Analogue Of Vitamin Research Articles

694 DRUG INDUCED KIDNEY INFARCTION: A CASE REPORT

Abstract Isotretinoin (ISO) is a synthetic analog of vitamin A. Notwithstanding the well-known long-term efficacy in the treatment of severe resistant cystic acne, ISO induces several side effects too. Dyslipidemia, increased liver enzymes, as well as reduction of biotidinase have been already reported [1]. Homocysteine (HCY), a sulfur-containing amino acid, is recycled into methionine by a transmethylation reaction requiring folate and vitamin B12. Given that during ISO treatment elevated liver enzymes (SGOT, SGPT) are often observed, it has been hypothesized that iatrogenic liver dysfunction could affect cystathionine-b-synthase, an enzyme involved in HCY metabolism, [2]. Several studies have highlighted that elevated plasma HCY concentrations are associated with an increased risk of premature occlusive vascular disease. We hereby report a case of drug-induced kidney infarction after ISO therapy. A previously healthy 18-year-old male, on therapy with 40 mg/die isotretinoin for acne, was admitted to the Emergency Unit for abdominal pain, nausea and vomiting and dyspnea. A trans-thoracic echocardiogram showed dilated and hypocontractile left ventricle. During the hospitalization he had a total body CT that showed the presence of an ischemic lesion on left kidney without other pathological findings. He started therapy with 12 IU/kg UFH as soon as a surgical emergency was excluded. Subsequently, he underwent a coronary angiogram that resulted unremarkable. Cardiac MRI showed extensive delayed gadolinium late enhancement with intramural linear pattern. In the hypothesis of drug-induced vasculitis, an extensive serological testing was performed. Elevation of serum liver enzymes (SGOT, SGPT), CRP, LDH was found. Mutations on MTHFR gene and Leiden Factor were not detected, neither alteration in coagulation parameters. Finally the dosage of plasmatic HCY resulted over the range of normality and ISO was discontinued. The patient was discharged on optimized medical therapy for heart failure. He is currently managed as outpatient. HCY levels could be found elevated in patients with ischemic events during ISO treatment. Given the widespread use of this drug for acne, it could be reasonable to dose HCY in patients with suspected liver dysfunction. Physicians should be aware of this scenario and should act swiftly to avoid uneventful outcomes. [1] Schulpis KH et al. Elevated plasma homocysteine levels in patients on isotretinoin therapy for cystic acne. Int J Dermatol. 2001 Jan;40(1):33-6. [2] Polat M, et al. Plasma homocysteine level is elevated in patients on isotretinoin therapy for cystic acne: a prospective controlled study. J Dermatolog Treat. 2008;19(4):229-32.

Abstract B081: Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells

Abstract The knowledge of immunomodulatory and reparative properties of Mesenchymal Stem cells (MSCs) are rapidly advancing and could be best suited as a therapeutic option for inflammatory or adverse immunological conditions such as cancer. In the last decade, Mesenchymal stem cells have attracted significant attention because of their accessibility, tumor-oriented homing capacity and the transplantation feasibility. Until date, MSC-based therapy for pancreatic cancer has not been demonstrated. As per the current understanding of the potentials of MSCs in regenerative medicine, we hypothesized their inhibitory influence on pancreatic cancer cells. For experimentation purposes, we have used human Wharton’s jelly derived MSCs (hWJ-MSCs) and pancreatic cell line models. Our findings show that secretion of soluble biologically active factors from hWJ-MSCs (secretome) had a greater impact on induction of anergy and apoptosis of pancreatic tumor cells. The mechanistic approach directed to influence the tumor microenvironment appear to be two pronged: one, via modulation of tumor glycoproteins (MUC-1 and EpCAM) and second, via GSK3β/Stat3/HIF1-α axis. Treatment with calcitriol, an analogue of Vitamin D known to regulate cell cycle, cell differentiation ca also reduce side effects of chemo-drugs, one of the mainstay of therapy in pancreatic cancer. Yet, the potential mechanism to exert anti-cancer effect remains underexplored. We attempted to elicit the involvement of VitD in one of the crucial stem-cell related embryonic pathway, the Sonic Hedgehog (SHH) pathway. Our data showed enhanced apoptosis of calcitirol treated-pCSCs cells when treated with salinomycin (SHH inhibitor). Further combinatorial treatment with secretome + VitD decreased copy numbers of transcription factors C-myc, SMO, PTCH1, PTCH2, and hypoxia-induced factor (HIF1-α) demonstrating the potential mechanism of action. In conclusion, our experimental evidence postulates a potential mechanism by which VitD-analogue regulate sHH-mTOR axis and in combination with mesenchymal stem cell secretome can affect the proliferation and migratory (oncogenic) capabilities of pancreatic cancer stem cells. So, what next? Do we have the evidence to suggest secretome as a novel cell-free therapeutic candidate!! Citation Format: Sangeeta Choudhury, Neha Chopra, Kriti Jain, Poonam Yadav, Surinder P. Singh, Yashika Charla. Synergistic paracrine action of Vitamin D and mesenchymal stem cell secretome in targeting pancreatic cancer stem cells [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B081.

