Molecular insight into the structural and functional aspects of arene Ru(II) complexes bearing bulky thiourea ligands.

Herein we report four new arene ruthenium(II) complexes [RuII(ηAird et al. (2002)6-p-cymene)(L1)к1(S)Cl2] (C1), [RuII(ηAird et al. (2002)6-benzene)(L1)к1(S)Cl2] (C2) where L1 is N-((2,6-dimethylphenyl)carbamothioyl)benzamide (L1), and [RuII(ηAird et al. (2002)6-p-cymene)(L2)к1(S)Cl2] (C3), [RuII(ηAird et al. (2002)6-benzene)(L2)к1(S)Cl2] (C4) where L2 is N-((2,6-diisopropylphenyl)carbamothioyl)benzamide (L2) which were synthesized and evaluated for biological activity. The monodentate coordination of thione sulphur (S) to ruthenium ion along with two terminal chloride was confirmed by X-Ray diffraction analysis thus revealing a typical "piano-stool" pseudo tetrahedral geometry. DPPH radical scavenging activity showed that ligands were less efficient however on complex formation it showed significant efficacy with C4 showing the highest activity. The ligands and ruthenium complexes exhibited minimal to no cytotoxic effects on HEK cells within the concentration range of 10-300 µM. Evaluating the cytotoxicity against prostate cancer cells (DU145) L1, L2 and C1 displayed more pronounced cytotoxic activity with C1 showing high cytotoxicity against the cancer cells, in comparison to cisplatin indicating its potential for further investigation and analysis. Considering this, compound C1 was used to further study its interaction with BSA using fluorescence spectroscopy and it was found to be 2.64 × 106 M-1. Findings from CD spectroscopy indicate the binding in the helix region which was further confirmed with the molecular docking studies.

Targeting chemokine-receptor mediated molecular signaling by ethnopharmacological approaches.

ETHNOPHARMACOLOGICAL RELEVANCE: Infection and inflammation are critical to global human health status and the goal of current pharmacological interventions intends formulating medications/preventives as a measure to deal with this situation. Chemokines and their cognate receptors are major regulatory molecules in many of these ailments. Natural products have been a keen source to the drug development industry, every year contributing significantly to the growing list of FDA approved drugs. A multiverse of natural resource is employed as a part of curative regimen in folk/traditional/ethnomedicine which can be employed to discover, repurpose, and design potent medications for the diseases of clinical concern. AIM OF THE STUDY: This review aims to systematically document the ethnopharmacologically active agents targeting the infectious-inflammatory diseases through the chemokine-receptor nexus. MATERIALS AND METHODS: Articles related to chemokine/receptor modulating ethnopharmacological anti-inflammatory, anti-infectious natural sources, bioactive compounds, and formulations have been examined with special emphasis on women related diseases. The available literature has been thoroughly scrutinized for the application of traditional medicines in chemokine associated experimental methods, their regulatory outcomes, and pertinence to women's health wherever applicable. Moreover, the potential traditional regimens under clinical trials have been critically assessed. RESULTS: A systematic and comprehensive review on the chemokine-receptor targeting ethnopharmaceutics from the available literature has been provided. The article discusses the implication of traditional medicine in the chemokine system dynamics in diverse infectious-inflammatory disorders such as cardiovascular diseases, allergic diseases, inflammatory diseases, neuroinflammation, and cancer. On this note, critical evaluation of the available data surfaced multiple diseases prevalent in women such as osteoporosis, rheumatoid arthritis, breast cancer, cervical cancer and urinary tract infection. Currently there is no available literature highlighting chemokine-receptor targeting using traditional medicinal approach from women's health perspective. Moreover, despite being potent in vitro and in vivo setups there remains a gap in clinical translation of these formulations, which needs to be strategically and scientifically addressed to pave the way for their successful industrial translation. CONCLUSIONS: The review provides an optimistic global perspective towards the applicability of ethnopharmacology in chemokine-receptor regulated infectious and inflammatory diseases with special emphasis on ailments prevalent in women, consecutively addressing their current status of clinical translation and future directions.

