New ferrocene integrated amphiphilic guanidines: Synthesis, spectroscopic elucidation, DFT calculation and in vitro α-amylase and α-glucosidase inhibition combined with molecular docking approach.

Three N, N', N″-trisubstituted ferrocenyl guanidines (MG-10, MG-12 and MG-14) were synthesized, characterized by several analytical methods such as FT-IR, 1H and 13C NMR, elemental analysis and UV-visible spectroscopy. These compounds have long chain aliphatic groups therefore their aliphatic nature has been evaluated by determining their critical micelle concentration (CMC). CMC point decreases from 0.036 mM to 0.013 mM with increase in the aliphatic chain length. The quantum mechanical parameters such as the energy of frontier molecular orbitals (EHOMO and ELUMO) and the Mulliken charge distribution on the optimized structures were determined using a DFT/B3LYP method combined with the 6-31G (d,p) basis set in the gas phase. The in vitro antidiabetic activity of synthesized compounds showed that MG-12 has IC50value 23.10 µg/mL against α-amylase while MG-10 has IC50value 27.32 µg/mL against α-glucosidase with the respective standard Acarbose (IC50value 20.12 µg/mL). Theoretical docking analysis demonstrated that MG-10 and MG-12 interacted with α-amylase by 3 types of interaction, including hydrogen bonds, hydrophobic interactions and electrostatic interactions.

Fabrication and prospective applications of graphene oxide-modified nanocomposites for wastewater remediation.

Water bodies have become polluted with heavy metals and hazardous contaminants as a result of fast development. Many strategies have been devised by researchers in order to remove hazardous contaminants from the aquatic environment. Utilizing graphene oxide-based composite materials as efficient adsorbents for waste water treatment, desalination, separation, and purification is gaining attraction nowadays. Some of their defining properties are high mechanical strength, hydrophilicity, remarkable flexibility, ease of synthesis, atomic thickness, and compatibility with other materials. In water treatment, high separation performance and stable graphene-based laminar structures have been the main goals. Magnetic separation is among the methods which received a lot of attention from researchers since it has been shown to be quite effective at removing harmful pollutants from aqueous solution. Graphene oxide-modified nanocomposites have provided optimal performance in water purification. This review article focusses on the fabrication of GO, rGO and MGO nanocomposites as well as the primary characterization tools needed to assess the physiochemical and structural properties of graphene-based nanocomposites. It also discusses the approaches for exploiting graphene oxide (GO), reduced graphene (rGO), and magnetic graphene oxide (MGO) to eliminate contaminants for long-term purification of water. The potential research hurdles for using fabricated MGOs as an adsorbent to remediate water contaminants like hazardous metals, radioactive metal ions, pigments, dyes, and agricultural pollutants are also highlighted.

Assessing the potential biological activities of TiO2 and Cu, Ni and Cr doped TiO2 nanoparticles.

Nanoparticles are like magic bullets and nanomaterials exhibit appealing properties. Their size and morphology can be switched by dopants for certain biological activities. Nanoparticles in combination with certain drugs enhance the antibiotic effects and may be valuable in combating bacterial resistance. The antimicrobial potency of nanoparticles depends upon their ability to bind to the surface of microbial cell membranes resulting in modulation of basic cell functions such as respiration. We report herein the antibacterial, antifungal and antioxidant activities of pure TiO2 and TiO2 doped with 4% Cu, Ni and Cr. The performance of pure and doped nanoparticles has been compared with reference compounds. A comparison of the antifungal activities of the samples doped with TiO2 reveals that Cu-TiO2 exhibits improved performance against A. fumigatus but lower antifungal activity against Mucor sp. and F. solani. Cu-TiO2 and Ni-TiO2 showed good antibacterial action against B. bronchiseptica, while Cr-TiO2 nanoparticles displayed better activity against S. typhimurium as compared to pure TiO2. Moreover, pristine TiO2 and Ni-TiO2 nanoparticles were found to demonstrate maximum total antioxidant capacity.