Abstract 15024: High Concentration Mineral Oil, Corn Oil and Their Constitutive Fatty Acids Do Not Influence Low-Density Lipoprotein (LDL) Oxidation Rates in vitro

Introduction: LDL transports dietary long chain fatty acids, constituents that may influence rates of lipid oxidation. Modified LDL promotes foam cell formation during atherosclerosis. The omega-3 fatty acid (n3-FA) eicosapentaenoic acid (EPA) administered as icosapent ethyl (IPE), reduced cardiovascular events in REDUCE-IT compared to mixed n3-FAs in similar high-risk patients (STRENGTH). Some have attributed these discordant outcomes, in part, to placebo choice (mineral versus corn oil) despite very limited oral absorption. We compared the effects of these oils and various FAs on rates of LDL oxidation at supra-pharmacologic doses. Methods: LDL was isolated from human plasma by isopycnic centrifugation, separated into test samples of 100 μg/mL before being incubated at 37°C for 30 min with pharmaceutical grade mineral or corn oil at high concentrations (100 μg/mL) that are comparable to treatment achieved n3-FAs (4 g/d) that have high oral absorption. We also tested FAs contained in these oils, including stearic acid (18:0), arachidic acid (20:0), and linoleic acid (18:2, n-6) as well as ascorbic acid (10 μM) and a water-soluble analog of vitamin E (Trolox, 10 μM) as controls. All samples then underwent copper-induced oxidation (20 μM) monitored by formation of malondialdehyde (MDA). Results: MDA formation increased from 0.28 ± 0.03 to 9.96 ± 0.58 μM ( p <0.001) with vehicle treatment from 0-2 h. Addition of either mineral or corn oil at 100 μg/mL did not significantly influence rates of MDA formation at 2 h (0.02% and 1.93% change vs vehicle, respectively). Nor did we observe any antioxidant activity with constituent FAs stearic acid, arachidic acid, or linoleic acid, FAs with no or two double bonds. As antioxidant controls, ascorbic acid and Trolox both reduced LDL oxidation by 93% and 94% (0.71 ± 0.11 and 0.62 ± 0.04 to 9.96 ± 0.58 μM, p <0.001) after 2 h. Conclusions: Neither mineral nor corn oils affected LDL oxidation even at supra-pharmacologic concentrations. Beyond poor oral absorption, mineral oil and its constituent fatty acids did not affect LDL oxidation, a property related to mechanisms of atherosclerosis.

