Noncovalent Complexes Research Articles

Alpha-Fetoprotein: A Revolutionary Anti-Cancer Drug

Alpha-fetoprotein is an oncofetal protein the embryo produces during fetal development. The protein serves two critical functions simultaneously: it delivers nutrients to growing embryo cells and immature myeloid-derived suppressor cells, so the mother’s immune system doesn’t attack the embryo. The protein is present in minuscule amounts in adults and elevated alpha-fetoprotein levels serve as pregnancy or tumor markers. Exogenous alpha-fetoprotein has a new application as an immunotherapy drug. It can deliver drugs in a natural shuttle manner to myeloid-derived suppressor cells and stimulate them to calm the hyperactive immune response during many physiological and pathological conditions. On the other hand, alpha-fetoprotein loaded with toxins kills myeloid-derived suppressor cells and unleashes natural killer cells and cytotoxic lymphocytes to erase cancer. Most cancers have cells that specifically bind alpha-fetoprotein, and this protein targets chemotherapy to them also. So, alpha-fetoprotein with toxins combines both potent cancer immunotherapy and targeted chemotherapy activities. Alpha-fetoprotein can be chemically conjugated with or bind toxins non-covalently. Both preparations have demonstrated superior efficacy and safety compared to chemotherapy alone. Alpha-fetoprotein-toxin immuno/chemotherapy is not personalized. There is no need to preselect patients for cancer treatments as they have elevated myeloid-derived suppressor cell levels. The anti-cancer efficacy of porcine alpha-fetoprotein non-covalent complexes with selected toxins administered orally is a remarkable discovery that needs research. Cancer treatment and prevention are different issues, and they could need different approaches. Alpha-fetoprotein administration with drugs or toxins could be as effective in early cancer and metastasis prevention as mifepristone pills in pregnancy prevention.

Rapid discrimination of enantiomers by ion mobility mass spectrometry and chemical theoretical calculation: Chiral mandelic acid and its derivatives

Because R/S-mandelic acids (MA) and their derivatives are critical starting materials or intermediates in the synthesis of chiral drugs, their chirality discrimination is important. In this study, R/S-MA and its derivatives, including R/S-2-phenylpropionic acid (2-PPA), R/S-methoxyphenylaceticacid (MPA), and R/S-2-hydroxy-4-phenylbutyric acid (HPBA), were accurate simultaneous mobility-discriminated by forming diastereomer complexes for the first time, which were obtained by simply mixing with cyclodextrins (α, β, γ-CD) and transition-metal ions (Mn2+, Fe2+, Co2+, Ni2+, Cu2+, and Zn2+). The mass spectra revealed non-covalent diastereomer complexes formed by CD, enantiomers, and metal ions, and ion-mobility spectrometry (IMS) was performed for 109 pairs of complexes. Significant chiral discrimination was observed in the formed diastereomeric complexes, and their separation peak-to-peak resolution (Rp−p) for the enantiomers depended on the transition metal ion type. In most cases, the Rp−p value gradually increases with CD size, with quaternary complexes having the largest Rp−p value. The greatest chiral distinctions of 2-PPA, MA, MPA, and HPBA were obtained by the diastereomeric complex ions of [(2-PPA)(α)2+Zn2+-H]+, [(MA)(α)2+Zn2+-H]+, [(MPA)2(β)+Co2+-H]+, and [(HPBA)(α)2+Fe2+-H]+, with Rp−p values of 1.35, 1.57, 1.70, and 0.71, respectively. Furthermore, the favorable conformation and collisional cross section (CCS) value of the different [CD + R/S-MA + Cu–H]+ complexes were measured using chemical theoretical calculations to detail their intermolecular interaction, revealing that [α-CD + R/S-MA + Cu–H]+ has two favored gas complexes, and the CCS calculated were consistent with the TIMS observed. In addition, R2 > 0.99 was obtained for the relative quantification of the chiral enantiomers. Overall, the proposed method provides a promising strategy for distinguishing the enantiomers of MA and their derivatives, with the advantages of simplicity, speed, and accuracy, without the need for complex chemical derivatization or chromatographic separation.

