Toxicological effects of active and inert ingredients of imazethapyr formulation Verosil® against Scenedesmus vacuolatus (Chlorophyta).

Imazethapyr, a selective systemic herbicide, is widely used in agriculture and it is frequently detected in water bodies close to application areas. Like other agrochemicals, imazethapyr is commercialized in formulations containing a mixture of additives that increase the effectiveness of the active ingredient. These complex mixtures may cause adverse effects on non-target primary producers, such as microalgae, when they reach freshwater bodies. The aim of this study was to assess the effects, separately, of the formulation Verosil®, the formulation additives, and technical-grade imazethapyr, in the acidic form or as ammonium salt, on the microalga Scenedesmus vacuolatus (Chlorophyta). Verosil®, formulation additives, and acid imazethapyr significantly inhibited the growth of S. vacuolatus (Verosil® > formulation additives > acid imazethapyr) and caused morphological alterations from 2 mg L-1, 4 mg L-1, and 60 mg L-1 onwards, respectively. Verosil® and formulation additives caused the most adverse effect including membrane disorganization, cytoplasm contraction, cell wall thickening, thylakoidal membrane disaggregation, and starch granule accumulation. In addition, Verosil® and formulation additives increased the chl a/chl b ratio, indicating possible alterations in photosystems as a stress response. The carotene/chl a ratio was also increased in microalgae exposed to both Verosil® and formulation additives, suggesting an antioxidant response to these toxic compounds. All these results support the hypothesis that the formulation additives contribute significantly to the toxicity and alterations caused by the commercial formulation Verosil® on S. vacuolatus.

Genomic regions associated with herbicide tolerance in a worldwide faba bean (Vicia faba L.) collection.

Weeds represent one of the major constraints for faba bean crop. The identification of molecular markers associated with key genes imparting tolerance to herbicides can facilitate and fasten the efficient and effective development of herbicide tolerant cultivars. We phenotyped 140 faba bean genotypes in three open field experiments at two locations in Lebanon and Morocco against three herbicide treatments (T1 metribuzin 250 g ai/ha; T2 imazethapyr 75 g ai/ha; T3 untreated) and one in greenhouse where T1 and T3 were applied. The same set was genotyped using genotyping by sequencing (GBS) which yield 10,794 high quality single nucleotide polymorphisms (SNPs). ADMIXTURE software was used to infer the population structure which revealed two ancestral subpopulations. To identify SNPs associated with phenological and yield related traits under herbicide treatments, Single-trait (ST) and Multi-trait (MT) Genome Wide Association Studies (GWAS) were fitted using GEMMA software, showing 10 and 14 highly significant associations, respectively. Genomic sequences containing herbicide tolerance associated SNPs were aligned against the NCBI database using BLASTX tool using default parameters to annotate candidate genes underlying the causal variants. SNPs from acidic endochitinase, LRR receptor-like serine/threonine-protein kinase RCH1, probable serine/threonine-protein kinase NAK, malate dehydrogenase, photosystem I core protein PsaA and MYB-related protein P-like were significantly associated with herbicide tolerance traits.

Modeling, Synthesis, and Biological Evaluation of Potential Retinoid-X-Receptor (RXR) Selective Agonists: Analogs of 4-[1-(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahyro-2-naphthyl)ethynyl]benzoic Acid (Bexarotene) and 6-(Ethyl(4-isobutoxy-3-isopropylphenyl)amino)nicotinic Acid (NEt-4IB).

Five novel analogs of 6-(ethyl)(4-isobutoxy-3-isopropylphenyl)amino)nicotinic acid-or NEt-4IB-in addition to seven novel analogs of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) were prepared and evaluated for selective retinoid-X-receptor (RXR) agonism alongside bexarotene (1), a FDA-approved drug for cutaneous T-cell lymphoma (CTCL). Bexarotene treatment elicits side-effects by provoking or disrupting other RXR-dependent pathways. Analogs were assessed by the modeling of binding to RXR and then evaluated in a human cell-based RXR-RXR mammalian-2-hybrid (M2H) system as well as a RXRE-controlled transcriptional system. The analogs were also tested in KMT2A-MLLT3 leukemia cells and the EC50 and IC50 values were determined for these compounds. Moreover, the analogs were assessed for activation of LXR in an LXRE system as drivers of ApoE expression and subsequent use as potential therapeutics in neurodegenerative disorders, and the results revealed that these compounds exerted a range of differential LXR-RXR activation and selectivity. Furthermore, several of the novel analogs in this study exhibited reduced RARE cross-signaling, implying RXR selectivity. These results demonstrate that modification of partial agonists such as NEt-4IB and potent rexinoids such as bexarotene can lead to compounds with improved RXR selectivity, decreased cross-signaling of other RXR-dependent nuclear receptors, increased LXRE-heterodimer selectivity, and enhanced anti-proliferative potential in leukemia cell lines compared to therapeutics such as 1.

