Proximity-Enabled Photochemical C-H Functionalization using a Covalent Organic Framework-Confined Fe2IV-µ-oxo Species in Water.

Water has been recognized as an excellent solvent for maneuvering both the catalytic activity and selectivity, especially in the case of heterogeneous catalysis. However, maintaining the active catalytic species in their higher oxidation states (IV/V) while retaining the catalytic activity and recyclability in water is an enormous challenge. Herein, we have developed a solution to this problem using covalent organic frameworks (COFs) to immobilize the (Et4N)2[FeIII(Cl)bTAML] molecules, taking advantage of the COF's morphology and surface charge. By using the visible light and [CoIII(NH3)5Cl]Cl2 as a sacrificial electron acceptor within the COF, we have successfully generated and stabilized the [(bTAML)FeIV-O-FeIV(bTAML)]- species in water. The COF backbone simultaneously acts as a porous host and a photosensitizer. This is the first time that the photochemically generated Fe2IV-µ-oxo radical cation species has demonstrated high catalytic activity with moderate to high yield for the selective oxidation of the unactivated C-H bonds, even in water. To enhance the catalytic activity and achieve good recyclability, we have developed a TpDPP COF film by transforming the TpDPP COF nanospheres. We have achieved the regio- and stereoselective functionalization of unactivated C-H bonds of alkanes and alkenes (3°:2° = 102:1 for adamantane with the COF film), which is improbable in homogeneous conditions. The film exhibits C-H bond oxidation with higher catalytic yield (32-98%) and a higher degree of selectivity (cis/trans = 74:1; 3°:2° = 100:1 for cis-decalin).

Selectivity in Electrochemical CO2 Reduction.

The electrocatalytic CO2 reduction reaction (CO2RR) to generate fixed forms of carbons that have commercial value is a lucrative avenue to ameliorate the growing concerns about the detrimental effect of CO2 emissions as well as to generate carbon-based feed chemicals, which are generally obtained from the petrochemical industry. The area of electrochemical CO2RR has seen substantial activity in the past decade, and several good catalysts have been reported. While the focus was initially on the rate and overpotential of electrocatalysis, it is gradually shifting toward the more chemically challenging issue of selectivity. CO2 can be partially reduced to produce several C1 products like CO, HCOOH, CH3OH, etc. before its complete 8e-/8H+ reduction to CH4. In addition to that, the low-valent electron-rich metal centers deployed to activate CO2, a Lewis acid, are prone to reduce protons, which are a substrate for CO2RR, leading to competing hydrogen evolution reaction (HER). Similarly, the low-valent metal is prone to oxidation by atmospheric O2 (i.e., it can catalyze the oxygen reduction reaction, ORR), necessitating strictly anaerobic conditions for CO2RR. Not only is the requirement of O2-free reaction conditions impractical, but it also leads to the release of partially reduced O2 species such as O2-, H2O2, etc., which are reactive and result in oxidative degradation of the catalyst.In this Account, mechanistic investigations of CO2RR by detecting and, often, chemically trapping and characterizing reaction intermediates are used to understand the factors that determine the selectivity in CO2RR. The spectroscopic data obtained from different intermediates have been identified in different CO2RR catalysts to develop an electronic structure selectivity relationship that is deemed to be important for deciding the selectivity of 2e-/2H+ CO2RR. The roles played by the spin state, hydrogen bonding, and heterogenization in determining the rate and selectivity of CO2RR (producing only CO, only HCOOH, or only CH4) are discussed using examples of both iron porphyrin and non-heme bioinspired artificial mimics. In addition, strategies are demonstrated where the competition between CO2RR and HER as well as CO2RR and ORR could be skewed overwhelmingly in favor of CO2RR in both cases.

DoE-based validation of a HPLC-UV method for quantification of rotigotine nanocrystals: Application to in vitro dissolution and ex vivo nasal permeation studies.

