Sunset Yellow protects against oxidative damage and exhibits chemoprevention in chemically induced skin cancer model.

Skin cancer and other skin-related inflammatory pathologies are rising due to heightened exposure to environmental pollutants and carcinogens. In this context, natural products and repurposed compounds hold promise as novel therapeutic and preventive agents. Strengthening the skin's antioxidant defense mechanisms is pivotal in neutralizing reactive oxygen species (ROS) and mitigating oxidative stress. Sunset Yellow (SY) exhibits immunomodulatory characteristics, evidenced by its capacity to partially inhibit the secretion of proinflammatory cytokines, regulate immune cell populations, and modulate the activation of lymphocytes. This study aimed to investigate the antioxidant and anti-genotoxic properties of SY using in-silico, in vitro, and physiochemical test systems, and to further explore its potential role in 7,12-dimethylbenz(a) anthracene (DMBA)/ 12-o-tetradecanoylphorbol-13-acetate (TPA)-induced two-stage skin carcinogenesis. In vitro experiments showed that pre-treatment of SY significantly enhanced the cell viability of HaCaT cells when exposed to tertiary-Butyl Hydrogen Peroxide (tBHP). This increase was accompanied by reduced ROS levels, restoration of mitochondrial membrane potential, and notable reduction in DNA damage in (SY + tBHP) treated cells. Mechanistic investigations using DPPH chemical antioxidant activity test and potentiometric titrations confirmed SY's antioxidant properties, with a standard reduction potential ( E o ) of 0.211 V. Remarkably, evaluating the effect of topical application of SY in DMBA/TPA-induced two-step skin carcinogenesis model revealed dose-dependent decreases in tumor latency, incidence, yield, and burden over 21-weeks. Furthermore, computational analysis and experimental validations identified GSK3ß, KEAP1 and EGFR as putative molecular targets of SY. Collectively, our findings reveal that SY enhances cellular antioxidant defenses, exhibits anti-genotoxic effects, and functions as a promising chemopreventive agent.

Therapeutic potential of short-chain fatty acid production by gut microbiota in neurodegenerative disorders.

Dietary fibers are a major source of short-chain fatty acids (SCFAs) in the body, and the fermentation products of SCFAs induced by intestinal microbiota affect energy metabolism. Apart from serving as an energy source in the intestines, SCFAs also inhibit autophagy, nucleotide-binding oligomerization domain-containing protein, LRR, and pyrin domain-containing protein 3 inflammasome. SCFAs provide numerous therapeutic benefits through their influence on cognitive functioning and neurodegenerative diseases (NDD) pathophysiology. Additionally, NDDs are associated with abnormalities in the gut microbiota, including an increased load of pathogens and opportunistic microbes. SCFAs maintain the healthy mitochondrial function and stimulate the maturation of microglia, which consequently suppresses the progression of NDD and cognitive decline by regulating inflammation and oxidative stress. Basically, SCFAs function as cofactors for the host's mitochondrial enzymes and are being studied for their ability to reverse the alteration in the gut microbiota seen in many NDDs and cardiac diseases. In the present review, the focus is on the detrimental and beneficial roles of SCFAs in NDD, emphasizing the effects of SCFA on following phenomenon: (1) alteration in gut microbiota profile associated with NDD, (2) the molecular mechanism of metabolic regulation by SCFA's, and its co-relation with NDD, (3) use of mitochondrial antioxidants as a strategy for maintaining microbiota diversity in the gut, and (4) the future direction of metabolism and neurodegeneration in the gut-brain axis. In addition, the interplay between gut microbiota, SCFAs, epithelial barrier, and neuroimmune signaling in neurodegeneration has been reviewed.

Biology of macrophage fate decision: Implication in inflammatory disorders.