Stability of Phenyl-Modified Triphenylphosphonium Conjugates and Interactions with DTPA.

Triphenylphosphonium (TPP+) conjugates are effective in targeting drugs and probes to the mitochondria due to their lipophilic character that allows them to readily cross membranes and their large cationic radius that enables mitochondrial uptake because of the mitochondria's negative membrane potential. TPP+ conjugates, while effectively sequestered by the mitochondria, are also known to uncouple oxidative phosphorylation (OXPHOS) and depolarize the mitochondrial membrane. xTPP+ conjugates with para-substitutions of functional groups on the phenyl rings of the TPP+ moiety display different levels of dose-mediated cytotoxicity due to differing potencies of uncoupling. xTPP+ conjugates having a para CF3 group substituted on the phenyl rings have been shown to afford significantly reduced uncoupling potency. In the present study, the analysis of a CF3-TPP+ conjugate with a decyl linker for stability revealed instability specific to the presence of DMSO in aqueous alkaline buffer. It is also demonstrated that the metal chelator, DTPA, forms a noncovalent protective complex with TPP+ moieties and prevents degradation of the CF3-TPP+ conjugate in aqueous DMSO. The stability of different xTPP+ conjugates and their interactions with DTPA are reported.

A Cost Effective Scheme for the Highly Accurate Description of Intermolecular Binding in Large Complexes.

There has been a growing interest in quantitative predictions of the intermolecular binding energy of large complexes. One of the most important quantum chemical techniques capable of such predictions is the domain-based local pair natural orbital (DLPNO) scheme for the coupled cluster theory with singles, doubles, and iterative triples [CCSD(T)], whose results are extrapolated to the complete basis set (CBS) limit. Here, the DLPNO-based focal-point method is devised with the aim of obtaining CBS-extrapolated values that are very close to their canonical CCSD(T)/CBS counterparts, and thus may serve for routinely checking a performance of less expensive computational methods, for example, those based on the density-functional theory (DFT). The efficacy of this method is demonstrated for several sets of noncovalent complexes with varying amounts of the electrostatics, induction, and dispersion contributions to binding (as revealed by accurate DFT-based symmetry-adapted perturbation theory (SAPT) calculations). It is shown that when applied to dimeric models of poly(3-hydroxybutyrate) chains in its two polymorphic forms, the DLPNO-CCSD(T) and DFT-SAPT computational schemes agree to within about 2 kJ/mol of an absolute value of the interaction energy. These computational schemes thus should be useful for a reliable description of factors leading to the enthalpic stabilization of extended systems.

Comparison of non-covalent binding interactions of six caffeoylquinic acids with β-lactoglobulin: Spectroscopic analysis, molecular docking and embedding of curcumin

In this study, we systematically compared the differences in the interactions of β-lactoglobulin (LG) with three mono-caffeoylquinic acids (MCQAs: 3-CQA, 4-CQA, and 5-CQA) and three dicaffeoylquinic acids (DCQAs: 3,4-DCQA, 3,5-DCQA, and 4,5-DCQA). Based on molecular docking techniques, it was concluded that the non-covalent binding of all six caffeoylquinic acids to LG was dominated by hydrophobic forces, among which the binding ability of DCQAs was stronger. The antioxidant assay revealed that caffeoylquinic acid significantly improved the antioxidant properties of LG, and the best antioxidant properties were achieved with 4,5-DCQA. The DPPH radical scavenging ability was increased by approximately 54 μmol Trolox/g-sample, and the ABTS radical scavenging ability increased by 29.26 μmol Trolox/g-sample. Six non-covalent complexes were used to embed curcumin, and the stability of the formed solution was further investigated and compared.