GPR75: An exciting new target in metabolic syndrome and related disorders.

The metabolic syndrome is a plethora of related disorders that are frequently associated with morbidity and mortality in addition to economic burden. While various treatment options are available, the need to understand the pathology and find new targets still remains. Recent data have suggested GPR75 as one such exciting target that has shown to a highly druggable potential. In this review, we have discussed the recent findings on GPR75 in terms of its expression and signaling and the way it could be a novel target in diseases associated with metabolic syndrome including obesity, dyslipidemia, diabetes, cardiovascular disease, and cerebrovascular disease. In addition, the opportunities and challenges related with the druggable potential of GPR75 have also been highlighted in this review.

Health improvement of human hair and their reshaping using recombinant keratin K31.

Hair, being one of the most important components of the beauty care processes, attracts the use of a variety of hair treating cosmetics. Conventional hair treating cosmetics are not satisfactory for one reason or the other. Commercially used keratins are isolated from wool or chicken feathers. As these lack complete sequence identity with human hair keratin, are likely to be less efficient than the human hair keratin. K31, a type I acidic keratin, is a major protein of human hair keratin complex and it is essential for maintaining the hair tensile strength. In this study keratin K31 (46 kDa) gene was expressed in Escherichia coli at a level of approximately 35% of the total cell proteins. The protein, however, was expressed as insoluble inclusion bodies. The expressed protein was refolded and purified by FPLC using an anion-exchange column. The CD analysis results showed that the K31 was properly refolded. MALDI-TOF mass spectroscopy showed the characteristics expected for human K31 keratin. The refolded and partially purified K31 protein, when applied on chemically damaged hairs, increased the diameter of the hair up to 49%. The mechanical strength of the bleached hair increased by almost 2 fold after a single treatment of K31. The protein also straightened curly hair efficiently on a single treatment for one hour. Application of K31 resulted in marked improvements in smoothness, diameter and mechanical strength of the damaged hair.

In silico and in vivo investigation of ferrocene-incorporated acyl ureas and homoleptic cadmium carboxylate derivatives for anticonvulsant, anxiolytic, and sedative potential.

In this study different derivatives of ferrocene-incorporated acyl ureas and homoleptic cadmium carboxylates were investigated for potential anticonvulsant, anxiolytic and sedative properties, using in-silico and in-vivo techniques. The molecular docking studies reveled that ferrocene compounds derivative 1-(4-bromobenzoyl)-3-(4-ferrocenylphenyl) urea (PB1) and cadmium compounds derivative bis (diphenylacetato) cadmium (II) (DPAA) exhibit binding affinities against various neurotherapeutic molecular targets involved in epilepsy, anxiety, and sedation. Both PB1 and DPAA showed high binding affinities against protein targets like mammalian shaker voltage dependent potassium channel beta subunit complex, calcium release-activated calcium channel, sodium channel 2A inactivation gate, human sodium/hydrogen exchanger regulatory factor, and gamma amino butyric acid A receptor associated protein. PB1 (2-10 mg/kg) and DPAA (1-5 mg/kg) delayed onset time of pentylenetetrazole-induced myoclonic jerks and tonic-clonic seizures in mice while decreased duration of tonic-clonic seizures, determining the anticonvulsant effect of these compounds. PB1 and DPAA (0.5-1 mg/kg) exhibited anxiolytic effect by increasing time spent and number of animals entries into open arms, while decreasing time spent in dark compartment. Furthermore, PB1 (0.5-1 mg/kg) and DPAA (0.1-1 mg/kg) reduced onset time of sleep and increased duration time of sleep in mice, showing sedative effect. Taken together, our results indicate that aforementioned derivatives of ferrocene and cadmium are potent neurotherapeutic agents possessing anticonvulsant, anxiolytic and sedative properties.

