Mechanistic insights into antifungal potential of Alexidine dihydrochloride and hexachlorophene in Candida albicans: a drug repurposing approach.

Candida albicans has been listed in the critical priority group by the WHO in 2022 depending upon its contribution in invasive candidiasis and increased resistance to conventional drugs. Drug repurposing offers an efficient, rapid, and cost-effective solution to develop alternative therapeutics against pathogenic microbes. Alexidine dihydrochloride (AXD) and hexachlorophene (HCP) are FDA approved anti-cancer and anti-septic drugs, respectively. In this study, we have shown antifungal properties of AXD and HCP against the wild type (reference strain) and clinical isolates of C. albicans. The minimum inhibitory concentrations (MIC50) of AXD and HCP against C. albicans ranged between 0.34 and 0.69 µM and 19.66-24.58 µM, respectively. The biofilm inhibitory and eradication concentration of AXD was reported comparatively lower than that of HCP for the strains used in the study. Further investigations were performed to understand the antifungal mode of action of AXD and HCP by studying virulence features like cell surface hydrophobicity, adhesion, and yeast to hyphae transition, were also reduced upon exposure to both the drugs. Ergosterol content in cell membrane of the wild type strain was upregulated on exposure to AXD and HCP both. Biochemical analyses of the exposed biofilm indicated reduced contents of carbohydrate, protein, and e-DNA in the extracellular matrix of the biofilm when compared to the untreated control biofilm. AXD exposure downregulated activity of tissue invading enzyme, phospholipase in the reference strain. In wild type strain, ROS level, and activities of antioxidant enzymes were found elevated upon exposure to both drugs. FESEM analysis of the drug treated biofilms revealed degraded biofilm. This study has indicated mode of action of antifungal potential of alexidine dihydrochloride and hexachlorophene in C. albicans.

Molecular insight into the structural and functional aspects of arene Ru(II) complexes bearing bulky thiourea ligands.

Herein we report four new arene ruthenium(II) complexes [RuII(η6-p-cymene)(L1)к1(S)Cl2] (C1), [RuII(η6-benzene)(L1)к1(S)Cl2] (C2) where L1 is N-((2,6-dimethylphenyl)carbamothioyl)benzamide (L1), and [RuII(η6-p-cymene)(L2)к1(S)Cl2] (C3), [RuII(η6-benzene)(L2)к1(S)Cl2] (C4) where L2 is N-((2,6-diisopropylphenyl)carbamothioyl)benzamide (L2) which were synthesized and evaluated for biological activity. The monodentate coordination of thione sulphur (S) to ruthenium ion along with two terminal chloride was confirmed by X-Ray diffraction analysis thus revealing a typical "piano-stool" pseudo tetrahedral geometry. DPPH radical scavenging activity showed that ligands were less efficient however on complex formation it showed significant efficacy with C4 showing the highest activity. The ligands and ruthenium complexes exhibited minimal to no cytotoxic effects on HEK cells within the concentration range of 10-300 µM. Evaluating the cytotoxicity against prostate cancer cells (DU145) L1, L2 and C1 displayed more pronounced cytotoxic activity with C1 showing high cytotoxicity against the cancer cells, in comparison to cisplatin indicating its potential for further investigation and analysis. Considering this, compound C1 was used to further study its interaction with BSA using fluorescence spectroscopy and it was found to be 2.64 × 106 M-1. Findings from CD spectroscopy indicate the binding in the helix region which was further confirmed with the molecular docking studies.

Targeting chemokine-receptor mediated molecular signaling by ethnopharmacological approaches.