Modification of structural and functional characteristics of casein treated with quercetin via two interaction modes: Covalent and non-covalent interactions

Preparation of complexes via interactions between proteins and polyphenols has become one of the methods to effectively improve utilization of proteins. In this study, the structural and functional characteristics modification of casein treated with different concentrations of quercetin (10, 20, 40, 80 and 160 μmol/g protein) via covalent and non-covalent interactions were investigated. Results revealed that covalent complexes had lower sulfhydryl group content and higher quercetin binding capacity than non-covalent ones at the same quercetin concentration. This was consistent with the results of fluorescence spectroscopy which revealed higher fluorescence quenching constant and binding sites number for the covalent complexes. Fourier transform infrared spectroscopy demonstrated similar secondary structural changing trend for covalent and non-covalent complexes. The α-helix, β-turn and random coil contents increased with increasing quercetin concentration while β-sheet content decreased. Addition of quercetin decreased surface hydrophobicity of the complexes, regardless of covalent or non-covalent interactions. Casein solubility was improved in covalent interaction, while the non-covalent interaction impaired it. Quercetin treatment improved foaming activity, emulsifying activity and antioxidant activity while decreasing foaming stability and emulsifying stability. The results could provide a theoretical foundation for potential applications of casein-quercetin complexes in the food industry.

New TEMPO–Appended 2,2′–Bipyridine-Based Eu(III), Tb(III), Gd(III) and Sm(III) Complexes: Synthesis, Photophysical Studies and Testing Photoluminescence-Based Bioimaging Abilities

Linked to Alzheimer's disease (AD), amyloids and tau-protein are known to contain a large number of cysteine (Cys) residues. In addition, certain levels of some common biogenic thiols (cysteine (Cys), homocysteine (Hcy), glutathione (GSH), etc.) in biological fluids are closely related to AD as well as other diseases. Therefore, probes with a selective interaction with the above-mentioned thiols can be used for the monitoring and visualizing changes of (bio)thiols in the biological fluids as well as in the brain of animal models of Alzheimer's disease. In this study, new Eu(III), Tb(III), Gd(III) and Sm(III) complexes of 2,2'-bipyridine ligands containing TEMPO fragments as receptor units for (bio)thiols are reported. The presence of free radical fragments of the ligand in the complexes was proved by using the electronic paramagnetic resonance (EPR) method. Among all the complexes, the Eu(III) complex turned out to be the most promising one as luminescence- and spin-probe for the detection of biogenic thiols. The EPR and fluorescent titration methods showed the interaction of the resulting complex with free Cys and GSH in solution. To study the practical applicability of the probes for the monitoring of AD in-vivo, by using the above-mentioned Eu(III)-based probe, the staining of the brain of mice with amyloidosis and Vero cell cultures supplemented with the cysteine-enriched medium was studied as well as the fluorescence titration of Bovine Serum Albumin, BSA (as the model for the thiol moieties containing protein), was carried out. Based on the results of fluorescence titration, the formation of a non-covalent inclusion complex between the above-mentioned Eu(III) complex and BSA was suggested.

UV-VUV Photofragmentation Spectroscopy of Isolated Neutral Fragile Macromolecules: A Proof-of-Principle Based on a Deprotonated Vancomycin-Peptide Noncovalent Complex.

The gas phase offers the possibility to analyze organic molecules by ultraviolet-vacuum ultraviolet (UV-VUV) spectroscopy without any solvent effect or limitation in terms of spectral range due to absorption by the solvent. Up to now, the size and chemical composition of neutral molecular systems under study have been limited by the use of vaporization methods based on thermal heating. Soft sources of gas-phase thermolabile molecular systems such as electrospray or matrix-assisted laser desorption ionization are appealing alternatives to heating-based techniques, but they lead to the production of ions. In such cases, UV-VUV action spectroscopy is then the method of choice to study the electronic structure and corresponding photodynamics of these gas-phase molecular ions. However, previous investigations have shown that the UV-VUV action spectrum of a given molecular ion depends on the charge state, which in many cases might be a caveat. Here, by means of synchrotron radiation coupled to mass spectrometry and through the test case of the glycopeptide antibiotic vancomycin noncovalently bound to a deprotonated small peptide, we show that the UV-VUV photofragmentation spectrum of neutral thermally fragile organic molecules can be obtained via charge-tagging action spectroscopy.

