Temperature and oxidation-sensitive liposomes were prepared by stabilizing dioleoylphosphatidylethanolamine (DOPE) bilayers with the ion pair of poly(ethyleneimine)/(phenylthio)acetic acid (PEI/PTA). An upper critical solution temperature (UCST) behavior was observed when PEI/PTA ion pair was suspended in an aqueous solution. It was observed that the UCST increased with increasing PTA content. The ion pair was self-assembled into nanospheres owing to its amphiphilic property which was confirmed by transmission electron microscopy. The FT-IR spectroscopic spectrum showed that the ion pair formed a salt bridge between the amino group and the carboxyl group and the PTA content in the ion pair was readily oxidized by H2O2. Further, DOPE liposomal membranes could be stabilized with PEI/PTA ion pair. Due to the amphiphilic property, the ion pair played a role as a stabilizer for the formation of DOPE liposomes. The liposome released its payload in a temperature-responsive manner, possibly because when the temperature is raised, the ion pair loses its amphiphilic property and can be detached from the liposomal membrane. The liposome was also oxidation-responsive in terms of release, possibly because the amphiphilic property of the ion pair disappears when the PTA is oxidized.
In the past few years, therapeutic microRNA (miRNA) and small interfering RNA (siRNA) are some of the most important biopharmaceuticals that are in commercial space as future medicines. This review summarizes the patents of miRNA- and siRNA-based new drugs, and also provides a snapshot about significant biopharmaceutical companies that are investing for the therapeutic development of miRNA and siRNA molecules. An insightful view about individual siRNA and miRNA drugs has been depicted with their present status, which is gaining attention in the therapeutic landscape. The efforts of the biopharmaceuticals are discussed with the status of their preclinical and/or clinical trials. Here, some of the setbacks have been highlighted during the biopharmaceutical development of miRNA and siRNA as individual therapeutics. Finally, a snapshot is illustrated about pharmacokinetics, pharmacodynamics with absorption, distribution, metabolism, and excretion (ADME), which is the fundamental development process of these therapeutics, as well as the delivery system for miRNA- and siRNA-based drugs.
Thecurrent research investigates the quality of ten different surface water sites in and around Jodhpur using water quality ratings. This paper gives insight into water pollution's qualitative and quantitative extent. The water quality index (WQI)is usedfor assessing and comparing water quality. In each study region, a five-point grading scale was adopted to classify water quality as a single understandable value. Twelveparameters were employed for determining the WQI of different sites: turbidity, TSS, TDS, conductivity, alkalinity, hardness, calcium, magnesium, chloride, fluoride, and nitrate. Multivariate analysis of the samplesrevealed that most of the individual parameters are not in harmony with the standard values prescribed by the regulating authorities. According to the study, seasonal fluctuations play a significant effect in the hydrochemistry of surface water, indicating a change in WQI. Thesamples showed less pollution in the pre-monsoonseason as compared to post-monsoon. Overall, this paper lays forth a strategy for proper utilization and protection, as well as assesses the quality of surface water to determine its suitability for various uses and its impact on groundwater quality.
Soibum, a naturally fermented bamboo-shoot food, is an important ethnical food of Manipur, India. This study was undertaken to optimise conditions for in vitro fermentation of bamboo shoot and to evaluate the nutritional parameter. Microbiological analysis was conducted to determine the bacterial population. In this study, bamboo shoot had been fermented and process optimised by using a bacterium (isolate FB2–4) which was identified as Serratia marcescens. It was used as inoculum for fermentation at different parameters and nutritional quality of final product was analysed. The experiments were varied for (1) fermentation of sterilised bamboo shoot with 16 different isolates (2) fermentation by using FB2–4 at different temperatures (30°C, 35°C and 40°C), (3) effect of different inoculum size of FB2–4 fermentation (104, 106, 108 cfu/ml). Bacterial isolate FB2–4 results better product compared with other isolates. The pH of sterilised in-vitro fermented samples was found to be around 3.7 and that of the control was recorded to be around pH 6. The amount of protein, sugar, amino acid in fermented Soibum was found to be 2.85g/100g, 1.2g/100g, 0.54g/100g, respectively. The nutritional parameter including concentrations of protein, sugar, amino acid were better when fermentation was done at temperature 30°C (3.92±0.5g/100g, 10.2±0.01g/100g, 0.54±0.04 g/100g, respectively) and inoculum size 104 cfu/ml (3.77±0.1g/100g, 10.6±0.06g/100g, 0.14±0.04g/100g, respectively). In this study, in-vitro fermentation condition was found enhanced good nutritional parameters compared with the Soibum.
Despite advancements in drug discovery techniques, developing medications for diverse ailments still remains challenging. As a result, novel techniques such as drug repurposing are required to develop therapeutics to treat both common and rare disorders. Drug repurposing is a potential approach in drug discovery for identifying new therapeutic applications for existing medications that are distinct from the original medical indication. Identification of new indications for existing drugs by drug repurposing has the potential to supplement traditional drug development by reducing the substantial monetary and time costs and hazards associated with the latter. To date, most of the repurposed drugs are a result of serendipitous discovery through careful observations by physicians, medical staffs and basic researchers. Repurposing approaches involving experimental screening and computational approaches are already developed to increase the speed and ease of the repurposing process. With the advancement of technologies such as proteomics, genomics, transcriptomics, metabolomics and the availability of massive databases resources such as drug omics data, disease omics data and so on, there are a plethora of opportunities to discover drugs by combining all of the above methods/approaches.