CD437 increases the iron uptake by metastatic melanoma cells

Background. CD437, an analog of vitamin A, is an agonist of the retinoic acid γ-receptor (RARγ). CD437 is also known to cause p53-independent DNA damage by a mechanism independent of the RAR-mediated pathway. In cancer patients, iron deficiency is constantly detect, the delivery of iron to tissues is also destroyed.Aim. To study the effect of CD437 on iron metabolism in metastatic melanoma cells, Mel Z.Materials and methods. In this study 2D cultivation of metastatic Mel Z melanoma cells, phase-contrast and fluorescence microscopy, flow cytofluorimetry were used.Results. In control cells without the addition of CD437 CD71, transferrin receptor, expressed 40 ± 4 % (p <0.05) of Mel Z cells, in the presence of CD437 CD71 expression increased to 80 ± 6 %. Next, we have studied the expression of ferritin. Iron, which is not involved in cell metabolism, is bound by ferritin. In control experiments, ferritin was expressed by 84 ± 6 % (p <0.05) of cells. When the cells grew in the presence of CD437, ferritin was expressed by all the cells (100 %, p <0.05). Such a scenario indicates that CD437 may contribute to the accumulation of free, unbound iron in the cell, which can induce ferroptosis. In control experiments without the addition of CD437, the level of membranes lipid peroxidation, an indicator of ferroptosis, was insignificant. Lipid peroxidation induced by CD437 was 55 ± 5 % (p <0.05) of the fluorescence intensity induced by erastin, positive control.Conclusion. CD437 increases the iron uptake by metastatic melanoma cells. The low level of membranes lipid peroxidation induced by CD437 does not allow it to be considered as an inducer of ferroptosis. Additional investigations are needed to find iron-binding targets alternative to ferritin.

Molecular docking study on vitamin D supplements to understand their interaction with VDR-RXRα heterodimer and VDRE of TAGAP gene

The expression level of T cell activation Rho GTPase activating protein (TAGAP) gene is higher in rheumatoid arthritis (RA) patients compared to healthy individuals. Vitamin D receptor element (VDRE) sequences present in the regulatory region of TAGAP gene are targeted by vitamin D dependent Vitamin D receptor (VDR) - retinoic acid X receptor (RXR) heterodimer complex to regulate the TAGAP gene expression. Reduction in the expression of the TAGAP gene can prevent different severity of RA disease conditions. Calcitriol is a proven vitamin D supplement prescribed to patients with RA. However, it is involved in causing hypercalcemia. Maxacalcitol, an analog of vitamin D, is shown to have less hypercalcemic activity when compared to calcitriol. This study was done to analyze and compare the binding modes of calcitriol and maxacalcitol with VDR. We also studied the interactions of these compounds with the VDR-RXRα heterodimer complex. In addition, the binding of the ligand-activated heterodimer complexes with VDREs of the TAGAP gene was also analyzed to comprehend the binding affinities of calcitriol and maxacalcitol to the gene. The current work utilizes in silico molecular docking and simulation analysis to understand the mechanism in each complex formation. Communicated by Ramaswamy H. Sarma

Diverse synthesis of α-tertiary amines and tertiary alcohols via desymmetric reduction of malonic esters

Amines and alcohols with a fully substituted α-carbon are structures of great value in organic synthesis and drug discovery. While conventional methods towards these motifs often rely on enantioselective carbon-carbon or carbon-heteroatom bond formation reactions, a desymmetric method is developed here by selectively hydrosilylating one of the esters of easily accessible α-substituted α-amino- and -oxymalonic esters. The desymmetrization is enabled by a suite of dinuclear zinc catalysts with pipecolinol-derived tetradentate ligands and can accommodate a diverse panel of heteroatom substituents, including secondary amides, tertiary amines, and ethers of different sizes. The polyfunctionalized reduction products, in return, have provided expeditious approaches to enantioenriched nitrogen- and oxygen-containing molecules, including dipeptides, vitamin analogs, and natural metabolites.

