Unlocking the Immunomodulatory Potential of Rosmarinic Acid Isolated from Punica granatum L. Using Bioactivity-Guided Approach: In Silico, In Vitro, and In Vivo Approaches.

BACKGROUND: Punica granatum L. is well-known for its multifaceted therapeutic potential, including anti-inflammatory and immunomodulatory activities. AIM: This study aimed to characterize an immunomodulatory compound isolated from Punica granatum L. using a bioactivity-guided approach. METHODS: Chromatographic techniques were adopted for isolation and purification of secondary metabolites. In silico, in vitro, and in vivo methods were performed to characterize the therapeutic potential of the isolated compound. RESULTS: Using preparative thin-layer chromatography, rosmarinic acid was isolated from F4 (column chromatography product obtained from a butanolic fraction of the extract). The impact of rosmarinic acid was assessed in rats using the neutrophil adhesion test, DTH response, and phagocytic index. In immunized rats, rosmarinic acid demonstrated significant immunomodulatory potential. Computational experiments, like molecular docking and molecular dynamics, were also conducted against two targeted receptors, Cereblon (PDB ID: 8AOQ) and human CD22 (PDB ID: 5VKM). Computational studies suggested that an increase in phagocytic index by rosmarinic acid could be attributed to inhibiting Cereblon and CD22. Pharmacokinetics and toxicity prediction also suggested the drug-likeness of rosmarinic acid. CONCLUSION: Rosmarinic acid is a potential candidate, but extensive research needs to be done to translate this molecule from bench to bedside.

Mechanism-based Suppression of Cancer by Targeting DNA-Replicating Enzymes.

The human genetic structure undergoes continuous wear and tear process due to the mere presence of extrinsic as well as intrinsic factors. In normal physiological cells, DNA damage initiates various checkpoints that may activate the repair system or induce apoptosis that helps maintain cellular integrity. While in cancerous cells, due to alterations in signaling pathways and defective checkpoints, there exists a marked deviation of error-free DNA repairing/synthesis. Currently, cancer therapy targeting the DNA damage response shows significant therapeutic potential by tailoring the therapy from non-specific to tumor-specific activity. Recently, numerous drugs that target the DNA replicating enzymes have been approved or some are under clinical trial. Drugs like PARP and PARG inhibitors showed sweeping effects against cancer cells. This review highlights the mechanistic study of different drug categories that target DNA replication and thus depicts the futuristic approach of targeted therapy.

Nanomedicine: Innovative Strategies and Recent Advances in Targeted Cancer Therapy.

Nanomedicine's application of nanotechnology in medicine holds tremendous potential for diagnosing and treating life-threatening diseases such as cancer. Unlike conventional therapies, nanomedicine offers a promising strategy to enhance clinical outcomes while minimizing severe side effects. The principle of drug targeting enables specific delivery of therapeutic agents to their intended sites, making it a more precise and effective therapy. Combination strategies, such as the co-delivery of chemotherapeutic drugs with nucleic acids or receptor-specific molecules, are being employed to enhance therapeutic outcomes. Nanocarriers and drug delivery systems designed using these approaches offer resourceful co-delivery of therapeutic agents for anticancer therapy. Targeted drug delivery via nanotechnology-based techniques has become an urgent need and has shown significant improvements in therapeutic implications, pharmacokinetics, specificity, reduced toxicity, and biocompatibility. This review discusses the extrapolation of nanomaterials for developing innovative and novel drug delivery systems for effective anticancer therapy. Additionally, we explore the role of nanotechnology-based concepts in drug delivery research.

siRNA-Based Novel Therapeutic Strategies to Improve Effectiveness of Antivirals: An Insight.

Since the ground-breaking discovery of RNA interference (RNAi), scientists have made significant progress in the field of small interfering RNA (siRNA) treatments. Due to severe barriers to the therapeutic application of siRNA, nanoparticle technologies for siRNA delivery have been designed. For pathological circumstances such as viral infection, toxic RNA abnormalities, malignancies, and hereditary diseases, siRNAs are potential therapeutic agents. However, systemic administration of siRNAs in vivo remains a substantial issue due to a lack of "drug-likeness" (siRNA are relatively larger than drugs and have low hydrophobicity), physiological obstacles, and possible toxicities. This write-up covers important accomplishment in the field of clinical trials and patents specially based of siRNAs using targeting viruses. Furthermore, it offers deep insight of nanoparticle applied for siRNA delivery and strategies to improve the effectiveness of antivirals.