ETHNOPHARMACOLOGICAL RELEVANCE: Infection and inflammation are critical to global human health status and the goal of current pharmacological interventions intends formulating medications/preventives as a measure to deal with this situation. Chemokines and their cognate receptors are major regulatory molecules in many of these ailments. Natural products have been a keen source to the drug development industry, every year contributing significantly to the growing list of FDA approved drugs. A multiverse of natural resource is employed as a part of curative regimen in folk/traditional/ethnomedicine which can be employed to discover, repurpose, and design potent medications for the diseases of clinical concern. AIM OF THE STUDY: This review aims to systematically document the ethnopharmacologically active agents targeting the infectious-inflammatory diseases through the chemokine-receptor nexus. MATERIALS AND METHODS: Articles related to chemokine/receptor modulating ethnopharmacological anti-inflammatory, anti-infectious natural sources, bioactive compounds, and formulations have been examined with special emphasis on women related diseases. The available literature has been thoroughly scrutinized for the application of traditional medicines in chemokine associated experimental methods, their regulatory outcomes, and pertinence to women's health wherever applicable. Moreover, the potential traditional regimens under clinical trials have been critically assessed. RESULTS: A systematic and comprehensive review on the chemokine-receptor targeting ethnopharmaceutics from the available literature has been provided. The article discusses the implication of traditional medicine in the chemokine system dynamics in diverse infectious-inflammatory disorders such as cardiovascular diseases, allergic diseases, inflammatory diseases, neuroinflammation, and cancer. On this note, critical evaluation of the available data surfaced multiple diseases prevalent in women such as osteoporosis, rheumatoid arthritis, breast cancer, cervical cancer and urinary tract infection. Currently there is no available literature highlighting chemokine-receptor targeting using traditional medicinal approach from women's health perspective. Moreover, despite being potent in vitro and in vivo setups there remains a gap in clinical translation of these formulations, which needs to be strategically and scientifically addressed to pave the way for their successful industrial translation. CONCLUSIONS: The review provides an optimistic global perspective towards the applicability of ethnopharmacology in chemokine-receptor regulated infectious and inflammatory diseases with special emphasis on ailments prevalent in women, consecutively addressing their current status of clinical translation and future directions.

Protein-Based Nanocarriers and Nanotherapeutics for Infection and Inflammation.

Infectious and inflammatory diseases are one of the leading causes of death globally. The status quo has become more prominent with the onset of the coronavirus disease 2019 (COVID-19) pandemic. To combat these potential crises, proteins have been proven as highly efficacious drugs, drug targets, and biomarkers. On the other hand, advancements in nanotechnology have aided efficient and sustained drug delivery due to their nano-dimension-acquired advantages. Combining both strategies together, the protein nanoplatforms are equipped with the advantageous intrinsic properties of proteins as well as nanoformulations, eloquently changing the field of nanomedicine. Proteins can act as carriers, therapeutics, diagnostics, and theranostics in their nanoform as fusion proteins or as composites with other organic/inorganic materials. Protein-based nanoplatforms have been extensively explored to target the major infectious and inflammatory diseases of clinical concern. The current review comprehensively deliberated proteins as nanocarriers for drugs and nanotherapeutics for inflammatory and infectious agents, with special emphasis on cancer and viral diseases. A plethora of proteins from diverse organisms have aided in the synthesis of protein-based nanoformulations. The current study specifically presented the proteins of human and pathogenic origin to dwell upon the field of protein nanotechnology, emphasizing their pharmacological advantages. Further, the successful clinical translation and current bottlenecks of the protein-based nanoformulations associated with the infection-inflammation paradigm have also been discussed comprehensively. SIGNIFICANCE STATEMENT: This review discusses the plethora of promising protein-based nanocarriers and nanotherapeutics explored for infectious and inflammatory ailments, with particular emphasis on protein nanoparticles of human and pathogenic origin with reference to the advantages, ADME (absorption, distribution, metabolism, and excretion parameters), and current bottlenecks in development of protein-based nanotherapeutic interventions.

Serum Metabolomics of Retinoblastoma: Assessing the Differential Serum Metabolic Signatures of Unilateral and Bilateral Patients.