The current work is focused on optimization, development, and validation of a sensitive and specific reversed-phase high-performance liquid chromatography (RP-HPLC) method for the estimation of rotigotine (RTG) in bulk and nanoformulations. The RP-HPLC method was effectively optimized using the concepts of design of experiments. Critical method variables (CMVs) were screened using Plackett-Burman design. Box-Behnken, a surface response methodology-based design, was further used for the optimization of CMVs with the number of theoretical plates and retention time (min) as responses. The optimized chromatographic conditions for the RP-HPLC method were: acetonitrile proportion: 54% v/v, pH of buffer: 5.0 (10 mM), and flow rate: 0.65 mL/min. The number of theoretical plates and retention time in the study were found to be 11206 and 7.65 min, respectively. The developed method exhibited good linearity (R2 = 0.9995) within a range of 25-600 ng/mL and LOD and LOQ were found to be 9 and 12 ng/mL, respectively. The developed RP-HPLC method was found sensitive, accurate, precise, specific, robust, and stability indicating according to the regulatory guidelines. The validated method was efficiently applied for in vitro dissolution study, ex vivo nasal permeation study, and estimation of drug content of RTG nanocrystals.

O2 reduction by iron porphyrins with electron withdrawing groups: to scale or not to scale.

Iron porphyrins are synthesized by systematically introducing electron withdrawing groups (EWGs) on pyrroles to evaluate the relationship between rate (k) and overpotential (η). The results indicate that while EWGs lead to a rise in the thermodynamic FeIII/II reduction potential (E0), the potential of the O2 reduction reaction (ORR) does not scale with E0. More importantly, the iron porphyrins with higher E0 show an order of magnitude higher rate of ORR than unsubstituted iron tetraphenyl porphyrin. This contests the scaling relationship often offered to predict rates of ORR by iron porphyrins based on their E0. Mechanistic investigations reveal that the rate-determining step (rds) of ORR change between these iron porphyrins with EWG's, as the pKa and E0 of several key intermediate species likely change on altering the macrocycle. These results suggest that linear dependence of log(rate) on E0 or η may only be valid for complexes where the rds of ORR remains the same.

Biochemical and artificial pathways for the reduction of carbon dioxide, nitrite and the competing proton reduction: effect of 2nd sphere interactions in catalysis.

Reduction of oxides and oxoanions of carbon and nitrogen are of great contemporary importance as they are crucial for a sustainable environment. Substantial research has been dedicated to these areas in the last few decades. These reductions require both electrons and protons and their thermodynamic potentials often make them compete with hydrogen evolution reaction i.e., the reaction of protons and electrons to generate H2. These reactions are abundant in the environment in microorganisms and are facilitated by naturally occurring enzymes. This review brings together the state-of-the-art knowledge in the area of enzymatic reduction of CO2, NO2- and H+ with those of artificial molecular electrocatalysis. A simple ligand field theory-based design principle for electrocatalysts is first described. The electronic structure considerations developed automatically yield the basic geometry required and the 2nd sphere interactions which can potentially aid the activation and the further reduction of these small molecules. A systematic review of the enzymatic reaction followed by those reported in artificial molecular electrocatalysts is presented for the reduction of CO2, NO2- and H+. The review is focused on mechanism of action of these metalloenzymes and artificial electrocatalysts and discusses general principles that guide the rates and product selectivity of these reactions. The importance of the 2nd sphere interactions in both enzymatic and artificial molecular catalysis is discussed in detail.

Activating the Fe(I) State of Iron Porphyrinoid with Second-Sphere Proton Transfer Residues for Selective Reduction of CO2 to HCOOH via Fe(III/II)-COOH Intermediate(s).