Towards identifying nicomorphine administration in doping control: synthesis of metabolites.

Aim: Nicomorphine is rapidly metabolized mainly to the biologically active 6-nicotinoyl morphine and morphine. In sport, morphine and nicomorphine use is prohibited whereas codeine use is permitted. Accredited laboratories routinely test for morphine hence must be able to distinguish morphine, as a metabolite of a prohibited substance, from that whose use is permitted. Results: Here we show a relatively simple method to synthesize the nicomorphine metabolites, 3-nicotinoyl and 6-nicotinoyl morphine, and indicate how they may be used to identify nicomorphine administration. Conclusion: This approach should help confirm that it is not codeine, an allowable analgesic in sport, that has been administered.

Two new lanthanide complexes with 5-(Pyrazol-1-yl)nicotinic acid: Structures and their anti-cancer properties.

Two new lanthanide complexes [PrL2(EA)2]NO3 (complex 1) and [SmL2(EA)2]NO3 (complex 2) (H2L = 5-(Pyrazol-1-yl)nicotinic acid, EA = CH3CH2OH) were synthesized. The structures were characterized by single crystal X-ray and elemental analysis. The interaction between the complex and fish sperm DNA(FS-DNA) was monitored using ultraviolet and fluorescence spectroscopy, and the binding constants were determined. Both complexes showed the ability to effectively bind DNA, and the molecular docking technology was used to simulate the binding of the complex and DNA. In addition, through the annexin V-Fluorescein Isothiocyanate(FITC)/ Propidium Iodide (PI) test experiment, tetrazollium [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide(MTT) in vitro test, and cell morphology apoptosis studies, it was shown that the complex can effectively induce HeLa tumor cell apoptosis. Compared with cisplatin and complex, complex 1 shows significant cancer cell inhibition, and we hope that this new type of complex will open up new ways for the next generation of drugs in biomedical applications.

Combination of retinoids and narrow-band ultraviolet B inhibits matrix metalloproteinase 13 expression in HaCaT keratinocytes and a mouse model of psoriasis.

Matrix metalloproteinase13 (MMP13) can be released by keratinocytes and fibroblasts and involved in the pathogenesis of skin disorders. Retinoic acid derivative drugs include tazarotene and acitretin. Tazarotene/acitretin and narrow-band ultraviolet B (NB-UVB) irradiation are common treatment options for psoriasis. However, their impact on MMP13 expression in the context of psoriasis has yet to be determined. The expression of MMP13 was analyzed in patients with psoriasis. The effects of tazarotene/acitretin and NB-UVB on MMP13 expression were also investigated in a mouse model of psoriasis. Human HaCaT keratinocytes were exposed to acitretin or NB-UVB and then assayed for cell proliferation and MMP13 expression levels. We showed that patients with psoriasis had increased levels of MMP13 protein in skin lesions and serum samples. Exposure to acitretin and NB-UVB irradiation alone or in combination led to reduction of cell proliferation and MMP13 expression in HaCaT cells. Consistently, tazarotene treatment or NB-UVB irradiation attenuated imiquimod-induced psoriasis-like dermatitis and decreased MMP13 expression in a mouse model. Based on these from HaCaT keratinocytes cells and animal experiments, we suggest that tazarotene/acitretin and NB-UVB irradiation can inhibit the expression of MMP13 in HaCaT keratinocytes and psoriasis mouse models. Blockade of MMP13 activity may have therapeutic potential in improving symptoms of psoriasis.

Insights into the Role of Transcriptional Gene Silencing in Response to Herbicide-Treatments in Arabidopsis thaliana.