Study of soybean protein isolate-tannic acid non-covalent complexes by multi-spectroscopic analysis, molecular docking, and interfacial adsorption kinetics

In this study, non-covalent complexes of soybean protein isolate (SPI) and tannic acid (TA) were prepared, and the interaction mechanism between SPI and TA was investigated by multiple methods of multi-spectroscopy and molecular docking techniques. The non-covalent binding to TA resulted in a reduction of the α-helix and β-sheet contents and a decrease in the fluorescence intensity. The fluorescence-quenching mechanism and molecular docking analysis determined that TA statically quenched the fluorescence of SPI with a binding constant of 1168 L/mol, a binding site number of 0.99, ΔG < 0, ΔH of −32.666 kJ/mol, and ΔS of −0.0466 kJ/mol, and the interaction between SPI and TA was dominated by hydrogen bonding. The interfacial adsorption kinetics study revealed that the maximum diffusion rate of the SPI-TA complex was 0.06771, which occurred at 1.0 mg/mL of TA. The emulsification activity index and emulsion stability index of the complexes under these conditions were 98 m2/g and 48.3 min, respectively. The above findings help to elucidate the mechanism of non-covalent binding of SPI with TA and promote the application of protein-polyphenol complexes in emulsions.

Lectin-Fortified Cationic Copper Sulfide Nanoparticles Gain Dual Targeting Capabilities to Treat Carbapenem-Resistant Acinetobacter baumannii Infection.

Targeted drug delivery maximizes the chance to combat infection caused by drug-resistant pathogens. Herein, lectin-fortified cationic copper sulfide (cCuS) nanoparticles were suggested for targeted adhesion to bacterial membranes and to enforce bacterial death. Jacalin, a lectin from jackfruit seed, was conjugated to fluorescein isothiocyanate (FITC), and its ability to recognize bacterial cell surface glycans was demonstrated. Jacalin formed a noncovalent complex with cCuS, which was investigated by fluorescence quenching measurements. The data revealed that jacalin-cCuS (JcCuS) had a good affinity with an association constant K a of 2.27 (± 0.28) × 104 M-1. The resultant JcCuS complex displayed excellent anti-infective activity against carbapenem-resistant Acinetobacter baumannii (CRAB). The minimum inhibitory concentration (MIC) of cCuS was 62.5 μM, which was 2-fold lower than that of the broad-spectrum antibiotic ciprofloxacin. Interestingly, the MIC of JcCuS was reduced to 15.63 μM, which was attributed to jacalin fortification. The mechanistic study unveiled that JcCuS affected the membrane integrity, depolarized the inner membrane, and produced excess reactive oxygen species to combat CRAB at a lower concentration compared to cCuS. A. baumannii formed a biofilm more readily, which played a critical role in pathogenesis and resistance in clinical settings. JcCuS (3.91 μM) displayed stronger antibiofilm activity without affecting the metabolic viability of CRAB. Microscopy analyses confirmed the inhibition of biofilm formation and disruption of the mature biofilm upon treatment with JcCuS. Furthermore, JcCuS hindered pellicle formation and inhibited the biofilm-associated virulence factor of CRAB such as exopolysaccharide, cell surface hydrophobicity, swarming, and twitching mobility. The anti-infective potential of JcCuS was demonstrated by rescuing CRAB-infected zebrafish. The reduction in pathogen proliferation in muscle tissues was observed in the treated group, and the fish recovered from the infection and was restored to normal life within 12 h. The findings illustrate that lectin fortification offers a unique advantage in enhancing the therapeutic potential of antimicrobials against human pathogens of critical priority worldwide.