The ability to tune the selectivity of CO2 reduction by first-row transition metal-based complexes via the inclusion of second-sphere effects heralds exciting and sought-after possibilities. On the basis of the mechanistic understanding of CO2 reduction by iron porphyrins developed by trapping and characterizing the intermediates involved ( J. Am. Chem. Soc. 2015, 137, 11214), a porphyrinoid ligand is envisaged to switch the selectivity of the iron porphyrins by reducing CO2 from CO to HCOOH as well as lower the overpotential to the process. The results show that the iron porphyrinoid designed can catalyze the reduction of CO2 to HCOOH using water as the proton source with 97% yield with no detectable H2 or CO. The iron porphyrinoid can activate CO2 in its Fe(I) state resulting in very low overpotential for CO2 reduction in contrast to all reported iron porphyrins, which can reduce CO2 in their Fe(0) state. Intermediates involved in CO2 reduction, Fe(III)-COOH and a Fe(II)-COOH, are identified with in situ FTIR-SEC and subsequently chemically generated and characterized using FTIR, resonance Raman, and Mössbauer spectroscopy. The mechanism of the reaction helps elucidate a key role played by a closely placed proton transfer residue in aiding CO2 binding to Fe(I), stabilizing the intermediates, and determining the fate of a rate-determining Fe(II)-COOH intermediate.

Electrocatalytic Reduction of Nitrogen to Hydrazine Using a Trinuclear Nickel Complex.

Activation and reduction of N2 have been a major challenge to chemists and the focus since now has mostly been on the synthesis of NH3. Alternatively, reduction of N2 to hydrazine is desirable because hydrazine is an excellent energy vector that can release the stored energy very conveniently without the need for catalysts. To date, only one molecular catalyst has been reported to be able to reduce N2 to hydrazine chemically. A trinuclear T-shaped nickel thiolate molecular complex has been designed to activate dinitrogen. The electrochemically generated all Ni(I) state of this molecule can reduce N2 in the presence of PhOH as a proton donor. Hydrazine is detected as the only nitrogen-containing product of the reaction, along with gaseous H2. The complex reported here is selective for the 4e-/4H+ reduction of nitrogen to hydrazine with a minor overpotential of ∼300 mV.

Hyaluronan-binding protein 1 (HABP1) overexpression triggers induction of senescence in fibroblasts cells.

Hyaluronan-binding protein 1 (HABP1), a multi-compartmental, multi-functional protein has a wide range of functions, which can be attributed to its ability to associate with a variety of cellular ligands. Earlier we have reported that HABP1 overexpression in rat normal fibroblasts (F-HABP07) shows chronic generation of reactive oxygen species (ROS), induction of autophagy, and apoptosis. However, a significant proportion of cells remained viable after the majority went through apoptosis from 60 to 72 h. In this study, an attempt has been made to delineate the cellular events in the declined population of surviving cells. It has been elucidated here that, these cells at later time points of growth, that is, 72 and 84 h, not only appeared to shrink but also are devoid of autophagic vacuoles and displayed polyploidy. F-HABP07 cells exhibited an altered cytoskeletal structure from their parental cell line F111, assumed to be caused upon inhibition of actin polymerization and decrease in IQ motif-containing GTPase activating protein 1 (IQGAP1), a key protein associated with maintenance of cytoskeletal integrity. Enhanced expression and nuclear localization of AKT observed in F-HABP07 cells appears to be contributing toward the maintenance of high ROS levels in these cells and also potentially modulating the IQGAP1 activity. These observations, in fact have been considered to result in sustained DNA damage, which then leads to increased expression of p53 and activation of p21 and carry out the cellular events responsible for senescence. Subsequent assessment of the presence of positive ß-gal staining and enhanced expression of p16INK4a in F-HABP07, confirmed that HABP1 overexpressing fibroblasts undergo senescence.

Synthetic Iron Porphyrins for Probing the Differences in the Electronic Structures of Heme a3, Heme d, and Heme d1.