Promising Repurposed Antiviral Molecules to Combat SARS-CoV-2: A Review.

COVID-19, an extremely transmissible and pathogenic viral disease, triggered a global pandemic that claimed lives worldwide. To date, there is no clear and fully effective treatment for COVID-19 disease. Nevertheless, the urgency to discover treatments that can turn the tide has led to the development of a variety of preclinical drugs that are potential candidates for probative results. Although most of these supplementary drugs are constantly being tested in clinical trials against COVID-19, recognized organizations have aimed to outline the prospects in which their use could be considered. A narrative assessment of current articles on COVID-19 disease and its therapeutic regulation was performed. This review outlines the use of various potential treatments against SARS-CoV-2, categorized as fusion inhibitors, protease inhibitors, and RNA-dependent RNA polymerase inhibitors, which include antiviral drugs such as Umifenovir, Baricitinib, Camostatmesylate, Nafamostatmesylate, Kaletra, Paxlovide, Darunavir, Atazanavir, Remdesivir, Molnupiravir, Favipiravir, and Ribavirin. To understand the virology of SARS-CoV-2, potential therapeutic approaches for the treatment of COVID-19 disease, synthetic methods of potent drug candidates, and their mechanisms of action have been addressed in this review. It intends to help readers approach the accessible statistics on the helpful treatment strategies for COVID-19 disease and to serve as a valuable resource for future research in this area.

Recent Catalytic Advances on the Sustainable Production of Primary Furanic Amines from the One-Pot Reductive Amination of 5-Hydroxymethylfurfural.

5-Hydroxymethylfurfural (5-HMF) represents a well-known class of lignocellulosic biomass-derived platform molecules. With the presence of many reactive functional groups in the structure, this versatile building block could be valorized into many value-added products. Among well-established catalytic transformations in biorefinery, the reductive amination is of particular interest to provide valuable N-containing compounds. Specifically, the reductive amination of 5-HMF with ammonia (NH3 ) and molecular hydrogen (H2 ) offers a straightforward and sustainable access to primary furanic amines [i. e., 5-hydroxymethyl-2-furfuryl amine (HMFA) and 2,5-bis(aminomethyl)furan (BAMF)], which display far-reaching utilities in pharmaceutical, chemical, and polymer industries. In the presence of heterogeneous catalysts contanining monometals (Ni, Co, Ru, Pd, Pt, and Rh) or bimetals (Ni-Cu and Ni-Mn), this elegant pathway enables a high-yielding and chemoselective production of HMFA/BAMF compared to other synthetic routes. This Review aims to present an up-to-date highlight on the supported metal-catalyzed reductive amination of 5-HMF with elaborate studies on the role of metal, solid support, and reaction parameters. Besides, the recyclability/adaptability of catalysts as well as the reaction mechanism are also provided to give valuable insights into this potential 5-HMF valorization strategy.

WITHDRAWN: Current Synopsis on siRNA Therapeutics as a Novel Anti-Cancer and Antiviral Strategy: Progress and Challenges

The article has been withdrawn at the request of the editor of the journal Current Pharmaceutical Biotechnology.Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php. BENTHAM SCIENCE DISCLAIMER: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Synthesis of 2,5-furandicarboxylic acid-enriched-chitosan for anti-inflammatory and metal ion uptake.

The main aim of the present study is to synthesize a hitherto unreported polymer of chitosan (CS) and 2,5-furandicarboxylic acid (FDCA) derived from renewable biomass resources. For this purpose, CS was chosen which had -NH2 groups as abundant active sites. Synthesis of 2,5-furandicarboxylic acid-enriched-chitosan polymer (CS-FDCA) was carried out by reaction involving EDC-NHS coupling reagents. The structure of CS-FDCA polymer was confirmed by various characterization techniques such as Fourier-transform infrared spectroscopy (FTIR), proton nuclear magnetic resonance (1H NMR), X-ray powder diffraction (XRD), high resolution-field emission scanning electron microscope (HR-FESEM), and thermogravimetric analysis (TGA). Moreover, CS and CS-FDCA were scrutinized to examine their efficacies towards ameliorate inflammation via detection of lipopolysaccharide (LPS) induced nitric oxide (NO) production. As compared to CS, CS-FDCA with low concentration (1.0 µM) exhibited the better efficacy to reduce the NO production. Furthermore, CS-FDCA polymer showed high as 12.6% of Cu2+ ion uptake while CS showed 9.2% of Cu2+ ion uptake. Overall, it can be inferred that CS-FDCA polymer is expected to be used for biomedical application and for the removal of metal contaminants from industrial wastewater.

