Spectroscopy and dynamics of beta-lactoglobulin complexed with rifampicin.

In this paper, we report the binding interaction of milk protein, beta-lactoglobulin (BLG), with an antibiotic against tuberculosis, rifampicin (RIF). BLG intrinsic fluorescence from tryptophan (Trp) amino acids was monitored to understand protein-drug interactions. Binding parameters and stoichiometry were estimated with the help of fluorescence spectral changes. Synchronous fluorescence spectroscopy was employed to exclusively monitor the Trp and Tyrosine (Tyr) environment in the presence of RIF. With the help of steady state fluorescence at different temperatures supported by time-resolved fluorescence, we confirmed that the protein forms a static complex with RIF. Thermodynamic parameters, ΔH and ΔS values, showed the involvement of hydrophobic forces between the RIF and BLG. Competitive displacement assay with ANS confirmed the BLG calyx as the binding site for RIF. Energy transfer mechanism from Trp to RIF was attributed to the fluorescence changes in protein upon complexation. The Förster resonance energy transfer (FRET) was used to find distance, energy transfer efficiency and rate of energy transfer between donor (BLG) and acceptor (RIF). Fourier-transform infrared (FTIR) spectroscopy was utilized for estimating changes in the secondary structure of BLG induced by RIF. Molecular docking was used to visualise the binding location of RIF on BLG. Molecular dynamics (MD) simulation studies showed a consistent binding interactions between BLG and RIF during the 100 ns simulation period and this well supported the increased beta sheet content in FTIR. Overall our results establish the potential of intrinsic fluorescence of BLG in combination with biophysical tools to rationalize drug-protein interactions.Communicated by Ramaswamy H. Sarma.

Dissecting the functional significance of HSP90AB1 and other heat shock proteins in countering glioblastomas and ependymomas using omics analysis and drug prediction using virtual screening.

Heat shock proteins (HSPs) are the evolutionary family of proteins that are highly conserved and present widely in various organisms and play an array of important roles and cellular functions. Currently, very few or no studies are based on the systematic analysis of the HSPs in Glioblastoma (GBMs) and ependymomas. We performed an integrated omics analysis to predict the mutual regulatory differential HSP signatures that were associated with both glioblastoma and ependymomas. Further, we explored the various common dysregulated biological processes operating in both the tumors, and were analyzed using functional enrichment, gene ontology along with the pathway analysis of the predicted HSPs. We established an interactome network of protein-protein interaction (PPIN) to identify the hub HSPs that were commonly associated with GBMs and ependymoma. To understand the mutual molecular mechanism of the HSPs in both malignancies, transcription factors, and miRNAs overlapping with both diseases were explored. Moreover, a transcription factor-miRNAs-HSPs coregulatory network was constructed along with the prediction of potential candidate drugs that were based on perturbation-induced gene expression analysis. Based on the RNA-sequencing data, HSP90AB1 was identified as the most promising target among other predicted HSPs. Finally, the ranking of the drugs was arranged based on various drug scores. In conclusion, this study gave a spotlight on the mutual targetable HSPs, biological pathways, and regulatory signatures associated with GBMs and ependymoma with an improved understanding of crosstalk involved. Additionally, the role of therapeutics was also explored against HSP90AB1. These findings could potentially be able to explain the interplay of HSP90AB1 and other HSPs within these two malignancies.

Spontaneous hydrogen production using gadolinium telluride.

Developing materials for controlled hydrogen production through water splitting is one of the most promising ways to meet current energy demand. Here, we demonstrate spontaneous and green production of hydrogen at high evolution rate using gadolinium telluride (GdTe) under ambient conditions. The spent materials can be reused after melting, which regain the original activity of the pristine sample. The phase formation and reusability are supported by the thermodynamics calculations. The theoretical calculation reveals ultralow activation energy for hydrogen production using GdTe caused by charge transfer from Te to Gd. Production of highly pure and instantaneous hydrogen by GdTe could accelerate green and sustainable energy conversion technologies.

Clinicomycological Profile and Risk Factors for Dermatophytosis at a Teaching Tertiary Care Centre in North India: A Cross-sectional Study.