A variety of heme derivatives are pervasive in nature, having different architectures that are complementary to their function. Herein, we report the synthesis of a series of iron porphyrinoids, which bear electron-withdrawing groups and/or are saturated at the ß-pyrrolic position, mimicking the structural variation of naturally occurring hemes. The effects of the aforementioned factors were systematically studied using a combination of electrochemistry, spectroscopy, and theoretical calculations with the carbon monoxide (CO) and nitric oxide (NO) adducts of these iron porphyinoids. The reduction potentials of iron porphyrinoids vary over several hundreds of millivolts, and the X-O (X = C, N) vibrations of the adducts vary over 10-15 cm-1. Density functional theory calculations indicate that the presence of electron-withdrawing groups and saturation of the pyrrole ring lowers the π*-acceptor orbital energies of the macrocycle, which, in turn, attenuates the bonding of iron to CO and NO. A hypothesis has been presented as to why cytochrome c containing nitrite reductases and cytochrome cd1 containing nitrite reductases follow different mechanistic pathways of nitrite reduction. This study also helps to rationalize the choice of heme a3 and not the most abundant heme b cofactor in cytochrome c oxidase.

Oral pharmacokinetic interaction of ester rich fruit juices and pharmaceutical excipients with tenofovir disoproxil fumarate in male Wistar rats.

1. The aim of this study was to evaluate the role of intestinal esterases on the absorption process of tenofovir disoproxil fumarate (TDF). 2. The esterase inhibition capacity of fruit juices (FJs) rich in ester linkages and pharmaceutical excipients (having ester bonds) was performed in vitro by incubating TDF with each FJ and excipient in the intestinal washings. The ex vivo everted gut sac model was also used to evaluate the absorption enhancement capacity of these FJs and excipients. Single-dose oral pharmacokinetic studies were performed by concomitant administration of TDF with each of the selected FJs and excipients. 3. The in vitro and ex vivo studies showed that cremophor-EL and all FJs prevented the metabolism of TDF with grapefruit juice (GFJ) having the highest level of inhibition. Further, the permeability flux of the monoester form of tenofovir was increased by 113% and 212% by cranberry juice (CBJ) and GFJ, respectively. The in vivo studies also showed that both CBJ and GFJ enhanced the oral bioavailability of TDF as the AUC was increased by 24% and 97%, respectively. 4. These results indicate that the prevention of the metabolic conversion of TDF to its monoester form is crucial in increasing the oral absorption of TDF.

Overexpression of hyaluronan-binding protein 1 (HABP1/p32/gC1qR) in HepG2 cells leads to increased hyaluronan synthesis and cell proliferation by up-regulation of cyclin D1 in AKT-dependent pathway.

Overexpression of the mature form of hyaluronan-binding protein 1 (HABP1/gC1qR/p32), a ubiquitous multifunctional protein involved in cellular signaling, in normal murine fibroblast cells leads to enhanced generation of reactive oxygen species (ROS), mitochondrial dysfunction, and ultimately apoptosis with the release of cytochrome c. In the present study, human liver cancer cell line HepG2, having high intracellular antioxidant levels was chosen for stable overexpression of HABP1. The stable transformant of HepG2, overexpressing HABP1 does not lead to ROS generation, cellular stress, and apoptosis, rather it induced enhanced cell growth and proliferation over longer periods. Phenotypic changes in the stable transformant were associated with the increased "HA pool," formation of the "HA cable" structure, up-regulation of HA synthase-2, and CD44, a receptor for HA. Enhanced cell survival was further supported by activation of MAP kinase and AKT-mediated cell survival pathways, which leads to an increase in CYCLIN D1 promoter activity. Compared with its parent counterpart HepG2, the stable transformant showed enhanced tumorigenicity as evident by its sustained growth in low serum conditions, formation of the HA cable structure, increased anchorage-independent growth, and cell-cell adhesion. This study suggests that overexpression of HABP1 in HepG2 cells leads to enhanced cell survival and tumorigenicity by activating HA-mediated cell survival pathways.

Intranasal nanotherapeutics for brain targeting and clinical studies in Parkinson's disease.