The activation of immune cells in response to stimuli present in their microenvironment is regulated by their metabolic profile. Unlike the signal transduction events, which overlap to a huge degree in diverse cellular processes, the metabolome of a cell reflects a more precise picture of cell physiology and function. Different factors governing the cellular metabolome include receptor signaling, macro and micronutrients, normoxic and hypoxic conditions, energy needs, and biomass demand. Macrophages have enormous plasticity and can perform diverse functions depending upon their phenotypic state. This review presents recent updates on the cellular metabolome and molecular patterns associated with M1 and M2 macrophages, also termed "classically activated macrophages" and "alternatively activated macrophages," respectively. M1 macrophages are proinflammatory in nature and predominantly Th1-specific immune responses induce their polarization. On the contrary, M2 macrophages are anti-inflammatory in nature and primarily participate in Th2-specific responses. Interestingly, the same macrophage cell can adapt to the M1 or M2 phenotype depending upon the clues from its microenvironment. We elaborate on the various tissue niche-specific factors, which govern macrophage metabolism and heterogeneity. Furthermore, the current review provides an in-depth account of deregulated macrophage metabolism associated with pathological disorders such as cancer, obesity, and atherosclerosis. We further highlight significant differences in various metabolic pathways governing the cellular bioenergetics and their impact on macrophage effector functions and associated disorders.

Immunotherapies in the treatment of immunoglobulin E­mediated allergy: Challenges and scope for innovation (Review).

Immunoglobulin E (IgE)­mediated allergy or hypersensitivity reactions are generally defined as an unwanted severe symptomatic immunological reaction that occurs due to shattered or untrained peripheral tolerance of the immune system. Allergen­specific immunotherapy (AIT) is the only therapeutic strategy that can provide a longer­lasting symptomatic and clinical break from medications in IgE­mediated allergy. Immunotherapies against allergic diseases comprise a successive increasing dose of allergen, which helps in developing the immune tolerance against the allergen. AITs exerttheirspecial effectiveness directly or indirectly by modulating the regulator and effector components of the immune system. The number of success stories of AIT is still limited and it canoccasionallyhave a severe treatment­associated adverse effect on patients. Therefore, the formulation used for AIT should be appropriate and effective. The present review describes the chronological evolution of AIT, and provides a comparative account of the merits and demerits of different AITs by keeping in focus the critical guiding factors, such as sustained allergen tolerance, duration of AIT, probability of mild to severe allergic reactions and dose of allergen required to effectuate an effective AIT. The mechanisms by which regulatory T cells suppress allergen­specific effector T cells and how loss of natural tolerance against innocuous proteins induces allergy are reviewed. The present review highlights the major AIT bottlenecks and the importantregulatory requirements for standardized AIT formulations. Furthermore, the present reviewcalls attention to the problem of 'polyallergy', which is still a major challenge for AIT and the emerging concept of 'component­resolved diagnosis' (CRD) to address the issue. Finally, a prospective strategy for upgrading CRD to the next dimension is provided, and a potential technology for delivering thoroughly standardized AIT with minimal risk is discussed.

Computational and Synthetic Biology Approaches for the Biosynthesis of Antiviral and Anticancer Terpenoids from Bacillus subtilis.

Recent advancements in medicinal research have identified several antiviral and anticancer terpenoids that are usually deployed as a source of flavor, fragrances and pharmaceuticals. Under the current COVID-19 pandemic conditions, natural therapeutics with the least side effects are the need of the hour to save the patients, especially, which are pre-affected with other medical complications. Although plants are the major sources of terpenoids; however, for the environmental concerns, the global interest has shifted to the biocatalytic production of molecules from microbial sources. The gram-positive bacterium Bacillus subtilis is a suitable host in this regard due to its GRAS (generally regarded as safe) status, ease in genetic manipulations and wide industrial acceptability. The B. subtilis synthesizes its terpenoid molecules from 1-deoxy-d-xylulose-5-phosphate (DXP) pathway, a common route in almost all microbial strains. Here, we summarize the computational and synthetic biology approaches to improve the production of terpenoid-based therapeutics from B. subtilis by utilizing DXP pathway. We focus on the in-silico approaches for screening the functionally improved enzyme-variants of the two crucial enzymes namely, the DXP synthase (DXS) and Farnesyl Pyrophosphate Synthase (FPPS). The approaches for engineering the active sites are subsequently explained. It will be helpful to construct the functionally improved enzymes for the high-yield production of terpenoid-based anticancer and antiviral metabolites, which would help to reduce the cost and improve the availability of such therapeutics for the humankind.