Retinoblastoma (Rb) is the most common pediatric eye cancer. To identify the biomarkers for early diagnosis and monitoring the progression of Rb in patients, mapping of the alterations in their metabolic profiles is essential. The present study aims at exploring the metabolic disparity in serum from Rb patients and controls using NMR-based metabolomics. A total of 72 metabolites, including carbohydrates, amino acids, and organic acids, were quantified in serum samples from 24 Rb patients and 26 controls. Distinct clusters of Rb patients and controls were obtained using the partial least-squares discriminant analysis (PLS-DA) model. Further, univariate and multivariate analyses of unilateral and bilateral Rb patients with respect to their age-matched controls depicted their distinct metabolic fingerprints. Metabolites including 2-phosphoglycerate, 4-aminobutyrate, proline, O-phosphocholine, O-phosphoethanolamine, and Sn-glycero-3-phosphocholine (Sn-GPC) showed significant perturbation in both unilateral and bilateral Rb patients. However, metabolic differences among the bilateral Rb cases were more pronounced than those in unilateral Rb cases with respect to controls. In addition to major discriminatory metabolites for Rb, unilateral and bilateral Rb cases showed specific metabolic changes, which might be the result of their differential genetic/somatic mutational backgrounds. This further suggests that the aberrant metabolic perturbation in bilateral patients signifies the severity of the disease in Rb patients. The present study demonstrated that identified serum metabolites have potential to serve as a noninvasive method for detection of Rb, discriminate bilateral from unilateral Rb patients, and aid in better understanding of the RB tumor biology.

Baicalin functionalized PEI-heparin carbon dots as cancer theranostic agent.

The worldwide prevalence of cancer and its significantly rising risks with age have garnered the attention of nanotechnology for prompt detection and effective therapy with minimal or no adverse effects. In the current study, heparin (HP) polymer derived heteroatom (N, S-) co-doped CDs were synthesized using hydrothermal synthesis method to efficiently deliver natural anticancer compound baicalin (BA). Heparin carbon dots (HCDs) were passivated with polyethylenimine (PEI) to improve its fluorescence quantum yield. The surface passivation of CDs by polycationic PEI polymer not only facilitated loading of BA, but also played a crucial role in the pH-responsive drug delivery. The sustained release of BA (up to 80 %) in mildly acidic pH (5.5 and 6.5) conditions endorsed its drug delivery potential for cancer-specific microenvironments. BA-loaded PHCDs exhibited enhanced anticancer activity as compared to BA/PHCDs indicating the effectiveness of the nanoformulation, Furthermore, the flow cytometry analysis confirmed that BA-PHCDs treated cells were arrested in the G2/M phase of cell cycle and had a higher potential for apoptosis. Bioimaging study demonstrated the excellent cell penetration efficiency of PHCDs with complete cytoplasmic localization. All this evidence comprehensively demonstrates the potency of BA-loaded PHCDs as a nanotheranostic agent for cancer.

Identifying Treatment Resistance Related Pathways by Analyzing Serum Extracellular Vesicles of Patients With Resistant Versus Regressed Retinoblastoma.