The New Strategy for Studying Drug-Delivery Systems with Prolonged Release: Seven-Day In Vitro Antibacterial Action.

The new method of antibacterial-drug-activity investigation in vitro is proposed as a powerful strategy for understanding how carriers affect drug action during long periods (7 days). In this paper, we observed fluoroquinolone moxifloxacin (MF) antibacterial-efficiency in non-covalent complexes, with the sulfobutyl ether derivative of β-cyclodextrin (SCD) and its polymer (SCDpol). We conducted in vitro studies on two Escherichia coli strains that differed in surface morphology. It was found that MF loses its antibacterial action after 3-4 days in liquid media, whereas the inclusion of the drug in SCD led to the increase of MF antibacterial activity by up to 1.4 times within 1-5 days of the experiment. In the case of MF-SCDpol, we observed a 12-fold increase in the MF action, and a tendency to prolonged antibacterial activity. We visualized this phenomenon (the state of bacteria, cell membrane, and surface morphology) during MF and MF-carrier exposure by TEM. SCD and SCDpol did not change the drug's mechanism of action. Particle adsorption on cells was the crucial factor for determining the observed effects. The proteinaceous fimbriae on the bacteria surface gave a 2-fold increase of the drug carrier adsorption, hence the strains with fimbriae are more preferable for the proposed treatment. Furthermore, the approach to visualize the CD polymer adsorption on bacteria via TEM is suggested. We hope that the proposed comprehensive method will be useful for the studies of drug-delivery systems to uncover long-term antibacterial action.

Coagulation Factor VIII Enhances the Cleavage of Von Willebrand Factor By ADAMTS13 In Vivo

Introduction: Coagulation factor VIII (FVIII) and von Willebrand factor (VWF) circulate as a noncovalent complex. This interaction helps increase the half-life of circulating FVIII and modulates FVIII immunogenicity. Our previous studies demonstrate that FVIII accelerates VWF proteolysis by ADAMTS13 in vitro under fluidic shear or under certain pathophysiological conditions. However, the physiological relevance of the FVIII-enhanced VWF proteolysis remains questionable. Here, we sought to determine if addition of recombinant FVIII at various concentrations to mice with or without circulating ADAMTS13 or to patients with hereditary thrombotic thrombocytopenic purpura (TTP) affects plasma VWF multimer distribution and its antigen levels. Methods: Recombinant human B-domain deleted FVIII (rFVIII) was intravenously administered into wild-type (WT),Adamts13+/-(A13+/-) and Adamts13-/- (A13-/-) mice. Blood samples were collected prior to and 24 hours following rFVIII infusion. In addition, FVIII was stably expressed in fviii-/-mice via administration of AAV8-BDDFVIII. Moreover, plasma was collected from patients with hereditary TTP who were treated with plasma derived FVIII concentrates. Plasma VWF multimers and antigen levels were determined by SDS-agarose gel electrophoresis followed by Western blotting and enzyme-linked immunoassay (ELISA), respectively. Paired T and Mann Whitney tests were performed to determine the statistical significance of the difference between two groups. Results: Our results demonstrated that an infusion of rFVIII at a low dose (40 ug/kg) and a high dose (160 ug/kg) into WT mice resulted in a dramatic reduction in plasma VWF multimer sizes (Fig. 1) and VWF antigen levels (not shown). FVIII at high dose but not at low dose could also significantly reduce the sizes of VWF multimers in Adamts13+/- and Adamts13-/- mice (Fig. 1). The enhanced degradation of VWF multimers in Adamts13-/- mice suggests that other VWF-cleaving enzymes may participate in the degradation of VWF-FVIII complex. In either Adamts13+/- or Adamts13-/- mice, administration of rFVIII at both low and high doses didn't result in significant changes in VWF antigen levels (not shown). Furthermore, a simultaneous infusion of both rFVIII and recombinant murine ADAMTS13 (rADAMTS13) into Adamts13-/- mice resulted in similar changes in plasma VWF multimer distribution (Fig. 1) and antigen levels (not shown). Importantly, all mice tolerated well to the high dose of rFVIII infusion without major thrombotic events during weeks of follow-up. The restoration of plasma FVIII to 100-200% of normal levels in the fviii-/- mice with AAV8-mediated gene therapy also led to a profound degradation of plasma VWF multimers and significantly reduced plasma levels of VWF antigen (not shown). Finally, a similar pattern of dramatically reduced plasma VWF multimers was observed in 3 out of 4 patients with hereditary TTP following treatment with plasma-derived FVIII concentrates (not shown). Conclusions: Our results demonstrate that supplementation of FVIII at physiological or super-physiological concentrations dramatically accelerates the degradation of VWF multimers in mice and human. These findings further support our hypothesis that FVIII is a physiological cofactor of ADAMTS13 in regulating VWF homeostasis. Our findings may also offer a scientific explanation how FVIII concentrates or perhaps rFVIII might work for the treatment of hereditary TTP and other arterial thrombosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effective screening of Coulomb repulsions in water accelerates reactions of like-charged compounds by orders of magnitude