Herbicide resistance is broadly recognized as the adaptive evolution of weed populations to the intense selection pressure imposed by the herbicide applications. Here, we tested whether transcriptional gene silencing (TGS) and RNA-directed DNA Methylation (RdDM) pathways modulate resistance to commonly applied herbicides. Using Arabidopsis thaliana wild-type plants exposed to sublethal doses of glyphosate, imazethapyr, and 2,4-D, we found a partial loss of TGS and increased susceptibility to herbicides in six out of 11 tested TGS/RdDM mutants. Mutation in REPRESSOR OF SILENCING 1 (ROS1), that plays an important role in DNA demethylation, leading to strongly increased susceptibility to all applied herbicides, and imazethapyr in particular. Transcriptomic analysis of the imazethapyr-treated wild type and ros1 plants revealed a relation of the herbicide upregulated genes to chemical stimulus, secondary metabolism, stress condition, flavonoid biosynthesis, and epigenetic processes. Hypersensitivity to imazethapyr of the flavonoid biosynthesis component TRANSPARENT TESTA 4 (TT4) mutant plants strongly suggests that ROS1-dependent accumulation of flavonoids is an important mechanism for herbicide stress response in A. thaliana. In summary, our study shows that herbicide treatment affects transcriptional gene silencing pathways and that misregulation of these pathways makes Arabidopsis plants more sensitive to herbicide treatment.

Novel Derivatives of Nicotinic Acid as Promising Anticancer Agents.

BACKGROUND: Cancer has become the second leading cause of death worldwide. Despite of the availability of significant number of anticancer agents, cancer is still incurable especially at the last stages. Remarkable targets for anticancer research and drug discovery are heterocyclic compounds, and among them, superior effect has been shown by the nitrogen containing compounds than non-nitrogen containing compounds. Nicotinic acid, a nitrogen containing moiety and its derivatives have gained an immense importance in the development of anticancer drugs owing to the wide variety of biological properties displayed by them. OBJECTIVE: The objective of this review is to provide researchers the information about various synthetic approaches used for the synthesis of anticancer drugs of nicotinic acid from 2001 onwards and to reveal their application and importance in the treatment of this dreadful disease. CONCLUSION: As indicated by this review, considerable work has been done in terms of synthesis and investigation of anticancer potential of nicotinamide derivatives. The information provided in this article may be of great value for the researchers seeking to develop efficient anticancer drugs.

MAL-associated methyl nicotinate for topical PDT improvement.

Photosensitization of all tissue in sufficient quantity to generate damage is one of the limiting factors for Photodynamic Therapy (PDT) efficiency. Methyl nicotinate (MN) is a thermogenic and vasodilating substance that facilitates the topical tissue penetration of some compounds. The topical MAL (methyl aminolevulinate) PDT is commonly used as a precursor of protoporphyrin IX (PpIX). This study investigates the safety of topical use in NM, as well as its ability to improve the efficiency of topical PDT. For this, we investigate the cytotoxicity of MN, as well as its actions in increasing cellular metabolism and vasodilation. Besides, its ability to optimize the formation of PpIX in the tissue when associated with MAL cream was investigated, besides assessing the severity of necrosis obtained by treatments. The cytotoxicity of MN was tested for concentrations of 0, 0.1, 0.25, 0.5, 0.75 and 1% in cell culture. For the concentration of 0.5%, the cellular metabolism was evaluated using confocal microscopy to calculate the redox rate. In the Chorioallantoic Membrane Model, vasodilation was evaluated for concentrations of 0.5 and 1% MN during 1 h of incubation. In the animal model, the healthy skin of Wistar rat was used to evaluate the production of PpIX in the tissue and the degree of necrosis obtained by Photodynamic therapy when using NM associated with methyl aminolevulinate. It was observed the non-cytotoxicity in vitro of MN in the concentration used (0.5%) and its ability to increase cellular metabolism. In a chorioallantoic model, the MN vasodilation power was demonstrated for different caliber of vessels. In vivo studies are showing that the incorporation of MN in the MAL cream increases the amount of PpIX produced in the tissue causing a higher effect on the epidermis after PDT. This improvement of the protocol may make the procedure more effective both in the destruction of tumor tissue and in the treatment of deeper cells decreasing possible recurrence, in addition to allowing improvements in the protocol, such as reducing the cream's incubation time.

TRPM8: A Therapeutic Target for Neuroinflammatory Symptoms Induced by Severe Dry Eye Disease.