Parkinson's disease (PD) is the second leading neurodegenerative disease globally, impacting the quality of life of millions of people. It is estimated that the treatment cost of PD in the USA can rise to 79 billion dollars by 2037. Limited drugs are approved by USFDA, which only provides symptomatic relief. Further, the drug efficacy is challenged due to low drug-brain concentration due to first-pass metabolism and blood-brain barrier (BBB). Intranasal drug administration can offer several advantages over systemic administration, providing efficient brain delivery. Nose-to-brain (N2B) drug delivery can enhance brain bioavailability, reduce enzymatic degradation, and reduce systemic adverse effects. However, due to poor absorption from the nasal mucosa, intranasal administration can be challenging for hydrophilic drugs. The drug mucociliary clearance, retention time, and nasal enzymatic degradation can also affect N2B drug delivery. Nanocarriers can enhance residence time, improve nasal permeation, increase brain uptake, and reduce enzymatic degradation. This review discusses the roles and applications of various N2B nanocarriers to treat PD effectively. Clinical trials of antiparkinson molecules is also covered. Lastly, safety aspects and prospects of potential nanotherapeutics for the effective treatment of PD are discussed.

Self-Assembled Lecithin-Chitosan Nanoparticles Improved Rotigotine Nose-to-Brain Delivery and Brain Targeting Efficiency.

Rotigotine (RTG) is a non-ergoline dopamine agonist and an approved drug for treating Parkinson's disease. However, its clinical use is limited due to various problems, viz. poor oral bioavailability (<1%), low aqueous solubility, and extensive first-pass metabolism. In this study, rotigotine-loaded lecithin-chitosan nanoparticles (RTG-LCNP) were formulated to enhance its nose-to-brain delivery. RTG-LCNP was prepared by self-assembly of chitosan and lecithin due to ionic interactions. The optimized RTG-LCNP had an average diameter of 108 nm with 14.43 ± 2.77% drug loading. RTG-LCNP exhibited spherical morphology and good storage stability. Intranasal RTG-LCNP improved the brain availability of RTG by 7.86 fold with a 3.84-fold increase in the peak brain drug concentration (Cmax(brain)) compared to intranasal drug suspensions. Further, the intranasal RTG-LCNP significantly reduced the peak plasma drug concentration (Cmax(plasma)) compared to intranasal RTG suspensions. The direct drug transport percentage (DTP (%)) of optimized RTG-LCNP was found to be 97.3%, which shows effective direct nose-to-brain drug uptake and good targeting efficiency. In conclusion, RTG-LCNP enhanced drug brain availability, showing the potential for clinical application.

Exploring Applications of Flexible Vesicular Systems as Transdermal Drug Delivery.

Deformable lipidic-nano carriers are a category of advanced liposomal formulations. Deformable lipidic-nano carriers have a specific character to transform by rearranging the lipidic backbone to squeeze themself through a pore opening ten times smaller than their diameter when exposed to a variable condition like hydration gradient as these have potentially been used as a non-invasive delivery system to transdermally migrate various therapeutic agents for over three decades. Despite their vast application in transdermal drug delivery system, non-uniformity to express their chemical nature still exist and authors use various terms synonymously and interchangeably with each other. The present study delineates the terminologies used to express different derived deformable vesicular carriers to harmonize the terminological use. It also includes the effectiveness of deformable nanocarriers like Transferosomes, Ethosomes, Menthosomes, Invasomes, and Glycerosomes in skin conditions like basal cell carcinoma, fungal and viral infections, and hyperpigmentation disorders, along with others. Various review and research articles were selected from the 'Pubmed' database. The keywords like Transferosomes, Flexi-vesicular system, ultra-deformable vesicles, and nano-vesicular systems were used to extract the data. The data was reviewed and compiled to categorically classify different flexible vesicular systems. The composition of the different vesicular systems is identified and a report of various pathological conditions where the use of flexible lipid nanocarrier systems was implemented is compiled. The review also offers suggestive approaches where the applicability of these systems can be explored further.

A new fluorescence-based method for rapid and specific quantification of rotigotine in chitosan nanoparticles.