BACKGROUND: Dermatophytosis has gained significant importance in recent years owing to increased incidence, more atypical lesions, changing mycological profile and growing antifungal resistance. Therefore, this study was planned to know the clinicomycological profile of dermatophytic infections in patients attending our tertiary care centre. MATERIALS AND METHODS: A total of 700 patients with superficial fungal infections belonging to all age groups and both sexes were taken up for this cross-sectional study. Sociodemographic and clinical details were noted on a prestructured proforma. Superficial lesions were clinically examined and the sample was collected by appropriate collection methods. Direct microscopy by potassium hydroxide wet mount was done to see hyphae. For culture Sabouraud's dextrose agar (SDA) with chloramphenicol and cyclohexamide was used. RESULTS: Dermatophytic infections were detected in 75.8% (531/700) patients. Young people belonging to age group of 21-30 years were commonly affected. Tinea corporis was the commonest clinical picture seen in 20% of the cases. Oral antifungals were taken by 33.1% and topical creams were used by 74.2% of the patients. Direct microscopy was positive in 91.3% and culture was positive for dermatophytes in 61% of the study subjects. T. mentagrophytes was the commonest dermatophyte isolated. CONCLUSION: Irrational use of topical steroids needs to be controlled. KOH microscopy can be useful as a point of care test for rapid screening of dermatophytic infections. Culture is necessary to differentiate various dermatophytes and to guide the antifungal treatment.

Decoding the Role of MDM2 as a Potential Ubiquitin E3 Ligase and Identifying the Therapeutic Efficiency of Alkaloids against MDM2 in Combating Glioblastoma.

Glioblastomas (GBMs) represent the most aggressive form of brain tumor arising from the malignant transformation of astrocytes. Despite various advancements, treatment options remain limited to chemotherapy and radiotherapy followed by surgery giving an overall survival of 14-15 months. These therapies are somewhere restricted in giving a better survival and cure. There is a need for new therapeutics that could potentially target GBM based on molecular pathways and pathology. Here, ubiquitin E3 ligases can be used as targets as they bind a wide array of substrates and therefore can be attractive targets for new inhibitors. Through this study, we have tried to sort various ubiquitin E3 ligases based on their expression, pathways to which these ligases are associated, and mutational frequencies, and then we tried to screen potent inhibitors against the most favorable E3 ligase as very few studies are available concerning inhibition of E3 ligase in GBM. Our study found MDM2 to be the most ideal E3 ligase and further we tried to target MDM2 against various compounds under the alkaloid class. Molecular Docking and MD simulations combined with ADMET properties and BBB scores revealed that only evodiamine and sanguinarine were effective in inhibiting MDM2. We also tried to give a proposed mechanism of how these inhibitors mediate the p53 signaling in GBM. Therefore, the new scaffolds predicted by the computational approach could help in designing promising therapeutic agents targeting MDM2 in glioblastoma.

Electrochemical Energy Harvesting Using Microbial Active Matter.

With the continuous growth in world population and economy, the global energy demand is increasing rapidly. Given that non-renewable energy sources will eventually deplete, there is increasing need for clean, alternative renewable energy sources, which will be inexpensive and involve minimum risk of environmental pollution. In this paper, harnessing the activity of cupric reductase NDH-2 enzyme present in Escherichia coli bacterial cells, we demonstrate a simple and efficient energy harvesting strategy within an electrochemical chamber without the requirement of any external fuels or force fields. The transduction of energy has been demonstrated with various strains of E. coli, indicating that this strategy could, in principle, be applicable for other microbial catalytic systems. We offer a simple mechanism of the energy transduction process considering the bacterial enzyme-mediated redox reaction occurring over the working electrode of the electrochemical cell. Also, the amount of energy generated has been found to be depending on the motility of bacteria within the experimental chamber, suggesting possible opportunities for developing microbial motility-controlled small scale power generators. Finally, we show that the Faradaic electrochemical energy harvested is large enough to power a commercial light emitting diode connected to an amplifier circuit. We expect the present study to generate sufficient interest within soft condensed matter and biophysics communities, and offer useful platforms for controlled energy generation at the small scales.

Epidemiological, clinical and mycological characteristics of pityriasis versicolor: Results of a study from a teaching hospital in rural part of Northern India.

