A Series of Benzylidenes Linked to Hydrazine‐1‐carbothioamide as Tyrosinase Inhibitors: Synthesis,Biological Evaluation and Structure−Activity Relationship

Tyrosinase is a type 3 copper enzyme responsible for skin pigmentation disorders, skin cancer, and enzymatic browning of vegetables and fruits. In the present article, 12 small molecules of 2‐benzylidenehydrazine‐1‐carbothioamide were designed, synthesized and evaluated for their anti‐tyrosinase activities followed by molecular docking and pharmacophore‐based screening. Among synthesized thiosemicarbazone derivatives, one compound, (2E)‐2‐[(4‐nitrophenyl)methylidene]hydrazine‐1‐carbothioamide, is the strongest inhibitor of mushroom tyrosinase with IC₅₀ of 0.05 μM which demonstrated a 128‐fold increase in potency compared to the positive control. Kinetic studies also revealed mix type inhibition by this compound. Docking studies confirmed the complete fitting of the synthesized compounds into the tyrosinase active site. The results underline the potential of 2‐benzylidenehydrazine‐1‐carbothioamides as potent pharmacophore to extend the tyrosinase inhibition in drug discovery.     

Integrative effects of stress- and stress tolerance-inducing elicitors on in vitro bioactive compounds of ajowan [Trachyspermum ammi (L.) Sprague] medicinal plant

Plant Cell, Tissue and Organ Culture (PCTOC) - In the present study, the integrative effects of two sets of stress tolerance-inducing and stress-inducing elicitors, including polyethylene...     

Biostimulants Derived from Moroccan Seaweeds: Seed Germination Metabolomics and Growth Promotion of Tomato Plant

Polysaccharides extracted from seaweeds can function as plant biostimulants. The aim of this study was to assess the effects of Polysaccharide Enriched Extracts (PEEs) obtained from 17 Moroccan seaweeds, on tomato seed germination and plant growth. Three concentrations (0.02, 0.05 and 0.1 mg mL⁻¹) of PEEs were applied to tomato seeds to evaluate their effect on 3 germination parameters: germination percentage (GP), germination speed (GS) and mean germination time (MGT). Metabolomic analysis by GC–MS was subsequently performed on seedlings. In the second experiment, four PEEs concentrations (0.02, 0.05, 0.1 and 0.2 mg mL⁻¹) were used as foliar spray or as soil application to tomato plants. Their growth parameters (number of leaves, shoot length, fresh and dry weight of stem and roots) and biochemical parameters (chlorophyll a and b) were measured. Results indicated a significant increase of GP and GS associated with a significant reduction of MGT of tomato seeds treated with 0.02 mg mL⁻¹ of PEEs obtained from Gigartina sp., Gigartina pistillata, Chondracanthus acicularis, Gelidium crinale, Schizymenia dubyi, Cystoseira. foeniculacea and Fucus spiralis. Similar results were also obtained by application of higher PEEs concentration (0.1 mg mL⁻¹) extracted from Ulva rigida, Codium tomentosum, Codium decorticatum and Bifurcaria bifurcata. Metabolomic analysis on seedlings detected the presence of some metabolites which could possibly be involved in seed germination enhancement or inhibition. The results of the second experiment showed that the same PEEs cited above at the same concentrations enhanced plant dry weight and chlorophyll a content except Gigartina sp., C. foeniculacea and C. decorticatum. Furthermore, soil application of PEEs was more effective in improving plant growth parameters than foliar application. The study shows the potential of PEEs from Moroccan seaweed to be used as biostimulants for a sustainable agriculture.