Purpose: To identify the genes and pathways responsible for treatment resistance (TR) in retinoblastoma (RB) by analyzing serum small extracellular vesicles (sEVs) of patients with TR active RB (TR-RB) and completely regressed RB (CR-RB). Methods: Serum-derived sEVs were characterized by transmission electron microscopy and nanoparticle tracking analysis. sEV transcriptome profiles of two TR-RB and one CR-RB with good response (>20 years tumor free) were compared to their age-matched controls (n = 3). Gene expression data were analyzed by the R Bioconductor package. The CD9 protein and mRNA expression of CD9, CD63, and CD81 were studied in five RB tumors and two control retinae by immunohistochemistry and quantitative reverse transcription-polymerase chain reaction. Results: The isolated serum sEVs were round shaped and within the expected size (30-150 nm), and they had zeta potentials ranging from -10.8 to 15.9 mV. The mean ± SD concentrations of sEVs for two adults and four children were 1.1 × 1012 ± 0.1 and 5.8 × 1011 ± 1.7 particles/mL. Based on log2 fold change of ±2 and P < 0.05 criteria, there were 492 dysregulated genes in TR-RB and 184 in CR-RB. KAT2B, VWA1, CX3CL1, MLYCD, NR2F2, USP46-AS1, miR6724-4, and LINC01257 genes were specifically dysregulated in TR-RB. Negative regulation of apoptotic signaling, cell growth, and proton transport genes were greater than fivefold expressed only in TR-RB. CD9, CD63, and CD81 mRNA levels were high in RB tumors versus control retina, with increased and variable CD9 immunoreactivity in the invasive areas of the tumor. Conclusions: Serum sEVs could serve as a potential liquid biopsy source for understanding TR mechanisms in RB.

A review on structural mechanisms of protein-persistent organic pollutant (POP) interactions.

With the advent of the industrial revolution, the accumulation of persistent organic pollutants (POPs) in the environment has become ubiquitous. POPs are halogen-containing organic molecules that accumulate, and remain in the environment for a long time, thus causing toxic effects in living organisms. POPs exhibit a high affinity towards biological macromolecules such as nucleic acids, proteins and lipids, causing genotoxicity and impairment of homeostasis in living organisms. Proteins are essential members of the biological assembly, as they stipulate all necessary processes for the survival of an organism. Owing to their stereochemical features, POPs and their metabolites form energetically favourable complexes with proteins, as supported by biological and dose-dependent toxicological studies. Although individual studies have reported the biological aspects of protein-POP interactions, no comprehensive study summarizing the structural mechanisms, thermodynamics and kinetics of protein-POP complexes is available. The current review identifies and classifies protein-POP interaction according to the structural and functional basis of proteins into five major protein targets, including digestive and other enzymes, serum proteins, transcription factors, transporters, and G-protein coupled receptors. Further, analysis detailing the molecular interactions and structural mechanism evidenced that H-bonds, van der Waals, and hydrophobic interactions essentially mediate the formation of protein-POP complexes. Moreover, interaction of POPs alters the protein conformation through kinetic and thermodynamic processes like competitive inhibition and allostery to modulate the cellular signalling processes, resulting in various pathological conditions such as cancers and inflammations. In summary, the review provides a comprehensive insight into the critical structural/molecular aspects of protein-POP interactions.

Half-sandwich ruthenium(II), rhodium(III) and iridium(III) fluorescent metal complexes containing pyrazoline based ligands: DNA binding, cytotoxicity and antibacterial activities.

A series of nine new complexes of ruthenium(II), rhodium(III), and iridium(III) incorporated with pyrazoline-based ligands were synthesized and characterized by various spectroscopic techniques such as FTIR, 1H NMR, 13C NMR, UV-Vis spectroscopy, ESI-MS spectrometry and X-ray crystallographic studies. All the synthesized compounds were assessed for their antibacterial abilities against Gram-positive and Gram-negative bacterial strains. The compounds showed better antibacterial activity against two Gram-positive bacteria (Staphylococcus aureus and Bacillus Thuringiensis), with activities superior to standard kanamycin. Antioxidant studies revealed the mild radical scavenging proficiency of the compounds. DNA binding studies using fluorescence spectroscopy showed that the compounds could bind to Salmon Milt DNA electrostatically via external contact and groove surface binding with moderate affinity. The synthesized complexes were tested for anticancer activity using cell cytotoxicity and apoptosis assays in Dalton's lymphoma (DL) cell lines. The findings were compared to cisplatin (the standard drug) under identical experimental conditions. The cell viability results showed that complex 7 induced higher cytotoxicity in the DL cell line than the other tested compounds. The results of the molecular docking analysis further suggest that selective complexes have complete contact with the active amino acids sites of anti-apoptotic Bcl-2 family protein.