Background and Objectives: Pityriasis versicolor is a common fungal infection of the skin which leads to the formation of scaly and discoloured small lesions on skin. The main objective of this study is to describe clinical and mycological characteristics and the predisposing factors in patients with pityriasis versicolor. Material and Methods: In this prospective, observational, hospital-based cross-sectional study, patients of all ages with clinically suspected lesions of pityriasis versicolor were included. After detailed history and thorough clinical examination, skin scrapings were examined with 10% potassium hydroxide (KOH) under light microscope. The scrapings were also subjected to culture examination. Results: A total of 113 patients [78 (69.0%) male; 35 (31%) female] were included in the study. A total of 87 (76.9%) patients were from rural area. Outdoor occupation and positive family history of pityriasis versicolor was present in 65 (57.5%) and 38 (33.6%) patients, respectively. Recurrent episodes were reported by 66 (60%) patients. Excessive sweating and oily skin were seen in 36 (31.8%) and 24 (21.1%) patients, respectively. History of occlusive clothing was present in 22 (19.4%) patients. Chest, back, and shoulders were affected in 36 (31.8%), 22 (19.4%), and 08 (07.0%) patients, respectively. Hypopigmented lesions were seen in 97 (85.8%) patients. Patches and macules were observed in 60 (53.1%) and 53 (46.9%) patients, respectively. A total of 27 (23.8%) patients reported mild prutitus. A total of 79 (69.9%) patients were KOH positive and culture negative, whereas 26 (23.0%) patients were KOH as well as culture positive. Eight (7.0%) patients were both KOH and culture negative. Conclusion: Pytiriasis versicolor is more common in young adults and males with the most common presentation of hypopigmentation lesions. In our study population, presentation with large patches was more common than macular lesions. Pruritus was more in patients with large patches than those with macules.

Spectroscopic analysis to identify the binding site for Rifampicin on Bovine Serum Albumin.

This article reports the interaction of rifampicin, one of the important antituberculosis drugs, with Bovine Serum Albumin (BSA). Herein, we have monitored the fluorescence properties of tryptophan (Trp) residue in BSA to understand the interactions between protein and rifampicin. Fluorescence intensity of BSA was quenched tremendously upon interacting with the drug. Using steady state and time-resolved spectroscopic tools the static and dynamic nature of quenching have been characterised. Time correlated single photon counting technique confirmed that out of two lifetime components ∼6.2 ns and ∼2.8 ns of BSA, the rifampicin has affected only the shorter lifetime component a lot that was assigned to Trp-213 residue. Hence, it was thought that the drug must have been located near to the amino acid residue. Molecular docking studies have revealed the structural information of drug-protein complex which supported the above conjecture, confirming the nearest tryptophan as Trp-213 to the complexing rifampicin molecule.

Polysaccharide-based nanofibers for pharmaceutical and biomedical applications: A review.

Nanofibers are fibrous nanocarriers that can be synthesized from natural polymers, synthetic polymers, semiconducting materials, composite materials, and carbon-based materials. Recently, natural polysaccharides-based nanofibers are gaining attention in the field of pharmaceuticals and biomedical as these are biocompatible, biodegradable, non-toxic, and economic. Nanofibers can deliver a significant amount of drug to the targeted site and provide effective interaction of therapeutic agent at the site of action due to a larger surface area. Other important advantages of nanofibers are low density, high porosity, small pore size, high mechanical strength, and low cost. In this review, natural polysaccharides such as alginate, pullulan, hyaluronic acid, dextran, cellulose, chondroitin sulfate, chitosan, xanthan gum, and gellan gum are discussed for their characteristics, pharmaceutical utility, and biomedical applications. The authors have given particular emphasis to the several fabrication processes that utilize these polysaccharides to form nanofibers, and their recent updates in pharmaceutical applications such as drug delivery, tissue engineering, skin disorders, wound-healing dressings, cancer therapy, bioactive molecules delivery, anti-infectives, and solubility enhancement. Despite these many advantages, nanofibers have been explored less for their scale-up and applications in advanced therapeutic delivery.

Precision Oncology, Signaling, and Anticancer Agents in Cancer Therapeutics.