Characterization, Antioxidant, and Antimicrobial Properties of Mulberry Lattices.

In order to find the most advantageous bioactive compounds from mulberry latex for drug development in the near future, this study was conducted to characterize and evaluate antioxidant and antimicrobial properties from four different mulberry lattices (BR-2, S-1, AR-14, and S-146). The characterization of the lattices was performed by scanning electron microscopy with energy-dispersive X-ray spectroscopy, gas chromatography coupled to mass spectroscopy, and Fourier transform infrared spectroscopy. Further, screenings of the antioxidant and antimicrobial potential of selected lattices were performed in vitro using 2,2-diphenyl-1-picrylhydrazyl assay and agar well diffusion methods, respectively. Interestingly, the outcome of the current study revealed that tested mulberry lattices contain a considerable amount of bioactive phytoconstituents, particularly antimicrobial and antioxidant compounds, as revealed by chromatographic analysis. BR-2 latex was found to have significant antioxidant activity (75%) followed by S-146 (64.6%) and AR-14 (52.9%). The maximum antimicrobial activity was found in BR-2 latex compared to other tested latex varieties. The results of this investigation showed that mulberry latex from the BR-2 type may successfully control both bacterial and fungal infections, with the added benefit of having enhanced antioxidant capabilities.

Baicalin functionalized PEI-heparin carbon dots as cancer theranostic agent.

The worldwide prevalence of cancer and its significantly rising risks with age have garnered the attention of nanotechnology for prompt detection and effective therapy with minimal or no adverse effects. In the current study, heparin (HP) polymer derived heteroatom (N, S-) co-doped CDs were synthesized using hydrothermal synthesis method to efficiently deliver natural anticancer compound baicalin (BA). Heparin carbon dots (HCDs) were passivated with polyethylenimine (PEI) to improve its fluorescence quantum yield. The surface passivation of CDs by polycationic PEI polymer not only facilitated loading of BA, but also played a crucial role in the pH-responsive drug delivery. The sustained release of BA (up to 80 %) in mildly acidic pH (5.5 and 6.5) conditions endorsed its drug delivery potential for cancer-specific microenvironments. BA-loaded PHCDs exhibited enhanced anticancer activity as compared to BA/PHCDs indicating the effectiveness of the nanoformulation, Furthermore, the flow cytometry analysis confirmed that BA-PHCDs treated cells were arrested in the G2/M phase of cell cycle and had a higher potential for apoptosis. Bioimaging study demonstrated the excellent cell penetration efficiency of PHCDs with complete cytoplasmic localization. All this evidence comprehensively demonstrates the potency of BA-loaded PHCDs as a nanotheranostic agent for cancer.

Gallate Moiety of Catechin Is Essential for Inhibiting CCL2 Chemokine-Mediated Monocyte Recruitment.

Leukocyte recruitment witnesses an orchestrated complex formation between the chemokines and their molecular partners. CCL2 chemokine that regulates monocyte trafficking is a worthwhile system from the pharmaceutical perspective. In the current study, four major catechins (EC/EGC/ECG/EGCG) were assessed for their inhibitory potential against CCL2-regulated monocyte/macrophage recruitment. Interestingly, catechins with the gallate moiety (ECG/EGCG) could only attenuate the CCL2-induced macrophage migration. These molecules specifically bound to CCL2 on a pocket comprising the N-terminal, ß0-sheets, and ß3-sheets, and the binding affinity of ECGC (Kd = 22 ± 4 µM) is ∼4 times higher than that of the ECG complex (Kd = 85 ± 6 µM). MD simulation analysis evidenced that the molecular specificity/stability of CCL2-catechin complexes is regulated by multiple factors, including stereospecificity, number of hydroxyl groups on the annular ring-B, the positioning of the carbonyl group, and the methylation of the galloyl ring. Further, a significant overlap on the binding surface of CCL2 for EGCG/ECG and receptor interactions as evidenced from NMR data provided the rationale for the observed inhibition of macrophage migration in response to EGCG/ECG binding. In summary, these galloylated epicatechins can be considered as potent protein-protein interaction (PPI) inhibitors that regulate CCL2-directed leukocyte recruitment for resolving inflammatory/immunomodulatory disorders.