Dry eye disease (DED) is commonly associated with ocular surface inflammation and pain. In this study, we evaluated the effectiveness of repeated instillations of transient receptor potential melastatin 8 (TRPM8) ion channel antagonist M8-B on a mouse model of severe DED induced by the excision of extra-orbital lacrimal and Harderian glands. M8-B was topically administered twice a day from day 7 until day 21 after surgery. Cold and mechanical corneal sensitivities and spontaneous ocular pain were monitored at day 21. Ongoing and cold-evoked ciliary nerve activities were next evaluated by electrophysiological multi-unit extracellular recording. Corneal inflammation and expression of genes related to neuropathic pain and inflammation were assessed in the trigeminal ganglion. We found that DED mice developed a cold allodynia consistent with higher TRPM8 mRNA expression in the trigeminal ganglion (TG). Chronic M8-B instillations markedly reversed both the corneal mechanical allodynia and spontaneous ocular pain commonly associated with persistent DED. M8-B instillations also diminished the sustained spontaneous and cold-evoked ciliary nerve activities observed in DED mice as well as inflammation in the cornea and TG. Overall, our study provides new insight into the effectiveness of TRPM8 blockade for alleviating corneal pain syndrome associated with severe DED, opening a new avenue for ocular pain management.

Exploration of Structure-Activity Relationship of Aromatic Aldehydes Bearing Pyridinylmethoxy-Methyl Esters as Novel Antisickling Agents.

Aromatic aldehydes elicit their antisickling effects primarily by increasing the affinity of hemoglobin (Hb) for oxygen (O2). However, challenges related to weak potency and poor pharmacokinetic properties have hampered their development to treat sickle cell disease (SCD). Herein, we report our efforts to enhance the pharmacological profile of our previously reported compounds. These compounds showed enhanced effects on Hb modification, Hb-O2 affinity, and sickling inhibition, with sustained pharmacological effects in vitro. Importantly, some compounds exhibited unusually high antisickling activity despite moderate effects on the Hb-O2 affinity, which we attribute to an O2-independent antisickling activity, in addition to the O2-dependent activity. Structural studies are consistent with our hypothesis, which revealed the compounds interacting strongly with the polymer-stabilizing αF-helix could potentially weaken the polymer. In vivo studies with wild-type mice demonstrated significant pharmacologic effects. Our structure-based efforts have identified promising leads to be developed as novel therapeutic agents for SCD.

Ser-653-Asn substitution in the acetohydroxyacid synthase gene confers resistance in weedy rice to imidazolinone herbicides in Malaysia.

The continuous and sole dependence on imidazolinone (IMI) herbicides for weedy rice control has led to the evolution of herbicide resistance in weedy rice populations across various countries growing IMI herbicide-resistant rice (IMI-rice), including Malaysia. A comprehensive study was conducted to elucidate occurrence, level, and mechanisms endowing resistance to IMI herbicides in putative resistant (R) weedy rice populations collected from three local Malaysian IMI-rice fields. Seed bioassay and whole-plant dose-response experiments were conducted using commercial IMI herbicides. Based on the resistance index (RI) quantification in both experiments, the cross-resistance pattern of R and susceptible (S) weedy rice populations and control rice varieties (IMI-rice variety MR220CL2 and non-IMI-rice variety MR219) to imazapic and imazapyr was determined. A molecular investigation was carried out by comparing the acetohydroxyacid synthase (AHAS) gene sequences of the R and S populations and the MR220CL2 and MR219 varieties. The AHAS gene sequences of R weedy rice were identical to those of MR220CL2, exhibiting a Ser-653-Asn substitution, which was absent in MR219 and S plants. In vitro assays were conducted using analytical grade IMI herbicides of imazapic (99.3%) and imazapyr (99.6%) at seven different concentrations. The results demonstrated that the AHAS enzyme extracted from the R populations and MR220CL2 was less sensitive to IMI herbicides than that from S and MR219, further supporting that IMI herbicide resistance was conferred by target-site mutation. In conclusion, IMI resistance in the selected populations of Malaysian weedy rice could be attributed to a Ser-653-Asn mutation that reduced the sensitivity of the target site to IMI herbicides. To our knowledge, this study is the first to show the resistance mechanism in weedy rice from Malaysian rice fields.

Responses of soil microbial biomass and enzyme activity to herbicides imazethapyr and flumioxazin.