BACKGROUND: The global alliance for genomics and healthcare facilities provides innovative solutions to expedite research and clinical practices for complex and incurable health conditions. Precision oncology is an emerging field explicitly tailored to facilitate cancer diagnosis, prevention, and treatment based on patients' genetic profiles. Advancements in "omics" techniques, next-generation sequencing, artificial intelligence, and clinical trial designs provide a platform for assessing the efficacy and safety of combination therapies and diagnostic procedures. METHODS: Data were collected from PubMed and Google Scholar using keywords "Precision medicine," "precision medicine and cancer," "anticancer agents in precision medicine," and reviewed comprehensively. RESULTS: Personalized therapeutics, including immunotherapy and cancer vaccines, serve as a groundbreaking solution for cancer treatment. Herein, we take a measurable view of precision therapies and novel diagnostic approaches targeting cancer treatment. The contemporary applications of precision medicine have also been described, along with various hurdles identified in the successful establishment of precision therapeutics. CONCLUSION: This review highlights the key breakthroughs related to immunotherapies, targeted anticancer agents, and target interventions related to cancer signaling mechanisms. The success story of this field in context to drug resistance, safety, patient survival, and improving quality of life is yet to be elucidated. We conclude that, in the near future, the field of individualized treatments may truly revolutionize the nature of cancer patient care.

Unboxing the molecular modalities of mutagens in cancer.

The etiology of the majority of human cancers is associated with a myriad of environmental causes, including physical, chemical, and biological factors. DNA damage induced by such mutagens is the initial step in the process of carcinogenesis resulting in the accumulation of mutations. Mutational events are considered the major triggers for introducing genetic and epigenetic insults such as DNA crosslinks, single- and double-strand DNA breaks, formation of DNA adducts, mismatched bases, modification in histones, DNA methylation, and microRNA alterations. However, DNA repair mechanisms are devoted to protect the DNA to ensure genetic stability, any aberrations in these calibrated mechanisms provoke cancer occurrence. Comprehensive knowledge of the type of mutagens and carcinogens and the influence of these agents in DNA damage and cancer induction is crucial to develop rational anticancer strategies. This review delineated the molecular mechanism of DNA damage and the repair pathways to provide a deep understanding of the molecular basis of mutagenicity and carcinogenicity. A relationship between DNA adduct formation and cancer incidence has also been summarized. The mechanistic basis of inflammatory response and oxidative damage triggered by mutagens in tumorigenesis has also been highlighted. We elucidated the interesting interplay between DNA damage response and immune system mechanisms. We addressed the current understanding of DNA repair targeted therapies and DNA damaging chemotherapeutic agents for cancer treatment and discussed how antiviral agents, anti-inflammatory drugs, and immunotherapeutic agents combined with traditional approaches lay the foundations for future cancer therapies.

Pharmacological intervention in oxidative stress as a therapeutic target in neurological disorders.

OBJECTIVES: Oxidative stress is a major cellular burden that triggers reactive oxygen species (ROS) and antioxidants that modulate signalling mechanisms. Byproducts generated from this process govern the brain pathology and functions in various neurological diseases. As oxidative stress remains the key therapeutic target in neurological disease, it is necessary to explore the multiple routes that can significantly repair the damage caused due to ROS and consequently, neurodegenerative disorders (NDDs). Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the critical player of oxidative stress that can also be used as a therapeutic target to combat NDDs. KEY FINDINGS: Several antioxidants signalling pathways are found to be associated with oxidative stress and show a protective effect against stressors by increasing the release of various cytoprotective enzymes and also exert anti-inflammatory response against this oxidative damage. These pathways along with antioxidants and reactive species can be the defined targets to eliminate or reduce the harmful effects of neurological diseases. SUMMARY: Herein, we discussed the underlying mechanism and crucial role of antioxidants in therapeutics together with natural compounds as a pharmacological tool to combat the cellular deformities cascades caused due to oxidative stress.

Combinatorial therapy in tumor microenvironment: Where do we stand?

