysfunction following preeclampsia., (Copyright © 2021 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

A series of new 5-aryl-2,2'-bipyridines and their (polyfluoro)salicylate complexes of Cu(II), Co(II) and Mn(II) were synthesized. Their antimicrobial activity was evaluated in vitro against six strains of Trichophytons, E. floccosum, M. canis, C. ablicans and Gram-negative bacteria N. gonorrhoeae. Among azo-ligands, Ph-bipy and Tol-bipy showed promising antifungal activity (minimum inhibitory concentration (MIC)<0.8-27 μM). Their antifungal action was found can be realized via binding Fe(III) ions. Tol-bipy suppressed growth of Gram-positive bacteria S. aureus, S. aureus MRSA and their monospecies biofilms (MIC 6-16 μM). Using molecular docking, the anti-staphylococcal action mechanism based on the inhibition of S. aureus DNA gyrase GyrB was proposed for the lead compounds. Among metal complexes, Cu(II) and Mn(II) complexes based on tetrafluorosalicylic acid and Tol-bipy or Ph-bipy had the high antifungal activity (MIC<0.24-32 μM). Mn(SalF 4 -2H) 2 (Tol-bipy) 2 ] suppressed the growth of seven Candida strains at MIC 12-24 μM. [Cu(Sal-2H)(Ph-bipy)] and [Cu(SalF 3 -2H)(Ph-bipy) 2 ] showed the promising anti-gonorrhoeae activity (MIC 4.2-5.2 μM). (Cu(SalF n -2H)(Tol-bipy) 2 ], [Cu(SalF 4 -2H)(Ph-bipy) 2 ] and [Cu(SalF 3 -2H)(Ph-bipy) 2 ]) were found active against the bacteria of S. aureus, S. aureus MRSA and their biofilms (MIC 2.4-41.4 μM). The most active compounds were tested for toxicity in vitro against human embryonic kidney (HEK-293) cells and in vivo experiments with CD-1 mice., (© 2021 Wiley-VCH GmbH.)

Background: Infections in neonates with herpes simplex virus 1 (HSV-1) following circumcision due to Metzitzah Be'Peh (MBP) performed by a Mohel occur each year in small numbers. One solution to this problem is the use of a mucus extractor device instead of MBP, which has been authorized by some rabbis. Yet, using a mucus extractor remains controversial among ultra-Orthodox Jews; thus, creating a need for additional solutions., Objectives: To seek to reduce HSV-1 infection of neonates due to MBP., Methods: We tested several oral rinse solutions for their ability to destroy virus infectivity following incubation for 30 seconds and using plaque reduction assays., Results: Corsodyl, Decapinol, and Listerine® all destroyed plaques formation of spiked virus, while Gengigel and Tantum Verde were found to be less effective. We focused specifically on Listerine® due to its efficacy in eliminating contagious HSV-1 from saliva after a 30-second oral rinse. Five different products of Listerine® reduced the infectivity of a spiked virus by more than 4 orders of magnitude in 30 seconds. We also showed that Listerine (up to 7% v/v) can stay in the mouth but did not harm living cells and therefore will not cause any damage to the injured tissue., Conclusions: Significant reduction in cases of infection with HSV-1 due to MBP can be achieved if Mohalim consistently adopt the practice of careful mouth washing with Listerine® just before performing MBP.

Pigeon Pea ( Cajanus cajan (L.) Millsp.) is a common food crop used in many parts of the world for nutritional purposes. One of its chemical constituents is cajanin stilbene acid (CSA), which exerts anticancer activity in vitro and in vivo. In an effort to identify molecular targets of CSA, we performed a kinome-wide approach based on the measurement of the enzymatic activities of 252 human kinases. The serine-threonine kinase WNK3 (also known as protein kinase lysine-deficient 3) was identified as the most promising target of CSA with the strongest enzymatic activity inhibition in vitro and the highest binding affinity in molecular docking in silico. The lowest binding affinity and the predicted binding constant pKi of CSA (-9.65 kcal/mol and 0.084 µM) were comparable or even better than those of the known WNK3 inhibitor PP-121 (-9.42 kcal/mol and 0.123 µM). The statistically significant association between WNK3 mRNA expression and cellular responsiveness to several clinically established anticancer drugs in a panel of 60 tumor cell lines and the prognostic value of WNK3 mRNA expression in sarcoma biopsies for the survival time of 230 patients can be taken as clues that CSA-based inhibition of WNK3 may improve treatment outcomes of cancer patients and that CSA may serve as a valuable supplement to the currently used combination therapy protocols in oncology.

Prophage-encoded Escherichia coli O157:H7 transcription factor (TF), PchE, inhibits biofilm formation and attachment to cultured epithelial cells by reducing curli fimbriae expression and increasing flagella expression. To identify pchE regulators that might be used in intervention strategies to reduce environmental persistence or host infections, we performed a computational search of O157:H7 strain PA20 pchE promoter sequences for binding sites used by known TFs. A common site shared by MarA/SoxS/Rob TFs was identified and the typical MarA/Rob inducers, salicylate and decanoate, were tested for biofilm and motility effects. Sodium salicylate, a proven biofilm inhibitor, but not sodium decanoate, strongly reduced O157:H7 biofilms by a pchE -independent mechanism. Both salicylate and decanoate enhanced O157:H7 motility dependent on pchE using media and incubation temperatures optimum for culturing human epithelial cells. However, induction of pchE by salicylate did not activate the SOS response. MarA/SoxS/Rob inducers provide new potential agents for controlling O157:H7 interactions with the host and its persistence in the environment. IMPORTANCE There is a need to develop E. coli serotype O157:H7 nonantibiotic interventions that do not precipitate the release and activation of virulence factor-encoded prophage and transferrable genetic elements. One method is to stimulate existing regulatory pathways that repress bacterial persistence and virulence genes. Here we show that certain inducers of MarA and Rob have that ability, working through both pchE -dependent and pschE -independent pathways.