Comprehensive Analysis of Serum Small Extracellular Vesicles-Derived Coding and Non-Coding RNAs from Retinoblastoma Patients for Identifying Regulatory Interactions.

The present study employed nanoparticle tracking analysis, transmission electron microscopy, immunoblotting, RNA sequencing, and quantitative real-time PCR validation to characterize serum-derived small extracellular vesicles (sEVs) from RB patients and age-matched controls. Bioinformatics methods were used to analyze functions, and regulatory interactions between coding and non-coding (nc) sEVs RNAs. The results revealed that the isolated sEVs are round-shaped with a size < 150 nm, 5.3 × 1011 ± 8.1 particles/mL, and zeta potential of 11.1 to −15.8 mV, and expressed exosome markers CD9, CD81, and TSG101. A total of 6514 differentially expressed (DE) mRNAs, 123 DE miRNAs, and 3634 DE lncRNAs were detected. Both miRNA-mRNA and lncRNA-miRNA-mRNA network analysis revealed that the cell cycle-specific genes including CDKNI1A, CCND1, c-MYC, and HIF1A are regulated by hub ncRNAs MALAT1, AFAP1-AS1, miR145, 101, and 16-5p. Protein-protein interaction network analysis showed that eye-related DE mRNAs are involved in rod cell differentiation, cone cell development, and retinol metabolism. In conclusion, our study provides a comprehensive overview of the RB sEV RNAs and regulatory interactions between them.

Double-Edged Nanobiotic Platform with Protean Functionality: Leveraging the Synergistic Antibacterial Activity of a Food-Grade Peptide to Mitigate Multidrug-Resistant Bacterial Pathogens.

While persistent efforts are being made to develop a novel arsenal against bacterial pathogens, the development of such materials remains a formidable challenge. One such strategy is to develop a multimodel antibacterial agent which will synergistically combat bacterial pathogens, including multidrug-resistant bacteria. Herein, we used pediocin, a class IIa bacteriocin, to decorate Ag° and developed a double-edged nanoplatform (Pd-SNPs) that inherits intrinsic properties of both antibacterial moieties, which engenders strikingly high antibacterial potency against a broad spectrum of bacterial pathogens including the ESKAPE category without displaying adverse cytotoxicity. The enhanced antimicrobial activity of Pd-SNPs is due to their higher affinity with the bacterial cell wall, which allows Pd-SNPs to penetrate the outer membrane, inducing membrane depolarization and the disruption of membrane integrity. Bioreporter assays revealed the upregulation of cpxP, degP, and sosX genes, triggering the burst of reactive oxygen species which eventually cause bacterial cell death. Pd-SNPs prevented biofilm formation, eradicated established biofilms, and inhibited persister cells. Pd-SNPs display unprecedented advantages because they are heat-resistant, retain antibacterial activity in human serum, and alleviate vancomycin intermediate Staphylococcus aureus (VISA) infection in the mouse model. In addition, Pd-SNPs wrapped in biodegradable nanofibers mitigated Listeria monocytogenes in cheese samples. Collectively, Pd-SNPs exhibited excellent biocompatibility and in vivo therapeutic potency without allowing foreseeable resistance acquisition by pathogens. These findings underscore new avenues for using a potent biocompatible nanobiotic platform to combat a wide range of bacterial pathogens.

Autophagy based cellular physiological strategies target oncogenic progression.