The tumor microenvironment plays a pivotal role in tumor initiation and progression by creating a dynamic interaction with cancer cells. The tumor microenvironment consists of various cellular components, including endothelial cells, fibroblasts, pericytes, adipocytes, immune cells, cancer stem cells and vasculature, which provide a sustained environment for cancer cell proliferation. Currently, targeting tumor microenvironment is increasingly being explored as a novel approach to improve cancer therapeutics, as it influences the growth and expansion of malignant cells in various ways. Despite continuous advancements in targeted therapies for cancer treatment, drug resistance, toxicity and immune escape mechanisms are the basis of treatment failure and cancer escape. Targeting tumor microenvironment efficiently with approved drugs and combination therapy is the solution to this enduring challenge that involves combining more than one treatment modality such as chemotherapy, surgery, radiotherapy, immunotherapy and nanotherapy that can effectively and synergistically target the critical pathways associated with disease pathogenesis. This review shed light on the composition of the tumor microenvironment, interaction of different components within tumor microenvironment with tumor cells and associated hallmarks, the current status of combinatorial therapies being developed, and various growing advancements. Furthermore, computational tools can also be used to monitor the significance and outcome of therapies being developed. We addressed the perceived barriers and regulatory hurdles in developing a combinatorial regimen and evaluated the present status of these therapies in the clinic. The accumulating depth of knowledge about the tumor microenvironment in cancer may facilitate further development of effective treatment modalities. This review presents the tumor microenvironment as a sweeping landscape for developing novel cancer therapies.

Chitosan-based microneedles as a potential platform for drug delivery through the skin: Trends and regulatory aspects.

Microneedles (MNs) fabrication using chitosan has gained significant interest due to its ability of film-forming, biodegradability, and biocompatibility, making it suitable for topical and transdermal drug delivery. The presence of amine and hydroxyl functional groups on chitosan permits the modification with tunable properties and functionalities. In this regard, chitosan is the preferred material for fabrication of MNs because it does not produce an immune response in the body and can be tailored as per required strength and functionalities. Therefore, many researchers have attempted to use chitosan as a drug delivery vehicle for hydrophilic drugs, peptides, and hormones. In 2020, the FDA has issued "Regulatory Considerations for Microneedling Products". This official guidance is a sign for future opportunities in the development of MNs. The present review focuses on properties, and modifications of chitosan used in the fabrication of MNs. The therapeutic and diagnostic applications of different types of chitosan-based MNs have been discussed. Further, the regulatory aspects of MN-based devices, and patents related to chitosan-based MNs are discussed.

Protocol based management of common sports injuries by integrated approach of Sandhi Marmabhighata - An open labeled clinical trial.

BACKGROUND: Sports injuries are the second most common type of accident after domestic (3.7%) and occupational accidents (3.1%). There is an average annual estimate of 8.6 million sports and recreational related injury incidents with an age-adjusted rate of 34.1 per 1000 populations. Common sports injuries are musculoskeletal injuries i.e. Sprains, Strains, Joint injuries, soft tissue injury (STI). The sports injury in Ayurveda can be co-related within dissimilar facets of trauma related ailments. OBJECTIVE: To evaluate the efficacy of a protocol-based management of common sports injuries using an integrated approach. MATERIALS AND METHODS: Integration of Ayurveda and Physiotherapy procedures was done and phase wise treatment was framed. Total 30 patients of age between 10 and 60 years ful-filling the inclusion criteria were selected for the present study. The patients were treated with Phase wise protocol consisting of three phase's i.e. Inflammatory (1-5 days), Stabilization and recovery (6-10 days), Muscle strengthening (11-17 days). Assessments were done through various variables like pain, tenderness, swelling, local temperature, manual muscle testing (MMT) and range of motion (ROM) at different time points. STATISTICAL ANALYSIS: Wilcoxon matched pair test was used to assess within group results for subjective parameters and paired t-test (Dependent t-test) was used to assess for objective parameters. RESULT: The study showed that integrated treatment approach has given significant results in the parameters like pain, loss of function, tenderness, local temperature, MMT and ROM. CONCLUSION: Phase wise management through integrated protocol is effective in the management of common sports injuries.

Protective role of anticancer drugs in neurodegenerative disorders: A drug repurposing approach.