Hydroxyl Groups on Annular Ring-B Dictate the Affinities of Flavonol-CCL2 Chemokine Binding Interactions.

Owing to the astounding biological properties, dietary plant flavonoids have received considerable attention toward developing unique supplementary food sources to prevent various ailments. Chemokines are chemotactic proteins involved in leukocyte trafficking through their interactions with G-protein-coupled receptors and cell surface glycosaminoglycans (GAGs). CCL2 chemokine, a foremost member of CC chemokines, is associated with the pathogenesis of various inflammatory infirmities, thus making the CCL2-Receptor (CCR2)/GAG axis a potential pharmacological target. The current study is designed to unravel the structural details of CCL2-flavonol interactions. Molecular interactions between flavonols (kaempferol, quercetin, and myricetin) with human/murine CCL2 orthologs and their monomeric/dimeric variants were systematically investigated using a combination of biophysical approaches. Fluorescence studies have unveiled that flavonols interact with CCL2 orthologs specifically but with differential affinities. The dissociation constants (K d) were in the range of 10-5-10-7 µM. The NMR- and computational docking-based outcomes have strongly suggested that the flavonols interact with CCL2, comprising the N-terminal and ß1- and ß3-sheets. It has also been observed that the number of hydroxyl groups on the annular ring-B imposed a significant cumulative effect on the binding affinities of flavonols for CCL2 chemokine. Further, the binding surface of these flavonols to CCL2 orthologs was observed to be extensively overlapped with that of the receptor/GAG-binding surface, thus suggesting attenuation of CCL2-CCR2/GAG interactions in their presence. Considering the pivotal role of CCL2 during monocyte/macrophage trafficking and the immunomodulatory features of these flavonols, their direct interactions highlight the promising role of flavonols as nutraceuticals.

Molecular insights into kinase mediated signaling pathways of chemokines and their cognate G protein coupled receptors.

Chemokines are small regulatory proteins that play a crucial role in the coordinated migration of cell populations to the site of infection/inflammation by binding to their cognate receptors. In principle, chemokine receptors, which are serpentine G protein-coupled receptors (GPCRs), mediate the series of downstream intracellular signaling events that occur inside the cells to resolve the pathogenicity. Intracellular signaling pathways regulated by the kinase protein sub-families are the center of attention for chemokine derived functional responses. Kinases potentially influence cell migration, cell growth, transcriptional activation, and other essential molecular events. The regulation and flow of the signals by the kinases are different for each physiological and pathological event and are tightly regulated by the nature and pairing of chemokine(s) with its receptor(s). For example, phosphoinositide 3-kinase (PI3K) is activated during the initial steps of the chemokine induced signaling cascade to regulate chemotaxis, transcription, and cell survival. G protein-coupled receptor kinase (GRKs) plays a crucial role in the desensitization and internalization of the chemokine receptors. The regulation of chemokine receptor is also governed by kinases like protein kinase A (PKA), protein kinase C (PKC), mitogen-activated protein kinases / extracellular signal-regulated kinases (MAPK/ERK), etc. It was also established that tyrosine-protein kinases (TECs) such as ITK and RLK play a significant role in chemokine signaling in T lymphocytes. On a similar note, many others like janus kinases (JAKs), Protein kinase B (PKB), PKC, etc. are also studied in chemokine mediated disease models. The present review elucidates the role of different kinases involved in the chemokine/chemokine receptor mediated signaling cascade during various pathophysiological processes.