The reaction kinetics between like-charged compounds in water is extremely slow due to Coulomb repulsions. Here, we demonstrate that by screening these interactions and, in consequence, increasing the local concentration of reactants, we boost the reactions by many orders of magnitude. The reaction between negatively charged Coenzyme A molecules accelerates ~5 million-fold using cationic micelles. That is ~104 faster kinetics than in 0.5 M NaCl, although the salt is ~106 more concentrated. Rate enhancements are not limited to micelles, as evidenced by significant catalytic effects (104–105-fold) of other highly charged species such as oligomers and polymers. We generalize the observed phenomenon by analogously speeding up a non-covalent complex formation—DNA hybridization. A theoretical analysis shows that the acceleration is correlated to the catalysts’ surface charge density in both experimental systems and enables predicting and controlling reaction rates of like-charged compounds with counter-charged species.

Tuning the Properties of Metal‐Organic Cages through Platinum Nanoparticle Encapsulation

AbstractMetal‐organic cages (MOCs) are promising candidates for drug deliveries, catalysis, and host‐guest systems. In addition, their own finite cavities can control to the sizes and shapes of metal nanoparticles (MNPs), leading to promote their catalytic performance. Herein, we used half‐sandwich rhodium moieties with pyridyl ligands through coordination‐driven self‐assembly strategy and bridged‐unit (tpphz)‐mediated host‐guest complex formation in concert to produce a sufficient cavity with about 2.0 nm of size that facilitate to prepare controllably sizes and shapes of MNPs. Specifically, a metal‐organic cage1, containing robust ligands (tpeb) and bridged units, has been successfully synthesized and fully characterized by several spectroscopic techniques. Its final structure was unambiguously confirmed by single‐crystal X‐ray diffraction (SCXRD). The pyridyl ligand units of1underwent noncovalent complexation with platinum nanoparticles to yield a Pt‐NPs@1 under UV‐visible irradiation of K2PtCl6. Moreover, UV and CV were carried out to determine the redox properties of1and Pt‐NPs@1, finding that Pt‐NPs@1has a good redox property. Therefore, the supramolecular composites were used as catalysis for degradation of dye stuffs in aqueous solution, exhibiting good selectivity and activity.