Immune cell engineering: opportunities in lung cancer therapeutics.

Engineered immune cells offer a prime therapeutic alternate for some aggressive and frequently occurring malignancies like lung cancer. These therapies were reported to result in tumor regression and overall improvement in patient survival. However, studies also suggest that the presence of cancer cell-induced immune-suppressive microenvironment, off-target toxicity, and difficulty in concurrent imaging are some prime impendent in the success of these approaches. The present article reviews the need and significance of the currently available immune cell-based strategies for lung cancer therapeutics. It also showcases the utility of incorporating nanoengineered strategies and details the available formulations of nanocarriers. In last, it briefly discussed the existing methods for nanoparticle fuctionalization and challenges in translating basic research to the clinics. Graphical Abstract.

Marble-burying behavior test as a murine model of compulsive-like behavior.

Object burying by rodents is a popular screening tool for anxiolytic agents. However, modulation of marble-burying by serotonin reuptake inhibitors prompted its link to obsessive-compulsive disorder/compulsive-like behavior. The Marble-burying behavior test is an acute test; however, some investigators incorporate the sub-acute treatment regimen as an essential component for screening anti-compulsive agents. The test exhibits between-laboratory methodological differences and demonstrates positive treatment responses to an array of pharmacotherapies, creating doubts about its predictive validity and construct validity. Numerous reviews are available on marble-burying behavior test, which incorporates the test as a part of anti-compulsive behavior-like screens, but none has made it a sole subject-matter for discussion. This review attempts to provide a comprehensive account of the marble-burying test as a model of compulsive-like disorders. It envisages the model's scientific origins, the preclinical research done and its correlation with the clinical research outcomes, and a detailed discussion about its validity. In conclusion, there appears a need to address the issue of construct and predictive validity of the model authoritatively; or the paradigm may remain squandered in the field of obsessive-compulsive disorder research.

Nano-engineered flavonoids for cancer protection.

Diet and environment are two critical regulators that influence an individual's epigenetic profile. Besides the anterograde signaling, mitochondria act as a key regulator of epigenetic alterations in cancer either by controlling the concentration of the cofactors, activity of vital enzymes or by affecting the transcription of NF-kappaB and associated signaling molecules. As epigenetic modifications are the major drivers of aberrant gene expression, designing novel nutri-epigenomic strategies to modulate reversible epigenetic modifications will be important for effective cancer protection. In this regard, nutraceuticals such as flavonoids holds significant promise to modulate the epigenome through a network of interconnected anti-redox mechanisms. However, low solubility, rapid metabolism and poor absorption of flavonoids in gastrointestinal tract hinder their use in clinical settings. Therefore, it is imperative to develop nano-engineered systems which could considerably improve the targeted delivery of these bioactive compounds with better efficacy and pharmacokinetic properties. Concerted efforts in nano-engineering of flavonoids using polymer, lipid and complexation based approaches could provide successful bench-to-bedside translation of flavonoids as broad spectrum anti-cancer agents.

Budding Alliance of Nanotechnology in RNA Interference Therapeutics.

RNA interference (RNAi), as a novel technique in which RNA molecules limit or silence the gene expression, is currently a hot research topic for producing novel therapeutic materials for challenging diseases. In the development of RNAi-based therapies, nanoscale particles, with a varying diameter along with facile modification methods that can mediate effective RNAi with targeting potential, are gaining wide interest. The nanotechnology itself has tremendous potential in the field of healthcare, especially for the development of better pharmaceuticals. Nano-enabled delivery has shown great success in the delivery of RNAi based therapeutics to specific locations in the body. Especially, siRNAs show great potential for use in nucleic acid therapeutics because of their potent and specific RNAi-triggering activity. This review summarizes the advanced nanocarriers such as solid lipid nanoparticles, gold nanoparticles, silver nanoparticles, iron oxide nanoparticles, polymeric nanoparticles, nanotransformers and curdlan nanoparticles with special emphasis on various aspects of siRNA-based therapeutics.