The use of herbicides is important for controlling weeds in crops. However, they can present impacts on soil properties, such as biological properties. In this study, we evaluated the responses of soil microbial biomass and enzymes activity to the application of the herbicides imazethapyr and flumioxazin and their mixture in an experiment under laboratory conditions, using soils with a different history of use. Soil microbial biomass C (MBC) decreased, while microbial biomass N (MBN) was not affected after the application of the herbicides as compared to the control. Soil respiration, respiratory quotient, and dehydrogenase (DHA) activity increased significantly after the application of the herbicides compared to the control. The hydrolysis of fluorescein diacetate (FDA) was not significantly different between the control and the herbicide treatments. The principal response curve showed the largest initial effects for the flumioxazin, followed by imazethapyr and their mixture. Flumioxazin had a different influence on soil respiration and respiratory quotient than imazethapyr and their mixture. Finally, the effects of herbicides on soil microbial biomass and enzymes are short-term as we observed recovery in the biological parameters over time.

Tazarotene-loaded in situ gels for potential management of psoriasis: biocompatibility, anti-inflammatory and analgesic effect.

Psoriasis is a chronic autoinflammatory disorder characterized by patches of abnormal skin. For psoriasis management, the application of topical retinoids as Tazarotene is recommended. However, Tazarotene could induce skin irritation limiting its use. Herein, it is evaluated the possible usage of in situ gels for tazarotene skin delivery. The topical in situ gels were developed using thermosensitive poloxamers via cold method. They were examined for their appearance, sol-gel temperature, clarity, pH, viscosity, in vitro release, and stability. Their biocompatibility was evaluated by investigating their cytotoxicity and irritation inducing capacity. The possible anti-inflammatory and analgesic activities were determined by measuring the nitric oxide and prostaglandin E2 levels production in LPS-stimulated RAW264.7 murine macrophage cells. It was revealed that the in situ gels had no cytotoxic effect (∼95-100% cell viability) and nor irritation potential (∼97% cell viability), according to the in vitro EpiDerm™ reconstituted skin irritation test. Additionally, the 10% tazarotene-in situ gels showed possible analgesic activity since the production of prostaglandin E2 (PGE2) was decreased. In further, both concentrations of 5% and 10% tazarotene-in situ gels inhibited significantly the nitrite oxide production at 16% and 19%, respectively. Finally, the prepared in situ gels can act as a potential non-irritant alternative option for tazarotene topical skin delivery.

Selective RAR agonists for acne vulgaris: A narrative review.

BACKGROUND: Acne vulgaris is a chronic disfiguring inflammatory disease of adolescents and adults affecting up to 90% of the population around the world. The sequence of etiopathogenesis in acne is not completely understood but involves abnormalities in sebum production, follicular plugging, proliferation of propionibacterium acnes, and chronic inflammation. AIMS: This review aims to summarize the features of the topical selective RAR agonists in treating acne vulgaris with a special emphasis on the 4th generation topical retinoid trifarotene. METHODS: Studies were identified by searching electronic databases (MEDLINE and PubMed) till August 2019 and reference lists of respective articles. Only articles published in English language were included. RESULTS: Topical retinoids have been first line of treatment for more than 30 years now in treating mild to moderate acne vulgaris. Third generation retinoids like adapalene and tazarotene are selective RAR and γ agonists, having an additional anti-inflammatory action along with their comedolytic effects and work well in combinations with topical antibiotics, due to the stability of chemical composition. CONCLUSION: Trifarotene is a new 4th generation retinoid with selective action on RAR-γ receptor alone, which is specific for skin, and it is safe for long-term maintenance therapy with good efficacy and tolerability.

Comparative study of antibacterial activity between Schiff base nicotinic hydrazide derivative and its silver architected nanoparticles with atomic force microscopic study of bacterial cell wall.

The threat of multi-drug resistant bacterial pathogens evokes researchers to synthesized safe and effective chemotherapeutic agents for nano-drug delivery system. In current study, Schiff base of nicotinic hydrazide(NHD) and its silver nanoparticles(NHD-AgNPs) were synthesized and characterized. These compounds were investigated for cytotoxicity, antibacterial and AFM activity. The NHD showed LD50 at >1000µg/mL while NHD-AgNPs didn't exhibit toxicity at 1000µg/mL against 3T3 cell line. The NHD showed zone of inhibition against two strains of salmonella enteric (ATCC 14028 and 700408) 45.29±1.66 and 48.01±1.43mm respectively at 160µg/mL (p<0.01) while NHD-AgNPs exhibited 55.87±2.08 and 52.88±1.42 mm respectively at 130µg/mL (p<0.001) in disc diffusion method. NHD showed more than 70% growth inhibition for both strains at 85 and 125µg/ml (p<0.01) respectively, while NHD-AgNPs inhibit 80% and 75% respectively at 75 and 125 µg/ml (p<0.01, p<0.001) against Alamar blue antibacterial assay. For morphological changes in bacterial cell wall NHD and NHD-AgNPs treated bacterial cells were observed under atomic force microscope(AFM) and treated bacterial cells were severely damaged with leaked cytoplasmic contents as compare to untreated bacterial cell. These results validate that NHD-AgNPs were highly active as compared to NHD against both strains at their MIC concentrations. In future, comparative wound healing potential will be emphasized.