     

Hybridization of wheat and Aegilops cylindrica: development,karyomorphology, DNA barcoding and salt tolerance of the amphidiploids

The development of salt‐tolerant genotypes is key to a better utilization of salinized irrigated lands. Given the relatively low genetic diversity within the cultivated wheats for salt tolerance, exploring the Aegilops cylindrica's genetic diversity for salt tolerance is thus crucial to breed wheat for saline environments. In the current study, wheat genotypes were hybridized with Ae. cylindrica (a hyper salt-tolerant genotype), and amphidiploid plants were produced using embryo rescue and chromosome doubling techniques. Crossability and cytological examinations of amphidiploids and BC₁ were performed before sequencing the ITS4/5 and trnE/trnF DNAs to explore the phylogenetic relationships of the amphidiploids and their parents. Finally, amphidiploids were assessed for salt tolerance. Only two common wheat cultivars (‘Chinese Spring’ and ‘Roshan’) were crossable with Ae. cylindrica. The resultant intergeneric hybrids possessed 70 chromosomes, and morphologically either were similar to the male parent in ‘Chinese Spring’ × Ae. cylindrica or tended to be intermediate between parents in ‘Roshan’ × Ae. cylindrica. The phylogenetic tree divided the genotypes into two groups, in which Clade I contained Ae. cylindrica and three amphidiploids, and Clade II consisted of female parents and one amphidiploid. Amphidiploids exhibited significantly higher tolerance to salt stress compared to the female parents (wheat cultivars) in terms of a higher dry matter, lower accumulation of Na, higher K, and higher K/Na ratio in their root and leaf tissues. Taken together, the amphiploid plants might contain valuable salt tolerance factors.

     

Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study

The ongoing coronavirus disease 19 (COVID-19) pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host-cell receptor angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate the RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the metastable, prefusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, molecular docking was employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex were analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.     

HPV16-E7 Protein T Cell Epitope Prediction and Global Therapeutic Peptide Vaccine Design Based on Human Leukocyte Antigen Frequency: An In-Silico Study

International Journal of Peptide Research and Therapeutics - Cervical cancer is the second most common leading cause of women's death due to cancer worldwide, about 528,000 patients’...     

Bacterial lipopolysaccharides form procollagen-endotoxin complexes that trigger cartilage inflammation and degeneration: implications for the development of rheumatoid arthritis

Introduction

We have previously reported that bacterial toxins, especially endotoxins such as lipopolysaccharides (LPS), might be important causative agents in the pathogenesis of rheumatoid arthritis (RA) in an in vitro model that simulates the potential effects of residing in damp buildings. Since numerous inflammatory processes are linked with the nuclear factor-κB (NF-κB), we investigated in detail the effects of LPS on the NF-κB pathway and the postulated formation of procollagen-endotoxin complexes.

Methods

An in vitro model of human chondrocytes was used to investigate LPS-mediated inflammatory signaling.

Results

Immunoelectron microscopy revealed that LPS physically interact with collagen type II in the extracellular matrix (ECM) and anti-collagen type II significantly reduced this interaction. BMS-345541 (a specific inhibitor of IκB kinase (IKK)) or wortmannin (a specific inhibitor of phosphatidylinositol 3-kinase (PI-3K)) inhibited the LPS-induced degradation of the ECM and apoptosis in chondrocytes. This effect was completely inhibited by combining BMS-345541 and wortmannin. Furthermore, BMS-345541 and/or wortmannin suppressed the LPS-induced upregulation of catabolic enzymes that mediate ECM degradation (matrix metalloproteinases-9, -13), cyclooxygenase-2 and apoptosis (activated caspase-3). These proteins are regulated by NF-κB, suggesting that the NF-κB and PI-3K pathways are involved in LPS-induced cartilage degradation. The induction of NF-κB correlated with activation of IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 phosphorylation and p65 nuclear translocation. Further upstream, LPS induced the expression of Toll-like receptor 4 (TLR4) and bound with TLR4, indicating that LPS acts through TLR4.

Conclusion

These results suggest that molecular associations between LPS/TLR4/collagen type II in chondrocytes upregulate the NF-κB and PI-3K signaling pathways and activate proinflammatory activity.