Evidence accumulated from past findings indicates that defective proteostasis may contribute to risk factors for cancer generation. Irregular assembly of abnormal proteins catalyzes the disturbance of cellular proteostasis and induces the ability of abnormal cellular proliferation. The autophagy mechanism plays a key role in the regular clearance of abnormal/poor lipids, proteins, and various cellular organelles. The results of functional and effective autophagy deliver normal cellular homeostasis, which establishes supportive metabolism and avoids unexpected tumorigenesis events. Still, the precise molecular mechanism of autophagy in tumor suppression has not been clear. How autophagy triggers selective or nonselective bulk degradation to dissipate tumor promotion under stress conditions is not clear. Under proteotoxic insults to knockdown the drive of tumorigenesis, it is critical for us to figure out the detailed molecular functions of autophagy in human cancers. The current article summarizes autophagy-based theragnostic strategies targeting various phases of tumorigenesis and suggests the preventive roles of autophagy against tumor progression. A better understanding of various molecular partners of autophagic flux will improve and innovate therapeutic approaches based on autophagic-susceptible effects against cellular oncogenic transformation.

Molecular Insights into Conformational Heterogeneity and Enhanced Structural Integrity of Helicobacter pylori DNA Binding Protein Hup at Low pH.

The summarized amalgam of internal relaxation modulations and external forces like pH, temperature, and solvent conditions determine the protein structure, stability, and function. In a free-energy landscape, although conformers are arranged in vertical hierarchy, there exist several adjacent parallel sets with conformers occupying equivalent energy cleft. Such conformational states are pre-requisites for the functioning of proteins that have oscillating environmental conditions. As these conformational changes have utterly small re-arrangements, nuclear magnetic resonance (NMR) spectroscopy is unique in elucidating the structure-dynamics-stability-function relationships for such conformations. Helicobacter pylori survives and causes gastric cancer at extremely low pH also. However, least is known as to how the genome of the pathogen is protected from reactive oxygen species (ROS) scavenging in the gut at low pH under acidic stress. In the current study, biophysical characteristics of H. pylori DNA binding protein (Hup) have been elucidated at pH 2 using a combination of circular dichroism, fluorescence, NMR spectroscopy, and molecular dynamics simulations. Interestingly, the protein was found to have conserved structural features, differential backbone dynamics, enhanced stability, and DNA binding ability at low pH as well. In summary, the study suggests the partaking of Hup protein even at low pH in DNA protection for maintaining the genome integrity.

Neurodegeneration & imperfect ageing: Technological limitations and challenges?

Cellular homeostasis is regulated by the protein quality control (PQC) machinery, comprising multiple chaperones and enzymes. Studies suggest that the loss of the PQC mechanisms in neurons may lead to the formation of abnormal inclusions that may lead to neurological disorders and defective aging. The questions could be raised how protein aggregate formation precisely engenders multifactorial molecular pathomechanism in neuronal cells and affects different brain regions? Such questions await thorough investigation that may help us understand how aberrant proteinaceous bodies lead to neurodegeneration and imperfect aging. However, these studies face multiple technological challenges in utilizing available tools for detailed characterizations of the protein aggregates or amyloids and developing new techniques to understand the biology and pathology of proteopathies. The lack of detection and analysis methods has decelerated the pace of the research in amyloid biology. Here, we address the significance of aggregation and inclusion formation, followed by exploring the evolutionary contribution of these structures. We also provide a detailed overview of current state-of-the-art techniques and advances in studying amyloids in the diseased brain. A comprehensive understanding of the structural, pathological, and clinical characteristics of different types of aggregates (inclusions, fibrils, plaques, etc.) will aid in developing future therapies.

Elucidating the bioremediation mechanism of Scenedesmus sp. IITRIND2 under cadmium stress.