Ultrafine particulate matter impairs mitochondrial redox homeostasis and activates phosphatidylinositol 3-kinase mediated DNA damage responses in lymphocytes.

Particulate matter (PM), broadly defined as coarse (2.5-10 µm), fine (0.1-2.5 µm) and ultrafine particles (≤0.1 µm), is a major constituent of ambient air pollution. Recent studies have linked PM exposure (coarse and fine particles) with several human diseases including cancer. However, the molecular mechanisms underlying ultrafine PM exposure induced cellular and sub-cellular repercussions are ill-defined. Since mitochondria are one of the major targets of different environmental pollutants, we herein aimed to understand the molecular repercussion of ultrafine PM exposure on mitochondrial machinery in peripheral blood lymphocytes. Upon comparative analysis, a significantly higher DCF fluorescence was observed in ultrafine PM exposed cells that confirmed the strong pro-oxidant nature of these particles. In addition, the depleted activity of antioxidant enzymes, glutathione reductase and superoxide dismutase suggested the strong association of ultrafine PM with oxidative stress. These results further coincided with mitochondrial membrane depolarization, altered mitochondrial respiratory chain enzyme activity and decline in mtDNA copy number. Moreover, the higher accumulation of DNA damage response proteins (γH2AX, pATM, p-p53), suggested that exposure to ultrafine PM induces DNA damage and triggers phosphatidylinositol 3 kinase mediated response pathway. Further, the alterations in mitochondrial machinery and redox balance among ultrafine PM exposed cells were accompanied by a considerably elevated pro-inflammatory cytokine response. Interestingly, the lower apoptosis levels observed in ultrafine particle treated cells suggest the possibility that the marked alterations may lead to the impairment of mitochondrial-nuclear cross talk. Together, our results showed that ultrafine PM, because of their smaller size possesses significant ability to disturb mitochondrial redox homeostasis and activates phosphatidylinositol 3 kinase mediated DNA damage response pathway, an unknown molecular paradigm of ultrafine PM exposure. Our findings also indicate that maneuvering through the mitochondrial function might be a viable, indirect method to modulate lymphocyte homeostasis in air pollution associated immune disorders.

Dendritic cell engineering for selective targeting of female reproductive tract cancers.

Female reproductive tract cancers (FRCs) are considered as one of the most frequently occurring malignancies and a foremost cause of death among women. The late-stage diagnosis and limited clinical effectiveness of currently available mainstay therapies, primarily due to the developed drug resistance properties of tumour cells, further increase disease severity. In the past decade, dendritic cell (DC)-based immunotherapy has shown remarkable success and appeared as a feasible therapeutic alternative to treat several malignancies, including FRCs. Importantly, the clinical efficacy of this therapy is shown to be restricted by the established immunosuppressive tumour microenvironment. However, combining nanoengineered approaches can significantly assist DCs to overcome this tumour-induced immune tolerance. The prolonged release of nanoencapsulated tumour antigens helps improve the ability of DC-based therapeutics to selectively target and remove residual tumour cells. Incorporation of surface ligands and co-adjuvants may further aid DC targeting (in vivo) to overcome the issues associated with the short DC lifespan, immunosuppression and imprecise uptake. We herein briefly discuss the necessity and progress of DC-based therapeutics in FRCs. The review also sheds lights on the future challenges to design and develop clinically effective nanoparticles-DC combinations that can induce efficient anti-tumour immune responses and prolong patients' survival.

Nanoengineered strategies for siRNA delivery: from target assessment to cancer therapeutic efficacy.

The promise of RNA interference (RNAi) technology in cancer therapeutics aims to deliver small interfering RNA (siRNA) for silencing of gene expression in cell type-specific pathway. However, the challenge for the delivery of stable siRNA is hindered by an immune-hostile tumor microenvironment and physiological barriers of the circulatory system. Therefore, the development and validation of safe, stable, and efficient nanoengineered delivery systems are highly essential for effective delivery of siRNA into cancer cells. This review focuses on gene-silencing mechanisms, challenges to siRNA delivery, design and delivery of nanocarrier systems, ongoing clinical trials, and translational prospects for siRNA-mediated cancer therapeutics.