The putative transcription factor CaMaf1 controls the sensitivity to lithium and rapamycin and represses RNA polymerase III transcription in Candida albicans.

Maf1 is a repressor of RNA polymerase (Pol) III transcription for tRNA. Nutrient deprivation and environmental stress repress Pol III transcription through Maf1 in Saccharomyces cerevisiae. The sole Candida albicans homolog CaMaf1 is a protein of 380 amino acids with conserved domains and motifs of the eukaryotic Maf1 family. Here, we show that C. albicans cells lacking CaMAF1 show elevated levels of tRNA. Deletion of CaMAF1 increases the sensitivity of C. albicans cells to lithium cation and SDS as well as tolerance to rapamycin and azole. In addition, deletion of CaMAF1 reduces the level of filamentation and alters the surface morphology of colonies. CaMaf1 is localized in the nucleus of log-phase growing cells. However, a dynamic change of subcellular localization of CaMaf1 exists during serum-induced morphological transition, with CaMaf1 being localized in the nuclei of cells with germ tubes and short filaments but outside of the nuclei of cells with long filaments. In addition, CaMaf1 is required for rapamycin-induced repression of CaERG20, encoding the farnesyl pyrophosphate synthetase involved in ergosterol biosynthesis. Therefore, CaMaf1 plays a role as a general repressor of Pol III transcription in C. albicans.

CaGdt1 plays a compensatory role for the calcium pump CaPmr1 in the regulation of calcium signaling and cell wall integrity signaling in Candida albicans.

BACKGROUND: Saccharomyces cerevisiae ScGdt1 and mammalian TMEM165 are two members of the UPF0016 membrane protein family that is likely to form a new group of Ca2+/H+ antiporter and/or a Mn2+ transporter in the Golgi apparatus. We have previously shown that Candida albicans CaGDT1 is a functional ortholog of ScGDT1 in the response of S. cerevisiae to calcium stress. However, how CaGdt1 together with the Golgi calcium pump CaPmr1 regulate calcium homeostasis and cell wall integrity in this fungal pathogen remains unknown. METHODS: Chemical sensitivity was tested by dilution assay. Cell survival was examined by measuring colony-forming units and staining with Annexin V-FITC and propidium iodide. Calcium signaling was examined by expression of downstream target gene CaUTR2, while cell wall integrity signaling was revealed by detection of phosphorylated Mkc1 and Cek1. Subcellular localization of CaGdt1 was examined through direct and indirect immunofluorescent approaches. Transcriptomic analysis was carried out with RNA sequencing. RESULTS: This study shows that Candida albicans CaGDT1 is also a functional ortholog of ScGDT1 in the response of S. cerevisiae to cell wall stress. CaGdt1 is localized in the Golgi apparatus but at distinct sites from CaPmr1 in C. albicans. Loss of CaGDT1 increases the sensitivity of cell lacking CaPMR1 to cell wall and ER stresses. Deletion of CaGDT1 and/or CaPMR1 increases calcium uptake and activates the calcium/calcineurin signaling. Transcriptomic profiling reveals that core functions shared by CaGdt1 and CaPmr1 are involved in the regulation of cellular transport of metal ions and amino acids. However, CaGdt1 has distinct functions from CaPmr1. Chitin synthase gene CHS2 is up regulated in all three mutants, while CHS3 is only up regulated in the pmr1/pmr1 and the gdt1/gdt1 pmr1/pmr1 mutants. Five genes (DIE2, STT3, OST3, PMT1 and PMT4) of glycosylation pathway and one gene (SWI4) of the cell wall integrity (CWI) pathway are upregulated due to deletion of CaGDT1 and/or CaPMR1. Consistently, deletion of either CaPMR1 or CaGDT1 activates the CaCek1-mediated CWI signaling in a cell wall stress-independent fashion. Calcineurin function is required for the integrity of the cell wall and vacuolar compartments of cells lacking both GDT1 and CaPMR1. CONCLUSIONS: CaPmr1 is the major player in the regulation of calcium homeostasis and cell wall stress, while CaGdt1 plays a compensatory role for CaPmr1 in the Golgi compartment in C. albicans.