Cadmium (Cd) is a non-biodegradable pollutant that has become a global threat due to its bioaccumulation and biomagnification in higher trophic levels of the food chain. Green technologies such as phycoremediation is an emerging approach and possess edge over conventional methods to remediate Cd from the environment. The present investigation elucidates the adaptive mechanism of a freshwater microalga, Scenedesmus sp. IITRIND2 under Cd stress. The microalga showed excellent tolerance to Cd stress with IC50 value of ~32 ppm. The microalga showed phenomenal removal efficiency (~80%) when exposed to 25 ppm of Cd. Such a high uptake of Cd by the cells was accompanied with increased total lipid content (~33% of dry cell weight). Additionally, the elevated level of ROS, lipid peroxidation, glycine-betaine, and antioxidant enzymes evidenced the activation of efficient antioxidant machinery for alleviating the Cd stress. Further, analysis of the fatty acid methyl ester (FAME) presented a steady increase in saturated and polyunsaturated fatty acids with biodiesel properties complying the American and European fuel standards. The study proposes an integrated approach for bioremediation of toxic Cd using hyper-tolerant microalgal strains along with biodiesel production from the generated algal biomass.

Heavy metal detoxification mechanisms by microalgae: Insights from transcriptomics analysis.

Heavy metal pollution in ecosystem is a global threat. The associated toxicity and carcinogenic nature of heavy metals/metalloids such as mercury, cadmium, lead, and arsenic are imposing a severe risk to both ecological diversity and human lives. Harnessing the adaptive feature of microalgae for remediating toxic heavy metal has reached a milestone in past few decades. Transcriptomics analyses have provided mechanistic insights to map the dynamics of cellular events under heavy metal stress, thus deciphering the strategic responses of microalgae. Here, the present review comprehensively addresses the elicited molecular responses of microalgae to detoxify the heavy metal stress. The review highlights the intricate role of biochemical components and signaling networks mediating stress responsive transitions of microalgae at physiological level. Furthermore, the differential gene expression signifying the transporters involved in uptake, distribution/sequestration, and efflux of heavy metal has also been reviewed. In a nutshell, this study provided a comprehensive understanding of the molecular mechanisms adopted by microalgae at transcriptome level to nullify the oxidative stress while detoxifying the heavy metals.

Ibuprofen-based advanced therapeutics: breaking the inflammatory link in cancer, neurodegeneration, and diseases.

Ibuprofen is a classical nonsteroidal anti-inflammatory drug (NSAID) highly prescribed to reduce acute pain and inflammation under an array of conditions, including rheumatoid arthritis, osteoarthritis, dysmenorrhea, and gout. Ibuprofen acts as a potential inhibitor for cyclooxygenase enzymes (COX-1 and COX-2). In the past few decades, research on this small molecule has led to identifying other possible therapeutic benefits. Anti-tumorigenic and neuroprotective functions of Ibuprofen are majorly recognized in recent literature and need further consideration. Additionally, several other roles of this anti-inflammatory molecule have been discovered and subjected to experimental assessment in various diseases. However, the major challenge faced by Ibuprofen and other drugs of similar classes is their side effects, and tendency to cause gastrointestinal injury, generate cardiovascular risks, modulate hepatic and acute kidney diseases. Future research should also be conducted to deduce new methods and approaches of suppressing the unwanted toxic changes mediated by these drugs and develop new therapeutic avenues so that these small molecules continue to serve the purposes. This article primarily aims to develop a comprehensive and better understanding of Ibuprofen, its pharmacological features, therapeutic benefits, and possible but less understood medicinal properties apart from major challenges in its future application.KEY POINTSIbuprofen, an NSAID, is a classical anti-inflammatory therapeutic agent.Pro-apoptotic roles of NSAIDs have been explored in detail in the past, holding the key in anti-cancer therapies.Excessive and continuous use of NSAIDs may have several side effects and multiple organ damage.Hyperactivated Inflammation initiates multifold detrimental changes in multiple pathological conditions.Targeting inflammatory pathways hold the key to several therapeutic strategies against many diseases, including cancer, microbial infections, multiple sclerosis, and many other brain diseases.

Epigallocatechin Gallate with Potent Anti-Helicobacter pylori Activity Binds Efficiently to Its Histone-like DNA Binding Protein.