Amorphous solid dispersion technique for improved drug delivery: basics to clinical applications.

Solid dispersion has emerged as a method of choice and has been extensively investigated to ascertain the in vivo improved performance of many drug formulations. It generally involves dispersion of drug in amorphous particles (clusters) or in crystalline particles. Comparatively, in the last decade, amorphous drug-polymer solid dispersion has evolved into a platform technology for delivering poorly water-soluble small molecules. However, the success of this technique in the pharmaceutical industry mainly relies on different drug-polymer attributes like physico-chemical stability, bioavailability and manufacturability. The present review showcases the efficacy of amorphous solid dispersion technique in the research and evolution of different drug formulations particularly for those with poor water soluble properties. Apart from the numerous mechanisms of action involved, a comprehensive summary of different key parameters required for the solubility enhancement and their translational efficacy to clinics is also emphasized.

Synthesis and characterization of a novel graft copolymer of partially carboxymethylated guar gum and N-vinylformamide.

Graft copolymer of partially carboxymethylated guar gum (CMGOH) and N-vinylformamide (NVF) was synthesized by free radical polymerization using 2,2-Azobis [2-(2-imadazolin-2-yl) propane] dihydrochloride (AIPH) as initiator. The effect of various reaction parameters such as concentration of NVF, CMGOH, sulphuric acid and AIPH, as well as reaction time and temperature were investigated, and the grafting conditions were optimized. Percent total conversion, % grafting, grafting efficiency (%) and percent add on under different conditions were evaluated and compared. The reaction mechanism for graft copolymerization discussed. Studies on swelling, metal ion uptake and flocculation properties were carried out in aqueous medium and the results obtained are presented and discussed. Both CMGOH and its corresponding graft copolymer samples were characterized by Fourier transform infrared spectroscopy and thermogravimetric analysis. Looking at the reasonable results obtained, the synthesized graft copolymers CMGOH-g-NVF, may be exploited as potential candidates for some industrial important applications as flocculent superabsorbent, and other similar applications.

Solid dispersion in pharmaceutical drug development: from basics to clinical applications.

The solubility of drugs is one of the most challenging aspects in developing formulations for novel drug discovery. Myriad of approaches have been developed and tested to overcome the associated intricacies involved with poor water soluble drugs. Out of the available technologies, solid dispersion (SD) method that significantly enhances the solubility and bioavailability by reducing particle size to a micro-molecular level is often viewed as a promising strategy. Although conceptual basis of manufacturing processes involved in SD method have been reported, formulation characteristics addressing solubility issues remains yet elusive. The current review portray the historical milestones, classification, probable mechanisms for enhancement of solubility, manufacturing processes at commercial level along with pioneer breakthroughs in field that enunciates the versatile pharmaceutical application for categories including anti-cancer and anti-retroviral drugs. Besides, our article also highlights the translational implications of drug development by SD method hitherto unreported.

Transdermal immunization: biological framework and translational perspectives.

INTRODUCTION: The renaissance in drug delivery research during the past decade led to several new approaches toward vaccine development. Transdermal immunization (TI) is a promising modality with both practical and immunological merits. Compared with conventional routes of administration, this needle-free delivery approach with ability to target the rich immunologically milieu of the skin provides a dual-edged benefit. It not only elicits an effective immune response in both systemic and mucosal compartments but has the potential to make vaccine delivery more equitable, safer and efficient. AREAS COVERED: Over the years, numerous studies have explored physical, chemical and nanocarrier-based strategies to develop vaccines using this attractive route of delivery. The review provides insight into the various facets including research at interface that might drive novel basic scientific ideas to translational outcomes. EXPERT OPINION: As we continue to develop TI as a vaccine delivery method, it is important to consider the practical application of this method and device strategies that best fit the public health needs. In the authors' view, nanoengineering-based approaches holds a great promise to overcome the associated challenges in TI and might help to translate early laboratory successes into the development of effective clinical prophylactics.