The plasma membrane protein Rch1 and the Golgi/ER calcium pump Pmr1 have an additive effect on filamentation in Candida albicans.

Pmr1 is the Golgi/ER calcium pump, while Rch1 is a newly identified negative regulator of calcium influx in the plasma membrane of yeast cells. We show here that CaRch1 plays a dominant role over CaPmr1 in response of Candida albicans to SDS and tunicamycin stresses, while CaPmr1 has a major role in cell wall stress. Deletion of CaRCH1 increases the calcium/calcineurin signaling level in cells lacking CaPMR1. Calcineurin function is required for the role of CaRch1 in SDS stresses, while it is required for the function of CaPmr1 under all conditions examined. Disruption of CaRCH1 alone does not reduce the cell wall chitin, mannan or ß-glucan content, but lack of CaRCH1 slightly decreases the chitin content of cells lacking CaPMR1. Furthermore, CaRch1 and CaPmr1 have an additive effect on filamentation of C. albicans cells in vitro. Cells lacking both CaRCH1 and CaPMR1 and cells lacking CaPMR1 alone show a similar degree of virulence attenuation, being much more attenuated than cells lacking CaRCH1 alone. Therefore, CaRch1 genetically interacts with CaPmr1 in the regulation of in vitro filamentation in C. albicans.

Synthesis, spectroscopic investigation, and DFT study of N,N'-disubstituted ferrocene-based thiourea complexes as potent anticancer agents.

In the present work, the synthesis, characterization (FT-IR, multinuclear (1H and 13C) NMR, AAS, Raman, and elemental analyses), DNA binding (cyclic voltammetry, UV-Vis spectroscopy), and in vitro biological screening of nine new ferrocene-incorporated thioureas (A1-A9) are reported. Furthermore, the single-crystal X-ray structure of compound A8 was also determined. The ferrocene-based N,N'-disubstituted thioureas were derived by allowing the ferrocenyl anilines to react with freshly prepared isothiocyanates under a N2 atmosphere in dry acetone. The DNA binding studies performed by cyclic voltammetry and UV-Vis spectroscopy produced results that are in close agreement with one another for the binding constants (K) and an electrostatic mode of interaction was observed. The DFT/B3LYP method was used to determine the charge distribution and HOMO/LUMO energies of the optimized structure. The DFT calculated HOMO and LUMO energies correlate well with the experimentally determined redox potential values. The synthesized ferrocenyl thioureas exhibited good scavenging activity against the 1,1-diphenyl-2-picrylhydrazyl radical (DPPH). These complexes were also scanned for their in vitro cytotoxic activity against MCF-7 carcinoma cells, and also towards the non-cancerous cell line MCF-10A. The results showed modest cytotoxicity against the subjected cancer cell line compared with a standard chemotherapeutic drug (cisplatin). However, these ferrocenyl derivatives have fewer toxic effects in normal cells.

Facile synthesis of fluoro, methoxy, and methyl substituted ferrocene-based urea complexes as potential therapeutic agents.