Dihydrotachysterol: a bad choice in the treatment of chronic hypoparathyroidism

Hypoparathyroidism is an endocrine disease caused by damage of the parathyroid glands and characterized by underproduction of parathyroid hormone. This can lead to severe hypocalcemia and its associated complications. The chronic hypoparathyroidism requires lifelong therapy including calcium and vitamin D analogues. The goal of treatment is to maintain the target parameters of phosphorus-calcium metabolism. At the same time, there is a risk of iatrogenic hypercalcemia on the standard therapy, up to the hypercalcemic crisis, often complicated by the acute renal failure. Moreover, chronic hypercalcemia acts as a predisposing factor for nephrolithiasis, nephrocalcinosis, chronic renal failure including pre- and dialysis stages.Dihydrotachysterol is a synthetic analogue of vitamin D, which was previously widely prescribed for hypocalcaemic hypoparathyroidism. In accordance with modern Russian and international guidelines, this drug should not be used in the treatment of chronic hypoparathyroidism. The main features in the metabolism of dihydrotachysterol (long elimination period, lack of feedback regulation of the active metabolites, high biological activity) and a narrow therapeutic window cause the frequent development of hypercalcemia and associated disorders.We present several clinical cases of patients with hypoparathyroidism treated with dihydrotachysterol, which was complicated by severe hypercalcemia and acute renal failure.

A Rare Case of Isotretinoin Syndrome Unintentional Maternal Exposur

Retinoids are synthetic analogs of vitamin A, they have a key role in cellular differentiation and developmental tissue specificity. Accutane (isotretinoin) is widely used to treat cases of cystic and conglobate acne resistant to other forms of therapy [1]. It has been estimated that 40% of pregnancies exposed to isotretinoin progress to spontaneous abortion and 35% develop embryopathy [2], either conotruncal heart defects (tetralogy of Fallot, transposition of the great arteries ...), Central nervous system malformations (hydrocephalus, agenesis of the vermis, hypoplasia of the cerebellum ...), ear defects (anotia, microtia, aplasia of the external auditory canal ...), as well as thymic malformations (aplasia, ectopia, hypoplasia). The risk period mainly concerns the first two months of pregnancy [3]. The present case is of an infant aged 2 months and 9 days with a history of prenatal exposure to isotretinoin, a now preventable clinical condition. He was born with a craniofacial malformation called dolichocephaly associated with bilateral micrognathia. Cardiological examinations revealed complex congenital heart disease with transposition of the great arteries, an anteriorly positioned aorta to the right of the pulmonary artery, and a 10-mm subpulmonary septal defect. Aside from his dysmorphic syndrome, his outcome was unfavorable.

IL7Rα and TSLPR expression on Langerhans cells in response to inflammatory stimulation

Abstract A key component of immune barriers are innate immune cells localized in the epithelium responsible for sensing local signals such as foreign antigens and cytokines. In the skin, specialized antigen presenting cells (APC) known as Langerhans cells (LC) can integrate these signals influencing downstream T cell activation and polarization. Thymic stromal lymphopoietin (TSLP) is a proinflammatory mediator released by keratinocytes that promotes LC to enhance type 2 immune response (Th2). When Th2 response becomes unbalanced, it induces type 2 inflammation as seen in atopic dermatitis. TSLP signaling is regulated by two cell surface receptor chains: TSLP receptor (TSLPR) and IL7Rα. Interestingly, IL7Rα is not commonly expressed in murine conventional APC such as dendritic cells (DC). Our previous findings have shown that IL7Rα expression regulates TSLP sensitivity of splenic DCs (sDC) ex vivo. However, the receptor expression dynamic in tissue resident LC and its biological implications has not yet been elucidated. In this study we enriched LC from healthy mice B6 mice using MACS magnetic beads. Cytokine surface receptors and pospho-STAT5 activation were assessed using flow cytometry. Moreover, topic administration of vitamin analog MC903 will be used to evaluate TSLPR and IL7Rα dynamic. Our current results indicate that IL7Rα is expressed on unstimulated LC contrary to sDC. Furthermore, TSLPR was not differently expressed between LC and sDC. Functional assessment of p-STAT5 ex vivo and the dynamic of these receptors in the context of MC903 treatment in vivo is yet to be measured. Our results suggest that tissue resident APC regulate differently cytokines receptors enabling spatial-temporal regulation of proinflammatory signals. Academy of Finland (IJ: grants: 25013080481 and 25013142041), The Competitive State Research Financing of the Expert Responsibility Area of Fimlab Laboratories (grant X51409 to IJ), Tampere University Hospital Support Foundation (IJ) and Tampere Tuberculosis Foundation (IJ).