Polymorphisms of G‐protein‐coupled receptor kinase 4γ (GRK4γ) are associated with human hypertension and induce hypertension in mice. Data suggest that three polymorphisms of GRK4γ (A142V, R65L, A486V) have increased activity compared to the wild‐type (wt) GRK4γ; however, the mechanism of activation of GRK4γ remains unknown. GRK5 and GRK6, which are members of the GRK4 family, are well studied and provide a model for GRK4. Electrostatic interactions hold together the regulators of G protein signaling homology (RH) domain and kinase domain (KD) of GRK5 in a closed (inactive) conformation, and the RH‐KD must separate (open) to display kinase activity. The opening of the RH‐KD may be a family‐wide biochemical mechanism. Molecular dynamics simulations (MD) of wt GRK4γ and A142V GRK4γ in a water water‐box indicate that GRK4γ shares similar electrostatic interactions as GRK5, but displays little spontaneous RH‐KD opening. When wt GRK4γ and A142V GRK4γ are simulated bound to a lipid membrane, domain separation statistically increases suggesting that GRK4γ is active when bound to a membrane matching initial biochemical characterization of GRK4. To investigate which GRK4γ residues interact with the membrane and the mechanism of membrane‐induced RH‐KD separation a frequency‐matrix of each residue's interaction with the membrane was clustered by K‐means and HDBSCAN. Both clustering techniques indicate that A142V GRK4γ samples a more diverse protein‐lipid interaction surface and the clusters consolidate into three different groups based on RH‐KD separation. As HDBSCAN does not force samples into a cluster, our analysis focused on the HDBSCAN clusters. The mean RH‐KD separation over 4.5 μs of simulation is 14.1% ± 11%. The large deviation is due to one cluster opening 31.4% of the time while another only 0.8% of the time; the rest of the clusters are near the mean. wt GRK4γ populates a unique and a shared cluster that is open 12.1% and 13.5% of the time, respectively. A142V GRK4γ populates three unique clusters and the shared cluster that open 12.7%, 31.4%, 0.8%, and 13.5% of the time, respectively. The 31.4% and 0.8% clusters have unique frequency‐matrixes suggesting that altered lipid interactions drive RH‐KD separation. Specifically, greater open probability associates with additional KD contacts with the membrane compared to the three average clusters, and loss of common interactions at the termini results in depressed open probability. The interaction data suggests that for GRK4γ to undergo domain separation it is more favorable to have the kinase domain anchored to the membrane. The KD attachment to the membrane allows for a hinge predicted to lie between the RH domain and KD to flex. Understanding the mechanism underlying GRK4γ domain separation allows for testing if domain separation is required for receptor phosphorylation and desensitization. Additionally, MD identified changes in orientation at the membrane resulting in increased RH‐KD separation provides a plausible and testable hypothesis to explain the observed increased activity of A142V GRK4γ. Support or Funding Information Support for this work is from WesternU MSPS program funds. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
BACKGROUNDNew chemotherapeutic agents and new protocols in oncology have led to an increasing survival rate in patients affected by tumours.Traditional chemotherapy drugs as well as the newer targeted agents are associated with a wide array of cutaneous toxicities. [1]Toxic effects on skin, hair and nails can negatively affect the quality of life and also lead to interruption or discontinuation of these drugs. [2]im-To study the various mucocutaneous adverse effects associated with cancer chemotherapy. MATERIALS AND METHODSA total of 200 patients with malignancies undergoing chemotherapy in the oncology ward and outpatient department were screened in this observational study.We have clinically examined 200 patients affected by cancer determining type, treatment and evolution of cutaneous side effects related to chemotherapy.It is a hospital-based observational study.All patients were counselled about the study and informed written consent was obtained.Patients were examined before start of chemotherapy treatment and after every cycle of chemotherapy.Data collected was analysed using SPSS version 16.0. RESULTSIn this study, 200 patients including 118 females and 82 males were studied.Majority (56%) of the patients belonged to the age group of 41 -60 years.The common indications for chemotherapy were carcinoma breast (29%), tongue (11%), buccal mucosa (10%), ovary (8%) and stomach (6%).Among the cutaneous adverse events noted, hair changes were the most common presentation and were reported in 156 (78%) patients.Skin changes were seen in 130 (65%) cases, nail changes in 102 (51%) cases and mucosal changes in 46 (23%) patients.Cisplatin, cyclophosphamide, 5-fluorouracil, carboplatin, paclitaxel and doxorubicin were the most frequently prescribed chemotherapeutic drugs. CONCLUSIONOncological therapies have become more selective and have low systemic toxicity because of their high specificity, but cutane ous side effects are common and may worsen the quality of life of these patients.Our observations necessitate a joint effort between dermatology and oncology for the early recognition and adequate treatment of the cutaneous adverse effects associated with cancer chemotherapy, which may help in reducing morbidity and improving compliance.
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