In the present work, the synthesis, characterization (FT-IR, multinuclear (1H and 13C) NMR, AAS, Raman, and elemental analysis), DNA binding (cyclic voltammetry, UV-Vis spectroscopy and viscometry), and in vitro biological assessment of nine new ferrocene-based ureas are reported. The desulphurization of ferrocenyl thioureas to the corresponding oxo analogues using aqueous sodium hydroxide and mercuric chloride led to the ferrocenyl ureas (F1-F9) in high yields. The DNA binding studies performed by cyclic voltammetry and UV-Vis spectroscopy produced results that are in close agreement with one another for the binding constants (K) and an electrostatic mode of interaction was observed. The nature and the extent of interaction with DNA was further investigated by viscometry. The DFT/B3LYP method was used to determine the charge distribution and HOMO/LUMO energies of the optimized structure. The DFT calculated HOMO and LUMO energies correlate well with the experimentally determined redox potential values. The synthesized ferrocenyl derivatives exhibited good scavenging activity against 1,1-diphenyl-2-picrylhydrazyl radical (DPPH). These complexes were also scanned for their in vitro cytotoxicity against human carcinoma cell line THP-1 (leukemia cells). The results showed a moderate level of cytotoxicity against the subjected cancer cell line as compared with the standard chemotherapeutic drug (cisplatin).

Computational and Pharmacological Evaluation of Ferrocene-Based Acyl Ureas and Homoleptic Cadmium Carboxylate Derivatives for Anti-diabetic Potential.

We investigated possible anti-diabetic effect of ferrocene-based acyl ureas: 4-ferrocenyl aniline (PFA), 1-(4-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DPC1), 1-(3-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DMC1), 1-(2-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DOC1) and homoleptic cadmium carboxylates: bis (diphenylacetato) cadmium (II) (DPAA), bis (4-chlorophenylacetato) cadmium (II) (CPAA), using in silico and in vivo techniques. PFA, DPC1, DMC1, DOC1, DPAA and CPAA exhibited high binding affinities (ACE ≥ -350 Kcal/mol) against targets: aldose reductase, peroxisome proliferator-activated receptor γ, 11ß-hydroxysteroid dehydrogenase-1, C-alpha glucosidase and glucokinase, while showed moderate affinities (ACE ≥ -250 Kcal/mol) against N-alpha glucosidase, dipeptidyl peptidase-IV, phosphorylated-Akt, glycogen synthase kinase-3ß, fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase, whereas revealed lower affinities (ACE < -250 Kcal/mol) vs. alpha amylase, protein tyrosine phosphatases 1B, glycogen phosphorylase and phosphatidylinositol 3 kinase. In alloxan (300 mg/Kg)-induced diabetic mice, DPAA and DPC1 (1-10 mg/Kg) at day 1, 5, 10, 15, and 20th decreased blood glucose levels, compared to diabetic control group and improved the treated animals body weight. DPAA (10 mg/Kg) and DPC1 (5 mg/Kg) in time-dependent manner (30-120 min.) enhanced tolerance of oral glucose overload in mice. DPAA and DPCI dose-dependently at 1, 5, and 10 mg/Kg decreased glycosylated hemoglobin levels in diabetic animals, as caused by metformin. These results indicate that aforementioned derivatives of ferrocene and cadmium possess anti-diabetic potential.

Antileishmanial, DNA Interaction, and Docking Studies of Some Ferrocene-Based Heteroleptic Pentavalent Antimonials.

A series of ferrocenyl pentavalent antimonials (1-8) were synthesized and characterized by elemental analysis, FT-IR, and multinuclear ((1) H and (13) C) NMR spectroscopy. These antimonials were evaluated for their antileishmanial potential against Leishmania tropica KWH23, and by biocompatibility and membrane permeability assays. Moreover, mechanistic studies were carried out, mediated by DNA targeting followed by computational docking of ferrocenyl antimonials against the leishmanial trypanothione reductase enzyme. It was observed that the antimonials 1-8 were 390-fold more efficacious (IC50 ) as compared with the standard antimonial drug used. Cytotoxicity results showed that these antimonials are highly active even at low concentrations and are biocompatible with human macrophages. Antimonials 1-8 exhibited extensive intercalation with DNA and, furthermore, docking interactions highlighted the potential interactive binding of the anitimonials within the trypanothione reductase active site, with van der Waals interactions contributing significantly to the process. Hence, it is suggested that the reported antimonials demonstrate high efficacy, less toxicity, and target multiple sites of the Leishmania parasite.