The effectiveness of using lipid- and water-soluble analogues of vitamin E as antioxidant protectors for cryopreservation of sperm of sterlet (Acipenser ruthenus) and Russian sturgeon (Acipenser gueldenstaedtii)

The aim of the research was to comparative study the effectiveness of synthetic antioxidants – lipid-soluble (butylated hydroxytoluene, BHT) and water–soluble (trolox) analogues of vitamin E for the cryopreservation of Russian sturgeon and sterlet sperm in the presence of the modified Stein’s medium. The ability of phenolic antioxidants to reduce the level of lipid peroxidation of sturgeon sperm, beneficial effect on the motility of thawed sperm has been shown. The addition of lipid- and water-soluble antioxidants to a basic cryomedim increased the fertilization rate of Russian sturgeon and sterlet sperm cells about 10% compared to the control experiment. The insignificant protective effect of these antioxidants presumably is explained by the use of a cryogenic medium with additive of toxic DMSO, therefore, it is necessary to develop a new composition of the cryo-medium with a minimum concentration of DMSO.

Synthesis and antioxidant activities of benzylic bromophenols inclusive of natural products.

The synthesis of natural products 2-(2,3-dibromo-4,5-dihydroxyphenyl)acetic acid (1) and 2-(2,6-dibromo-3,5-dihydroxyphenyl)acetic acid (2) and as well as their derivatives 25 and 26 were carried out by substitution, hydrolysis and demethylation reactions of the corresponding four benzyl bromides. The antioxidant potentials of benzylic acid-derived bromophenols were, for the first time, appraised by several outstanding bioanalytical methods. Besides these, we estimated the antioxidant effects which were studied using the methods of DPPH·, ABTS•+ scavenging activities, ferric (Fe3+) and cupric (Cu2+) ions and Fe3+-TPTZ reducing capacities. Benzylic acid-derived bromophenols were found as effective DPPH•, and ABTS•+ scavengers. The potential antioxidant activities of bromophenol derivatives 1, 2 and 17-28 were compared to standard antioxidants including BHA, BHT, α-Tocopherol, and Trolox, which is a water-soluble analog of vitamin E. We expect that this innovative work will direct future studies exploring the antioxidant properties of food, medicinal, and industrial applications.

Serum 25-Hydroxy Vitamin D

Background: Acne vulgaris (AV) is a chronic inflammatory disease of the pilosebaceous apparatus. Vitamin D controls the immune system and the proliferation and differentiation of sebocytes and keratinocytes. In addition, it has antioxidant and anti-comedogenic properties. In vitro studies showed that Vitamin D had a functional part in the acne development. Serum Vitamin D levels were previously estimated in AV patients with conflicting results. Objective: To compare 25-hydroxyvitamin D (25[OH] D) serum level in AV patients with healthy controls and to assess the association between 25(OH) D and disease severity to detect any possible role of Vitamin D in AV pathogenesis and treatment. Materials and Methods: 25 (OH) D levels were estimated in 80 AV patients and 40 age- and sex-matched controls using the enzyme-linked immunosorbemt assay technique. Results: 25(OH) D serum levels were significantly lower in patients as compared to controls. Although of no statistical significances, serum 25(OH) D levels were lower in severe and very severe cases than mild and moderate cases. There was significant negative correlation between serum 25(OH) D level and age of onset of AV. However, there were nonsignificant correlations between 25(OH) D blood levels and other patients' characters such as age, sex, occupation, duration of the disease, family history of AV, body mass index, and sites of the lesions. Conclusions: Vitamin D may have a role in the pathogenesis of in AV patients. Further studies on a larger number of patients are recommended to confirm the validity of our results and to evaluate the therapeutic role of Vitamin D supplementation or topical vitamin analogs in acne treatment.

Effects of Menadione on Survival, Feeding, and Tunneling Activity of the Formosan Subterranean Termite.