Application of soy protein isolate fiber and soy soluble polysaccharide non-covalent complex: A potential way for pH-triggered release

The non-covalent interactions between protein and polysaccharide have the potential to design responsive materials. In this study, soy protein isolate fiber/soy soluble polysaccharide (SPIF/SSPS) non-covalent complex was used to create an emulsion, and the pH–response performance was evaluated by investigating their microstructure, interfacial properties, and stability at pH values of 2.0–10.0. The SPIF/SSPS complex was relatively stable at pH 2.0 and 4.0, and the corresponding emulsions had uniform droplets that showed outstanding storage stability after 21 days. However, the SPIF/SSPS complex was dissociated gradually with the elevation of pH, especially under alkaline condition, that caused the flocculation and coalescence in emulsion. This phenomenon not only relate to electrostatic repulsion, but also relate to the disintegration of SPIF. Furthermore, the encapsulated curcumin is released rapidly from emulsion when the pH increased above 6.0. This research may provide an outstanding pH-response strategy that have the potential for pH-triggered release.

Elusive intermediates in cisplatin reaction with target amino acids: Platinum(II)-cysteine complexes assayed by IR ion spectroscopy and DFT calculations

The reactivity of a widely used metal based antineoplastic drug, cisplatin, cis-PtCl2(NH3)2, with L-cysteine (Cys) has been investigated using a combination of electrospray ionization mass spectrometry (ESI-MS), IRMPD gas phase ion spectroscopy and DFT calculations. The cysteine lateral chain represents one of the main platination sites in proteins, which is believed to be related to the resistance mechanisms to cisplatin. The vibrational features of the mass-selected substitution product cis-[PtCl(NH3)2(Cys)]+ and the intercepted cis-[PtCl(NH3)2(H2O)(Cys)]+ intermediate complex were compared to calculated IR spectra, enabling the assessment of the sampled ions structures. In cis-[PtCl(NH3)2(Cys)]+, cysteine was found to bind platinum through the sulfur atom as a thiolate zwitterion, highlighting the enhanced acidity of the cysteine thiol group upon metal coordination. The cis-[PtCl(NH3)2(H2O)(Cys)]+ structure complies with the non-covalent encounter complex, formed by cis-[PtCl(NH3)2(H2O)]+ and neutral cysteine. This species is able to undergo the substitution process to produce cis-[PtCl(NH3)2(Cys)]+ when activated as a mass-isolated ion suggesting its participation in the reaction mechanism of cisplatin with cysteine in solution. Finally, the DFT-calculated energy profile for the substitution reaction was correlated with the peculiar gas-phase reactivity of this non-covalent complex, resulting to be 10-fold less reactive toward substitution than the corresponding methionine complex.

Emergence of MUC1 in Mammals for Adaptation of Barrier Epithelia.

Simple SummaryThe evidence reviewed here indicates that MUC1-C evolved in mammals to promote inflammatory adaptation in barrier tissues that extends to resident stem cells and immune cells. Inflammatory memory is an essential process that protects barrier niches against future insults. Evolutionary adaptations arising from natural selection, as for example the MUC1 gene, can be beneficial for survival. However, prolonged activation of MUC1-C in settings of chronic inflammation represents an adverse adaptation that promotes cancer.The mucin 1 (MUC1) gene was discovered based on its overexpression in human breast cancers. Subsequent work demonstrated that MUC1 is aberrantly expressed in cancers originating from other diverse organs, including skin and immune cells. These findings supported a role for MUC1 in the adaptation of barrier tissues to infection and environmental stress. Of fundamental importance for this evolutionary adaptation was inclusion of a SEA domain, which catalyzes autoproteolysis of the MUC1 protein and formation of a non-covalent heterodimeric complex. The resulting MUC1 heterodimer is poised at the apical cell membrane to respond to loss of homeostasis. Disruption of the complex releases the MUC1 N-terminal (MUC1-N) subunit into a protective mucous gel. Conversely, the transmembrane C-terminal (MUC1-C) subunit activates a program of lineage plasticity, epigenetic reprogramming and repair. This MUC1-C-activated program apparently evolved for barrier tissues to mount self-regulating proliferative, inflammatory and remodeling responses associated with wound healing. Emerging evidence indicates that MUC1-C underpins inflammatory adaptation of tissue stem cells and immune cells in the barrier niche. This review focuses on how prolonged activation of MUC1-C by chronic inflammation in these niches promotes the cancer stem cell (CSC) state by establishing auto-inductive nodes that drive self-renewal and tumorigenicity.