Diagnostic significance of serum and salivary lipid levels in oral precancer and oral cancer.

INTRODUCTION: Lipids are one of the major constituents of the cell. Variations in the serum lipids have been considered a cofactor of carcinogenesis, as lipids play a crucial role in cell integrity. Saliva is an ultrafiltrate of plasma and correlates with the serum, which may be used as an alternate method of serum lipid level estimation. The study was conducted to find any correlation between serum and salivary lipid levels and to evaluate the changes in serum and salivary lipid levels in oral precancer and cancer patients. AIMS AND OBJECTIVES: This study aimed to evaluate the changes in serum and salivary lipid levels in oral precancer and cancer patients and to correlate salivary lipid levels with serum lipid levels. MATERIALS AND METHODS: The study was an in vivo study conducted on randomly selected 129 patients with oral cancer and oral precancer. The selected subjects were divided into four groups as Group 1 - healthy control, Group 2 - oral submucous fibrosis, Group 3 - leukoplakia, and Group 4 - oral cancer. Serum and salivary lipid levels were estimated biochemically and statistically analyzed for any correlation with oral precancer and cancer. RESULTS: Lipid level estimation showed no statistically significant difference on comparison of intergroup serum and saliva total cholesterol level and high-density lipoproteins among all four groups, whereas intergroup comparison of serum and saliva triglycerides (TG) levels among the four groups showed a statistically significant difference in saliva TG level. The correlation of serum and salivary lipid levels showed a significant positive correlation. CONCLUSION: In the present study association between serum/salivary lipid levels and oral precancer and oral cancer could not be established. A positive association was there in serum and salivary lipids hence salivary lipid levels may be used as a noninvasive technique for serum lipid level estimation.

Theory for size segregation in flowing granular mixtures based on computation of forces on a single large particle.

We measure the upward force acting on a single, unconstrained, large particle in a granular medium of small particles flowing over inclined plane using discrete element method (DEM) simulation. Based on the computed force, we obtain an expression for the flux of large particles in a binary mixture of large and small particles and predict the equilibrium concentration profile and the velocity profile of the flowing layer. The theoretical predictions are in very good agreement with the DEM simulation results for a wide range of concentrations of large particles and inclination angles.

Emodin inhibited NADPH-quinone reductase competitively and induced cytotoxicity in rat primary hepatocytes.

Consumption of Cassia occidentalis (CO) seeds, a ubiquitously distributed weed plant, is responsible for a pathological condition known as hepato-myo-encephalopathy (HME). The toxicity of CO seeds is largely attributed to the presence of anthraquinones (AQs). Here, we report that Emodin, a CO anthraquinone, inhibits the enzymatic activity of NADPH-Quinone reductase, which is an intracellular enzyme fundamentally involved in the detoxification of quinone containing compounds. Emodin binds to the active site of the enzyme and acts as a competitive inhibitor with respect to 2, 6-Dichlorophenolindophenol, a known substrate of NADPH-Quinone reductase. Moreover, our in-vitro study further revealed that Emodin was cytotoxic to primary rat hepatocytes.

WITHDRAWN: The Atlas of Inflammation Resolution (AIR).

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.mam.2020.100894. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

The Atlas of Inflammation Resolution (AIR).