Simple SummarySubterranean termites are wood-feeding insects that construct foraging tunnels in soil to search for cellulose-based food sources. The Formosan subterranean termite is an invasive species to the United States and one of the most destructive termites in the world. Management of these termites depends on understanding termite behavior and the use of termiticides that are effective, safe, and cost-efficient. Menadione, also known as vitamin K3, is safely used in animal feeds but toxic to some insects due to disruption of energy production by interference with mitochondrial respiration. In this study, we examined how menadione affected the survival, feeding, and tunneling activity of the Formosan subterranean termite. We found that when menadione was applied to food (paper) or tunneling substrate (sand), this compound caused mortality and reduced feeding activity in termites in a dose-dependent manner. When provided with both treated and untreated sand, termites were deterred from tunneling and feeding on the side treated with menadione. Overall, our findings demonstrated strong toxicity and repellency of menadione against the Formosan subterranean termite, suggesting this compound can be potentially used as a termite control agent.The Formosan subterranean termite, Coptotermes formosanus Shiraki, is a highly destructive pest and a cosmopolitan invasive species. Sustainable termite management methods have been improving with the search for novel insecticides that are effective, safe, and cost efficient. Menadione, also known as vitamin K3, is a synthetic analogue and biosynthetic precursor of vitamin K with low mammalian toxicity. Menadione has shown insecticidal activity in several insects, presumably due to interference with mitochondrial oxidative phosphorylation. However, little is known about its effectiveness against termites. In this study, we evaluated the toxicity and repellency of menadione in C. formosanus. Our results showed that menadione affected the survival and feeding activity of termites both in filter paper and substrate (sand) treatments, and menadione influenced termite tunneling activity in treated sand. In a no-choice assay, ≥90% mortality after seven days and minimal or no food consumption were recorded when sand was treated with menadione at 6 to 600 ppm. In a two-choice assay with a combination of treated and untreated sand, termites were deterred by menadione at 6 to 600 ppm and exhibited low mortality (≤30%) over seven days, while tunneling activity was prevented with 60 to 600 ppm of menadione treatment. Overall, our study demonstrated dose-dependent toxicity and repellency of menadione in C. formosanus. The potential use of menadione as an alternative termite control agent is discussed.

1,25-Dihydroxyvitamin D3 and 20-Hydroxyvitamin D3 Upregulate LAIR-1 and Attenuate Collagen Induced Arthritis

Vitamin D plays a crucial role in regulation of the immune response. However, treatment of autoimmune diseases with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] doses sufficient to be effective is prohibitive due to its calcemic and toxic effects. We use the collagen-induced arthritis (CIA) model to analyze the efficacy of the noncalcemic analog of vitamin D, 20S-hydroxyvitamin D3 [20S(OH)D3], as well as 1,25(OH)2D3, to attenuate arthritis and explore a potential mechanism of action. Mice fed a diet deficient in vitamin D developed a more severe arthritis characterized by enhanced secretion of T cell inflammatory cytokines, compared to mice fed a normal diet. The T cell inflammatory cytokines were effectively suppressed, however, by culture of the cells with 20S(OH)D3. Interestingly, one of the consequences of culture with 1,25(OH)2D3 or 20S(OH)D3, was upregulation of the natural inhibitory receptor leukocyte associated immunoglobulin-like receptor-1 (LAIR-1 or CD305). Polyclonal antibodies which activate LAIR-1 were also capable of attenuating arthritis. Moreover, oral therapy with active forms of vitamin D suppressed arthritis in LAIR-1 sufficient DR1 mice, but were ineffective in LAIR-1−/− deficient mice. Taken together, these data show that the effect of vitamin D on inflammation is at least, in part, mediated by LAIR-1 and that non-calcemic 20S(OH)D3 may be a promising therapeutic agent for the treatment of autoimmune diseases such as Rheumatoid Arthritis.

Tunneling in the Hydrogen-Transfer Reaction from a Vitamin E Analog to an Inclusion Complex of 2,2-Diphenyl-1-picrylhydrazyl Radical with β-Cyclodextrin in an Aqueous Buffer Solution at Ambient Temperature.