A new, simple, rapid and sensitive fluorescence-based method has been developed and validated for the estimation of rotigotine (RTG) in bulk and nanoformulations. RTG is a dopamine agonist approved by both the United States Food and Drug Administration and the European Medicines Agency for the treatment of Parkinson's disease and restless leg syndrome. To date, no fluorescence-based analytical method has been reported for the estimation of RTG in any pharmaceutical dosage forms. The developed method is validated as per the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guidelines. A solution of the pure drug in phosphate buffer pH 6.4 exhibited strong fluorescence emission (λem) at a wavelength of 298 nm when excited (λex) at a wavelength of 277 nm. The developed method demonstrated good linearity over a range of 250-2500 ng/mL. Limit of detection and limit of quantitation values were found to be 36.25 ng/mL and 109.85 ng/mL respectively. The developed method was found to be accurate, precise, specific and robust. The validated method was successfully applied for the estimation of entrapment efficiency and drug loading of in-house intranasal RTG-loaded chitosan nanoparticles.

Design of Experiment (DoE)-Approach Based RP-HPLC Analytical Method Development and Validation for Estimation of Efavirenz in Bulk and Formulations.

Present study reports design of experiment (DoE) based development and validation of a simple, rapid and sensitive reversed-phase high-performance liquid chromatography (RP-HPLC) method for estimation of efavirenz (EFZ), a non-nucleotide reverse transcriptase inhibitor (NNRTs), used in the treatment of acquired immunodeficiency syndrome (AIDS). Plackett-Burman design was explored to screen the critical method variables (CMVs) for the RP-HPLC method. A response surface Box-Behnken design was employed to optimize the screened CMVs which affect the analytical responses (ARs) of RP-HPLC method. Using the optimized CMVs the HPLC method was developed and validated according to International Conference on Harmonization (ICH) guidelines. EFZ in marketed formulation was estimated using the validated method. Acetonitrile proportion, pH of the phosphate buffer and mobile phase flow rate were the CMVs and retention time and number of theoretical plates were the ARs for the study. The optimized chromatographic parameters were acetonitrile proportion in mobile phase: 51.17%v/v, pH of phosphate buffer: 4.04 and flow rate: 1.25 mL/min. Use of these optimized parameters resulted in retention time of 11.031 min and 9,498.787 number of theoretical plates as ARs of the HPLC method. The method was further validated in harmony with current ICH guidelines Q2 (R1). The method was capable of the successful estimation of EFZ in marketed formulation. The study depicts successful development and validation of a simple RP-HPLC method of EFZ using DoE approach.

Recent developments in the synthesis of bio-inspired iron porphyrins for small molecule activation.

Nature utilizes a diverse set of tetrapyrrole-based macrocycles (referred to as porphyrinoids) for catalyzing various biological processes. Investigation of the differences in electronic structure and reactivity in these reactions have revealed striking differences that lead to diverse reactivity from, apparently, similar looking active sites. Therefore, the role of the different heme cofactors as well as the distal superstructure in the proteins is important to understand. This article summarizes the role of a few synthetic metallo-porphyrinoids towards catalyzing several small molecule activation reactions, such as the ORR, NiRR, CO2RR, etc. The major focus of the article is to enlighten the synthetic routes to the well-decorated active-site mimic in a tailor-made fashion pursuing a retrosynthetic approach, learning from the biosynthesis of the cofactors. Techniques and the role of the second-sphere residues on the reaction rate, selectivity, etc. are incorporated emulating the basic amino acid residues fencing the active sites. These bioinspired mimics play an important role towards understanding the role of the prosthetic groups as well as the basic residues towards any reaction occurring in Nature.

Upsurge in autophagy, associated with mifepristone-treated polycystic ovarian condition, is reversed upon thymoquinone treatment.