Acute inflammation is a protective reaction by the immune system in response to invading pathogens or tissue damage. Ideally, the response should be localized, self-limited, and returning to homeostasis. If not resolved, acute inflammation can result in organ pathologies leading to chronic inflammatory phenotypes. Acute inflammation and inflammation resolution are complex coordinated processes, involving a number of cell types, interacting in space and time. The biomolecular complexity and the fact that several biomedical fields are involved, make a multi- and interdisciplinary approach necessary. The Atlas of Inflammation Resolution (AIR) is a web-based resource capturing an essential part of the state-of-the-art in acute inflammation and inflammation resolution research. The AIR provides an interface for users to search thousands of interactions, arranged in inter-connected multi-layers of process diagrams, covering a wide range of clinically relevant phenotypes. By mapping experimental data onto the AIR, it can be used to elucidate drug action as well as molecular mechanisms underlying different disease phenotypes. For the visualization and exploration of information, the AIR uses the Minerva platform, which is a well-established tool for the presentation of disease maps. The molecular details of the AIR are encoded using international standards. The AIR was created as a freely accessible resource, supporting research and education in the fields of acute inflammation and inflammation resolution. The AIR connects research communities, facilitates clinical decision making, and supports research scientists in the formulation and validation of hypotheses. The AIR is accessible through https://air.bio.informatik.uni-rostock.de.

Role of fractal analysis in detection of dysplasia in potentially malignant disorders.

BACKGROUND: Fractal analysis is, a noninvasive method, used to determine the intricate characteristics of the matter. Oral leukoplakia (OL), a potential malignant disorder, has definite propensity to turn in to malignancy. In such lesions, fractal dimension analysis (FDA) could be helpful in the early detection of malignant transformation. OBJECTIVES: To determine the efficacy of fractal dimension analysis in detecting malignancy potential of oral leukoplakia. MATERIALS AND METHODS: After ethical clearance, we enrolled 121 patients in our study. Lesions were photographed before and after toluidine staining. Image J software was used to analyze fractal dimensions (FDs) of digital image and results were compared with biopsy. RESULTS: Fractal dimension value is significantly higher in leukoplakia with dysplastic changes. FD values increase as age of patients increases. FD value in leukoplakia with different tobacco products showed more positive correlation with surti/khaini abusers. CONCLUSION: Fractal dimension analysis is a useful method in determination of complication in OL cases and can be used as an effective, noninvasive screening tool at primary healthcare centers for early intervention.

Celecoxib reduces Deoxynivalenol induced proliferation, inflammation and protein kinase C translocation via modulating downstream targets in mouse skin.

Exposure to mycotoxins is mostly by ingestion but also occurs by the dermal and inhalation routes. The present study for the first time demonstrated that mycotoxin Deoxynivalenol (DON), permeates through Swiss albino mice skin, which demands awareness of health risks in people who are dermally exposed to mycotoxins especially agricultural farmers. Despite the widespread contamination of DON in food commodities studies to alleviate DON's toxicity are sparsely reported. Thus effective measures to combat mycotoxins associated toxicity remains an imperative aspect to be considered from the angle of dermal exposure. Topical application of Celecoxib (1-2 mg), followed by DON (100 µg) application on the dorsal side of mice, resulted in substantial decrease in DON-induced (i) edema, hyperplasia, cell proliferation (ii) inhibition of cytokine and prostaglandin-E2 levels (iii) phosphorylation of ERK1/2, JNK, p38, MAPKKs, CREB, P90-RSK (iv) downregulation of c-Jun, c- Fos, phospho-NF-kB and their downstream target proteins cyclin D1 and COX-2. Using Ro-31-8220 (Protein-Kinase-C inhibitor), it was observed PKC was responsible for DON induced upregulation of COX-2 and iNOS proteins. Treatment of Celecoxib decreased DON-induced translocation of Protein Kinase C isozymes (α,ε,γ), demonstrating the role of PKC in DON-mediated biochemical and molecular alterations responsible for its dermal toxicity. The present findings indicate that topical application of celecoxib is effective in the management of inflammatory skin disorders induced by foodborne fungal toxin DON. The skin permeation potential of Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor NSAID, was also assessed, and the results indicated that the permeation was relatively lower as compared to the oral mode of administration. Hence topical use of celecoxib may be preferred over oral dosing because of lower systemic absorption and to avoid the unwanted side effects. This study provides a prospect for exploring the clinical efficacy of topically applied COX-2 inhibitors for the management of inflammatory skin disorders induced by foodborne fungal toxins.