Recently, increasing attention has been paid to quantum mechanical behavior in biology. In this study, we investigated the involvement of quantum mechanical tunneling in the hydrogen-transfer reaction from Trolox, a water-soluble analog of vitamin E (α-tocopherol), to 2,2-diphenyl-1-picrylhydrazyl radical (DPPH•) in a phosphate buffer solution (0.05 M, pH 7.0). DPPH• was used as a reactivity model of reactive oxygen species and solubilized in water using β-cyclodextrin (β-CD). The second-order rate constants, kH and kD, in 0.05 M phosphate buffer solutions prepared with H2O (pH 7.0) and D2O (pD 7.0), respectively, were determined for the reaction between Trolox and DPPH•, using a stopped-flow technique at various temperatures (283–303 K). Large kinetic isotope effects (KIE, kH/kD) were observed for the hydrogen-transfer reaction from Trolox to the β-CD-solubilized DPPH• in the whole temperature range. The isotopic ratio of the Arrhenius prefactor (AH/AD = 0.003), as well as the isotopic difference in the activation energies (19 kJ mol−1), indicated that quantum mechanical tunneling plays a role in the reaction.

Treatment and Management of Psoriasis: A review

Psoriasis is a common, chronic inflammatory skin disease affecting many people of the world now a days. Psoriasis is principally an immunological T lymphocyte-driven disease, relating both the distinctive and T-cell-mediated immune systems. The mostly affected sites comprise the scalp, extensor surfaces of the knees and elbows, umbilicus, genitalia, anterior lower legs and nails. This disease can significantly impact on a patient's quality of life and is connected co-morbidities comprise psoriatic arthritis, obesity and the metabolic syndrome, diseases of cardiovascular system and liver with fats. Provided treatment is depends on disease severity, quality of life, patient preference, relevant co-morbidities and efficacy of the treatment. Treatment such as topical emollients, tar, analogues of vitamin D and corticosteroids are first line for local/mild disease. Psoriasis cannot be fully cured once it affects a person but can be managed by proper taking care of the skin according to the doctors. Patient counseling can also add benefits in the management of psoriasis.

Reduced infiltration of regulatory T cells in tumours from mice fed daily with gamma-tocotrienol supplementation.

Gamma-tocotrienol (γT3) is an analogue of vitamin E with beneficial effects on the immune system, including immune-modulatory properties. This study reports the immune-modulatory effects of daily supplementation of γT3 on host T helper (Th) and T regulatory cell (Treg ) populations in a syngeneic mouse model of breast cancer. Female BALB/c mice were fed with either γT3 or vehicle (soy oil) for 2weeks via oral gavage before they were inoculated with syngeneic 4T1 mouse mammary cancer cells (4T1 cells). Supplementation continued until the mice were euthanized. Mice (n=6) were euthanized at specified time-points for various analysis (blood leucocyte, cytokine production and immunohistochemistry). Tumour volume was measured once every 7days. Gene expression studies were carried out on tumour-specific T lymphocytes isolated from splenic cultures. Supplementation with γT3 increased CD4+ (p<0.05), CD8+ (p<0.05) T-cells and natural killer cells (p<0.05) but suppressed Treg cells (p<0.05) in peripheral blood when compared to animals fed with the vehicle. Higher interferon (IFN)-γ and lower transforming growth factor (TGF)-ꞵ levels were noted in the γT3 fed mice. Immunohistochemistry findings revealed higher infiltration of CD4+ cells, increased expression of interleukin-12 receptor-beta-2 (IL-12ꞵ2R), interleukin (IL)-24 and reduced expression of cells that express the forkhead box P3 (FoxP3) in tumours from the γT3-fed animals. Gene expression studies showed the down-regulation of seven prominent genes in splenic CD4+ T cells isolated from γT3-fed mice. Supplementation with γT3 from palm oil-induced T cell-dependent cell-mediated immune responses and suppressed T cells in the tumour microenvironment in a syngeneic mouse model of breast cancer.