The third-generation retinoid adapalene triggered DNA damage to induce S-phase arrest in HaCat cells.

Epidermal proliferative diseases consisted of a series of common skin diseases, most of which were recurrent chronic skin diseases, and had greatly negative influence on the life quality of patient. Retinoids exhibited vital roles in the treatment of many skin diseases. Our recent study demonstrated that adapalene significantly inhibited the growth of HaCat cells, and the inhibitory activity was stronger than other retinoids, such as all-trans-retinoic acid, acitretin, isotretinoin, tazarotene, and bexarotene. Further study showed that adapalene suppressed the colony formation of HaCat cells, and it dramatically triggered S-phase arrest and apoptosis, rather than G1 phase arrest which was reported in other retinoids in several studies. Additionally, adapalene treatment greatly upregulated the protein expression of DNA damage marker γ-H2AX, which was in accord with the results of the elongation of tail moment by comet electrophoresis analysis. Moreover, DNA damage was triggered and DNA repair was suppressed synchronously with adapalene treatment, which accounted for the mechanism of S-phase arrest induced by adapalene. In summary, our recent work demonstrated that adapalene showed strong anti-proliferation activity in HaCat cells and could be an alternative agent for the epidermal proliferative disease.

Skin blood flow response to topically applied methyl nicotinate: Possible mechanisms.

BACKGROUND: Methyl nicotinate (MN) induces a local cutaneous erythema in the skin and may be valuable as a local provocation in the assessment of microcirculation and skin viability. The mechanisms through which MN mediates its vascular effect are not fully known. The aim of this study was to characterize the vasodilatory effects of topically applied MN and to study the involvement of nitric oxide (NO), local sensory nerves, and prostaglandin-mediated pathways. METHODS: MN was applied on the skin of healthy subjects in which NO-mediated (L-NMMA), nerve-mediated (lidocaine/prilocaine), and cyclooxygenase-mediated (NSAID) pathways were selectively inhibited. Microvascular responses in the skin were measured using laser speckle contrast imaging (LSCI). RESULTS: NSAID reduced the MN-induced perfusion increase with 82% (P < .01), whereas lidocaine/prilocaine reduced it with 32% (P < .01). L-NMMA did not affect the microvascular response to MN. CONCLUSION: The prostaglandin pathway and local sensory nerves are involved in the vasodilatory actions of MN in the skin.

The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells.

STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented. In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

Tazarotene Released from Aligned Electrospun Membrane Facilitates Cutaneous Wound Healing by Promoting Angiogenesis.

Wound treatment is a long-lasting clinical issue. Poor angiogenesis leading to delayed wound closure causes huge challenges for healing. Functional electrospun membranes have been established as an efficient strategy to promote wound recovery by protecting and improving vascular regeneration. Here, we aimed to investigate the effect of tazarotene, an active drug for angiogenesis, loaded in aligned electrospun nanofibrous barrier on a soft tissue wound. This aligned membrane was arranged in a single direction, and tazarotene could be released from its nanofibers sustainably. The in vitro study demonstrated that compared with the random drug-loaded or other control groups, the aligned tazarotene-loaded membranes [poly-caprolactone (PCL)/AT] could stimulate proliferation, migration, angiogenesis, and vascular endothelial growth factor secretion and its gene expression of human umbilical vein endothelial cells. Furthermore, the in vivo model showed that the prepared tazarotene-loaded aligned membrane significantly accelerated the speed of healing, improved the neovascularization and re-epithelialization, and inhibited the inflammatory reaction in the wound area. All these results above indicated that the PCL/AT nanofibrous dressing, which could promote angiogenesis because of both stimulation of structure and chemical signals, is a promising wound-caring material.