Emodin inhibited NADPH-quinone reductase via competitive mode of inhibition and induced cytotoxicity in rat primary hepatocytes.

Consumption of Cassia occidentalis (CO) seeds, a ubiquitously distributed weed plant, is responsible for a pathological condition known as hepato-myo-encephalopathy (HME). The toxicity of CO seeds is largely attributed to the presence of anthraquinones. Here, we report that Emodin, a CO anthraquinone, inhibits the enzymatic activity of NADPH-Quinone reductase, which is an intracellular enzyme fundamentally involved in the detoxification of quinone containing compounds. Emodin binds to the active site of the enzyme and acts as a competitive inhibitor with respect to 2, 6-Dichlorophenolindophenol, a known substrate of NADPH-Quinone reductase. Moreover, our in-vitro study further revealed that Emodin was cytotoxic to primary rat hepatocytes.

Occurrence and toxicity of a fusarium mycotoxin, zearalenone.

Zearalenone (ZEA) is a mycotoxin produced by the fungi of Fusarium genera, which contaminates the cereals and food stuffs worldwide. Fusarium mycotoxins are considered as important metabolites related to animal and human health. Evidences indicate that ZEA has been found to be present in different food stuffs from developed countries like USA, Canada, France, Germany, Japan, etc. and developing nations like Egypt, Thailand, Iran, Croatia, Philippines, etc. The toxicokinetic studies reveal that following oral exposure of ZEA, the compound is absorbed through gastrointestinal tract (GIT), gets metabolized and distributed to different body parts. ZEA has been shown to cause reproductive disorders in laboratory animals. Although the toxicity of ZEA in humans have not been conclusively established nonetheless, limited evidences indicate that ZEA can cause hyper estrogenic syndrome. Though, ZEA causes low acute toxicity, but reports are available confirming the systemic toxicity caused by ZEA. There is no review available that addresses the occurrence, systemic toxicity and the probable mechanisms of ZEA toxicity. This review shall address the world-wide occurrence and in vivo & in vitro toxicity studies of ZEA over the past 20 years. The review shall also discuss the toxicokinetics of ZEA and metabolites; illustrates the systemic toxicity and probable mechanisms of action leading to the risk associated with ZEA.

Theoretical calculation of the buoyancy force on a particle in flowing granular mixtures.

Simulations and experiments of granular mixtures comprising two different sizes flowing over an inclined plane under the influence of gravity show segregation, where large particles rise to the free surface. The segregation results from differential forces acting on the particles. The buoyancy force experienced by the particles is an important component of the total force acting on the particles and, in this work, we theoretically calculate the buoyant force on intruder particles of different sizes in a flowing granular medium. The effective particle volume for buoyancy force calculation is obtained as the partial molar volume of the large particle from the equation of state for a binary mixture of hard spheres. The theoretical results are in good agreement with results obtained from discrete element method (DEM) simulations. Our calculations show that the buoyancy force on a particle is always smaller than the weight of the particle for larger particles. The ratio of the buoyancy force to the weight of the large particles decreases with increasing size ratio and increases with increasing concentration of the particles. This ratio approaches unity in the limiting cases of size ratio and large particle concentration approaching unity. These theoretical calculations establish a method for obtaining the buoyancy force experienced by particles in flowing mixtures.

Correction to: Bisphenol-A Mediated Inhibition of Hippocampal Neurogenesis Attenuated by Curcumin via Canonical Wnt Pathway.

Correction to be published. The authors regret that inadvertent errors were observed in Fig. 3A, 5A&D and 8D. The corrected representative images are now incorporated. These corrections do not change the conclusions, text of the article and figure legends.