Compatibility of a Thermoresponsive and Controlled Release System for Promoting Sinonasal Cilia Regeneration

The current clinical goal for managing chronic rhinosinusitis (CRS), a heterogenous disease of the paranasal sinuses, is to control inflammation, yet adjunct therapies that promote mucosal regeneration can improve the long-term health of the upper airways. The small natural openings to the sinuses, however, limit the efficacy of traditional drug delivery methods (i.e., nasal sprays and irrigation). Accordingly, a conformable thermoresponsive and controlled release system ("TEMPS", Thermogel, Extended-release Microsphere-based delivery to the Paranasal Sinuses) is developed. The poly(lactic-co-glycolic acid) microsphere component enables the encapsulation of numerous therapeutics, such as retinoic acid (RA), an analog of vitamin A (VA). Studies in CRS patients and preclinical models have shown that aqueous RA or VA gels promoted the differentiation of ciliated cells and improved mucosal healing following repeat applications. In the present study, TEMPS is designed for the controlled release of RA such that a single dose of RA-TEMPS delivers bioactive drug for at least 30 days. Furthermore, as TEMPS will be in direct contact with sinonasal tissue, its compatibility with ciliated human nasal epithelium is explored. After ex vivo incubation in thermogel for 24 h, cilia motility is maintained, providing evidence that TEMPS can be compatible for application along the sinonasal epithelium.

The use of tocofersolan as a rescue agent in larval zebrafish exposed to benzo[a]pyrene in early development

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants created by incomplete combustion. Benzo(a)pyrene (BaP), the prototypic PAH, is known to exert toxicity through oxidative stress which is thought to occur through inhibition of antioxidant scavenging systems. The use of agents that reduce oxidative stress may be a valuable route for ameliorating the adverse effects of PAHs on neural development and behavior. This study was conducted to determine if tocofersolan (a synthetic water-soluble analog of vitamin E) supplementation can prevent or reduce neurobehavioral deficits in zebrafish embryos exposed to BaP during early development. Newly hatched zebrafish were assessed on locomotor activity and light responsivity. Zebrafish embryos were exposed to vehicle (DMSO), tocofersolan (0.3 μM–3 μM), and/or BaP (5 μM) from 5−120 hours post-fertilization. This concentration range was below the threshold for producing overt dysmorphogenesis or decreased survival. One day after the end of exposure the larval fish were tested for locomotor activity under alternating light and dark 10 min periods, BaP (5 μM) was found to cause locomotor hypoactivity in larval fish. Co-exposure of tocofersolan (1 μM) restored control-like locomotor function. Based on the findings of this study, this model can be expanded to assess the outcome of vitamin E supplementation on other potential environmental neurotoxicants, and lead to determination if this rescue persists into adulthood.

PPM-18, an Analog of Vitamin K, Induces Autophagy and Apoptosis in Bladder Cancer Cells Through ROS and AMPK Signaling Pathways.

PPM-18, identified as a novel analog of vitamin K, has been reported to play a critical role in the suppression of seizures. However, the concerns that whether PPM-18, like vitamin K, exerts anticancer activity remain to be further investigated. Here, we found that PPM-18 remarkably suppressed the proliferation and induced apoptosis in bladder cancer cells. Furthermore, a significant autophagic effect of PPM-18 on bladder cancer cells was also demonstrated, which profoundly promoted apoptotic cell death. Mechanistically, PPM-18 activated AMP-activated protein kinase (AMPK), whereas it repressed PI3K/AKT and mTORC1 pathways in bladder cancer cells. Inhibition of AMPK markedly relieved PPM-18–induced autophagy and apoptosis, indicating that PPM-18 is able to induce autophagy and apoptosis in bladder cancer cells via AMPK activation. Moreover, reactive oxygen species (ROS) were notably accumulated in PPM-18–treated bladder cancer cells, and treatment with ROS scavengers not only eliminated ROS production but also abrogated AMPK activation, which eventually rescued bladder cancer cells from PPM-18–triggered autophagy and apoptotic cell death. In bladder cancer xenografts, the anticancer activities of PPM-18, including suppressing the growth of tumors and inducing autophagy and apoptosis in tumor cells, were also established. Collectively, this study was the first to demonstrate the anticancer effect of PPM-18 on bladder cancer cells in vitro and in vivo through eliciting autophagy and apoptosis via ROS and AMPK pathways, which might provide new insights into the potential utilization of PPM-18 for future bladder cancer treatment.