The disease heterogeneity and little therapeutic progress in neurodegenerative diseases justify the need for novel and effective drug discovery approaches. Drug repurposing is an emerging approach that reinvigorates the classical drug discovery method by divulging new therapeutic uses of existing drugs. The common biological background and inverse tuning between cancer and neurodegeneration give weight to the conceptualization of repurposing of anticancer drugs as novel therapeutics. Many studies are available in the literature, which highlights the success story of anticancer drugs as repurposed therapeutics. Among them, kinase inhibitors, developed for various oncology indications evinced notable neuroprotective effects in neurodegenerative diseases. In this review, we shed light on the salient role of multiple protein kinases in neurodegenerative disorders. We also proposed a feasible explanation of the action of kinase inhibitors in neurodegenerative disorders with more attention towards neurodegenerative disorders. The problem of neurotoxicity associated with some anticancer drugs is also highlighted. Our review encourages further research to better encode the hidden potential of anticancer drugs with the aim of developing prospective repurposed drugs with no toxicity for neurodegenerative disorders.

Dry reforming activity due to ionic Ru in La1.99Ru0.01O3: the role of specific carbonates.

Dry reforming of methane was carried out over La2-2xRu2xO3 (x = 0.005, 0.01). Substitution of just 0.5 atom% of Ru in La2O3 enhanced the activity by 20 times in terms of conversion when compared to the activity exhibited by La2O3. The oxygen storage capacity of the Ru doped sample was considerably higher than undoped La2O3, which resulted in higher conversions of CH4 and CO2. The measured conversion of CH4 and CO2 was 72 and 80%, respectively, at 850 °C. The same was merely 4% with La2O3 under the same experimental conditions. DRIFTS studies demonstrated the role of a specific type of carbonates in promoting the activity of the catalyst. DFT calculations provided the rationale behind the selection of the Ru-in-La2O3 methane dry reforming catalyst. The surface structures of the pure and Ru-substituted compounds were determined, corroborating the experimental observation of enhanced oxygen storage capacity on Ru substitution. Different active surface oxygen species were identified and their roles in improving reducibilities and improving reactivities were established. The experimentally observed surface carbonate species were also identified using calculations. The combined experiment + calculation approach proved ionic Ru in La2-2xRu2xO3 to be a novel and efficient dry reforming catalyst.

Morphology controlled graphene-alloy nanoparticle hybrids with tunable carbon monoxide conversion to carbon dioxide.

Selective oxidation of CO to CO2 using metallic or alloy nanoparticles as catalysts can solve two major problems of energy requirements and environmental pollution. Achieving 100% conversion efficiency at a lower temperature is a very important goal. This requires sustained efforts to design and develop novel supported catalysts containing alloy nanoparticles. In this regard, the decoration of nanoalloys with graphene, as a support for the catalyst, can provide a novel structure due to the synergic effect of the nanoalloys and graphene. Here, we demonstrate the effect of nano-PdPt (Palladium-Platinum) alloys having different morphologies on the catalytic efficiency for the selective oxidation of CO. Efforts were made to prepare different morphologies of PdPt alloy nanoparticles with the advantage of tuning the capping agent (PVP - polyvinyl pyrollidone) and decorating them on graphene sheets via the wet-chemical route. The catalytic activity of the G-PdPt hybrids with an urchin-like morphology has been found to be superior (higher % conversion at 135 °C lower) to that with a nanoflower morphology. The above experimental observations are further supported by molecular dynamics (MD) simulations.

Correction: Green synthesis of 1,4-benzodiazepines over La2O3 and La(OH)3 catalysts: possibility of Langmuir-Hinshelwood adsorption.

[This corrects the article DOI: 10.1039/C6RA22719H.].

Unusual Clinical Presentations in Early-Onset Childhood Sarcoidosis: A Correlation or Coincidence?

Sarcoidosis is a multisystem granulomatous disease which frequently affects young adults. Because of its rarity, the exact incidence and prevalence of childhood sarcoidosis is not known. It mostly affects children of older age group i.e., 13-15 years. Early onset sarcoidosis (<5 years) is characterized by a triad of arthritis, uveitis and rash. Late onset sarcoidosis present with a multisystem disease similar to adults, with frequent pulmonary infiltrations and lymphadenopathy. Herein, we report a case of early-onset childhood sarcoidosis in a four-year-old female along with uncommon clinical features like cutaneous ulceration, onycholysis and geographical tongue and its rarity in the literature.