Effect of substitution of methanatoboron difluoride derivatives on non-covalent interactions with tetraphenylporphyrin

Tetraphenylporphyrin (TPP) forms non-covalent supra-molecular complexes with methanatoboron difluoride (MBDF) derivatives in dichloromethane. The photo-chemical properties of the association equilibrium of free TPP and MBDFs with the respective supra-molecular complexes were investigated in the ground state. There is formation of isosbestic points which had been taken as proof of the existence of equilibrium between the absorbing species. Monte Carlo simulation and Density functional theory calculation established the experimental results of non-covalent interactions in terms of loss of planarity and frontier molecular orbital calculations defines the electron donor and acceptor. The direction of electron flow is confirmed by the electrochemical indices. The electron rich substituent in MBDF favours the non-covalent binding ability between TPP and MBDF. Both H-bonding and charge transfer interactions are primarily responsible in stabilising these complexes.&#x0D; Bangladesh J. Sci. Ind. Res. 57(3), 163-172, 2022

Highly catalytic supramolecular host–guest complex for high value directional conversion of lignin to syringyl monomer

In order to meet the challenge of enzyme catalysis of waste lignin, laccase (LAC)- guaiacyl(G)-type monomers noncovalent supramolecular system (LGS) were constructed for conversion of lignin. In this contribution, the catalytic effect of LGS formed by LAC and G-type monomers was studied. LAC changes the secondary structure conformation of its binding site to accommodate the G-type monomer, which is bound by hydrogen bonding and hydrophobic interactions. A mechanistic study highlights that the non-covalent complexation accelerates the internal electron transfer rate of LGS and syringol substrate for subsequent coupling reactions. In the presence of guaiacol/4-ethylguaiacol/vanillin-LAC, the conversion of dealkali lignin were 16.44, 29.12 and 22.72, respectively, higher than that in the presence of LAC alone. And the product of syringyl monomer was significantly increased in the actual lignin catalysis. Our work explains the mechanisms underlying existing enzyme-substrate interactions and enhanced catalytic system can be used for efficient utilization of waste.

The von Willebrand factor–binding aptamer rondaptivon pegol as a treatment for severe and nonsevere hemophilia A

AbstractFactor VIII (FVIII) circulates in a noncovalent complex with von Willebrand Factor (VWF), the latter determining FVIII half-life. The VWF-binding aptamer rondaptivon pegol (BT200) increases plasma levels of VWF/FVIII in healthy volunteers. This trial assessed its safety, pharmacokinetics, and pharmacodynamics in hemophilia A. Nineteen adult patients (ages 20-62 years, 4 women) with hemophilia A (8 mild, 2 moderate, and 9 severe) received subcutaneous injections of rondaptivon pegol. After an initial fixed dose of 3 mg on days 0 and 4, patients received weekly doses of 2 to 9 mg until day 28. Severe hemophilia A patients underwent sparse-sampling population pharmacokinetics individual profiling after the final dose of rondaptivon pegol. Adverse events, pharmacokinetics, and pharmacodynamics were assessed. FVIII activity and VWF levels were measured. All patients tolerated rondaptivon pegol well. The geometric mean half-life of rondaptivon pegol was 5.4 days and rondaptivon pegol significantly increased VWF levels. In severe hemophilia A, 6 doses of rondaptivon pegol increased the half-lives of 5 different FVIII products from a median of 10.4 hours to 31.1 hours (range, 20.8-56.0 hours). Median FVIII increased from 22% to 48% in mild hemophilia A and from 3% to 7.5% in moderate hemophilia A. Rondaptivon pegol is a first-in-class prohemostatic molecule that extended the half-life of substituted FVIII approximately 3-fold and increased endogenous FVIII levels approximately 2-fold in hemophilia patients. This trial was registered at www.clinicaltrials.gov as #NCT04677803.