Helicobacter pylori (H. pylori)-a human gastric pathogen-forms a major risk factor for the development of various gastric pathologies such as chronic inflammatory gastritis, peptic ulcer, lymphomas of mucosa-associated lymphoid tissues, and gastric carcinoma. The complete eradication of infection is the primary objective of treating any H. pylori-associated gastric condition. However, declining eradication efficiencies, off-target effects, and patient noncompliance to prolong and broad-spectrum antibiotic treatments has spurred the clinical interest to search for alternative effective and safer therapeutic options. As natural compounds are safe and privileged with high levels of antibacterial-activity, previous studies have tested and reported a plethora of such compounds with potential in vitro/in vivo anti-H. pylori activity. However, the mode of action of majority of these natural compounds is unclear. The present study has been envisaged to compile the information of various such natural compounds and to evaluate their binding with histone-like DNA-binding proteins of H. pylori (referred here as Hup) using in silico molecular docking-based virtual screening experiments. Hup-being a major nucleoid-associated protein expressed by H. pylori-plays a strategic role in its survival and persistent colonization under hostile stress conditions. The ligand with highest binding energy with Hup-that is, epigallocatechin-(-)gallate (EGCG)-was rationally selected for further computational and experimental testing. The best docking poses of EGCG with Hup were first evaluated for their solution stability using long run molecular dynamics simulations and then using fluorescence and nuclear magnetic resonance titration experiments which demonstrated that the binding of EGCG with Hup is fairly strong (the resultant apparent dissociation constant (k D) values were equal to 2.61 and 3.29 ± 0.42 µM, respectively).

LRSAM1 E3 ubiquitin ligase promotes proteasomal clearance of E6-AP protein.

Numerous proteins participate and actively contribute to the various cellular mechanisms, where several of them are crucial for regular metabolism, including survival. Thus, to maintain optimal cellular physiology, cells govern protein quality control functions with the assistance of comprehensive actions of molecular chaperones, the ubiquitin-proteasome system, and autophagy. In the ubiquitin-proteasome pathway, few quality control E3 ubiquitin ligases actively participate against misfolded protein aggregation generated via stress conditions. But how these quality control E3s active expression levels returned to basal levels when cells achieved re-establishment of proteostasis is still poorly understood. Our current study demonstrated that LRSAM1 E3 ubiquitin ligase promotes the proteasomal degradation of quality control E3 ubiquitin ligase E6-AP. We have observed the co-localization and recruitment of LRSAM1 with E6-AP protein and noticed that LRSAM1 induces the endogenous turnover of E6-AP. Partial depletion of LRSAM1 elevates the levels of E6-AP and affects overall cell cycle regulatory proteins (p53 and p27) expression, including the rate of cellular proliferation. The current finding also provides an excellent opportunity to better understand the basis of the E6-AP associated pathomechanism of Angelman Syndrome disorder. Additionally, this study touches upon the novel potential molecular strategy to regulate the levels of one quality control E3 ubiquitin ligase with another E3 ubiquitin ligase and restore proteostasis and provide a possible therapeutic approach against abnormal protein aggregation diseases.

Protein nanocomposites: Special inferences to lysozyme based nanomaterials.

Protein nanocomposites have attracted considerable research interest in recent times owing to the combined advantageous properties of nanotechnology and proteins. Lysozyme holds enormous potential in various biomedical applications as it possesses antibacterial properties, anti-inflammatory, anti-cancer, and analgesic properties. Considering its multifunctional aspects, structural stability and ease of production and modification, special focus has been attributed to this protein. Nanocomposites have either been fabricated completely from lysozyme or have been conjugated to lysozyme considering its versatile biotechnological applications. The current review describes the recent advances of protein nanocomposites using lysozyme as a prime example. Along with the principles, techniques, and applications involved in protein based nanocomposites, this review also provides a comprehensive account of interactions between lysozyme and different nanoparticles. Numerous studies that have integrated the utilization of lysozyme and nanotechnology for a variety of applications have also been discussed at length.