Polycystic ovarian syndrome (PCOS) is a multi-factorial gynecological endocrine disorder. It affects fertility in women and also predisposes to insulin resistance, type 2 diabetes mellitus, obesity etc. Earlier, significance of autophagy has been explored in PCOS-related metabolic disorders and during normal folliculogenesis. Increasing evidences reveal connection of autophagy with chronic inflammatory behaviour, an associated phenomena in polycystic ovaries. However, understanding of the association of autophagy with PCOS is still obscure. This study reveals that increased autophagy in mifepristone (RU486) treated KK-1 cells and in vivo PCO rat model is characterized by upregulated Androgen Receptor (AR) expression and downregulated PCO biomarker aromatase. The prevalence of autophagy has been observed to be concomitant with increased expression of two autophagic markers Beclin1 and MAP-LC3-II while the autophagy substrate p62/SQSTM1 was downregulated. Immunohistochemical staining revealed increased localization of MAP-LC3 in the compacted granulosa layers of the follicular cysts in the PCO model. The PCO rat models also demonstrated augmented levels of p65, the active subunit of NF-κB, which acts as a transcriptional regulator of several pro-inflammatory factors. NF-κB repressor and anti-inflammatory herbal drug thymoquinone, known to alleviate PCO condition, downregulated autophagy modules substantially. Pre-treatment with thymoquinone upregulated aromatase, reduced AR levels and decreased autophagic markers as well as p65 levels, simulating super-ovulated condition. In conclusion, the anti-inflammatory phytochemical thymoquinone alleviated PCO condition.

Drug Permeation against Efflux by Two Transporters.

The development of new antibiotics against Gram-negative bacteria is hampered by the powerful protective properties of their cell envelope. This envelope consists of two membranes augmented by efflux transporters, which act in synergy to restrict cellular access to a broad range of chemical compounds. Recently, a kinetic model of this system has been constructed. The model revealed a complex, nonlinear behavior of the system, complete with a bifurcation, and matched very well to experimental uptake data. Here, we expand the model to include multiple transporters and apply it to an experimental analysis of antibiotic accumulation in wild-type and efflux-deficient Escherichia coli. We show that transporters acting across the inner and outer membranes have synergistic effects with each other. In contrast, transporters acting across the same membrane are additive as a rule but can be synergistic under special circumstances owing to a bifurcation controlled by the barrier constant. With respect to ethidium bromide, the inner membrane transporter MdfA was synergistic to the TolC-dependent efflux across the outer membrane. The agreement between the model and drug accumulation was very good across a range of tested drug concentrations and strains. However, antibiotic susceptibilities related only qualitatively to the accumulation of the drugs or predictions of the model and could be fit to the model only if additional assumptions were made about the physiological consequences of prolonged cell exposure to the drugs. Thus, the constructed model correctly predicts transmembrane permeation of various compounds and potentially their intracellular activity.

Multi-functional, multicompartmental hyaluronan-binding protein 1 (HABP1/p32/gC1qR): implication in cancer progression and metastasis.

Cancer is a complex, multi-factorial, multi-stage disease and a global threat to human health. Early detection of nature and stage of cancer is highly crucial for disease management. Recent studies have proved beyond any doubt about the involvement of the ubiquitous, myriad ligand binding, multi-functional human protein, hyaluronan-binding protein 1 (HABP1), which is identical to the splicing factor associated protein (p32) and the receptor of the globular head of the complement component (gC1qR) in tumorigenesis and cancer metastasis. Simultaneously three laboratories have discovered and named this protein separately as mentioned. Subsequently, different scientists have worked on the distinct functions in cellular processes ranging from immunological response, splicing mechanism, sperm-oocyte interactions, cell cycle regulation to cancer and have concentrated in their respective area of interest, referring it as either p32 or gC1qR or HABP1. HABP1 overexpression has been reported in almost all the tissue-specific forms of cancer and correlated with stage and poor prognosis in patients. In order to tackle this deadly disease and for therapeutic intervention, it is imperative to focus on all the regulatory aspects of this protein. Hence, this work is an attempt to combine an assortment of information on this protein to have an overview, which suggests its use as a diagnostic marker for cancer. The knowledge might assist in the designing of drugs for therapeutic intervention of HABP1/p32/gC1qR regulated specific ligand mediated pathways in cancer.