Role and uptake of metal-based nanoconstructs as targeted therapeutic carriers for rheumatoid arthritis.

Rheumatoid Arthritis (RA) is a chronic autoimmune systemic inflammatory disease that affects the joints and other vital organs and diminishes the quality of life. The current developments and innovative treatment options have significantly slowed disease progression and improved their quality of life. Medicaments can be delivered to the inflamed synovium via nanoparticle systems, minimizing systemic and undesirable side effects. Numerous nanoparticles such as polymeric, liposomal, and metallic nanoparticles reported are impending as a good carrier with therapeutic properties. Other issues to be considered along are nontoxicity, nanosize, charge, optical property, and ease of high surface functionalization that make them suitable carriers for drug delivery. Metallic nanoparticles (MNPs) (such as silver, gold, zinc, iron, titanium oxide, and selenium) not only act as good carrier with desired optical property, and high surface modification ability but also have their own therapeutical potential such as anti-oxidant, anti-inflammatory, and anti-arthritic properties, making them one of the most promising options for RA treatment. Regardless, cellular uptake of MNPs is one of the most significant criterions for targeting the medication. This paper discusses the numerous interactions of nanoparticles with cells, as well as cellular uptake of NPs. This review provides the mechanistic overview on MNPs involved in RA therapies and regulation anti-arthritis response such as ability to reduce oxidative stress, suppressing the release of proinflammatory cytokines and expression of LPS induced COX-2, and modulation of MAPK and PI3K pathways in Kuppfer cells and hepatic stellate cells. Despite of that MNPs have also ability to regulates enzymes like glutathione peroxidases (GPxs), thioredoxin reductases (TrxRs) and act as an anti-inflammatory agent.

Targeting Pathways and Integrated Approaches to Treat Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic symmetrical systemic disorder that not only affects joints but also other organs such as heart, lungs, kidney, and liver. Approximately there is 0.5%-1% of the total population affected by RA. RA pathogenesis still remains unclear due to which its appropriate treatment is a challenge. Further, multitudes of factors have been reported to affect its progression i.e. genetic factor, environmental factor, immune factor, and oxidative factor. Therapeutic approaches available for the treatment of RA include NSAIDs, DMARDs, enzymatic, hormonal, and gene therapies. But most of them provide the symptomatic relief without treating the core of the disease. This makes it obligatory to explore and reach the molecular targets for cure and long-term relief from RA. Herein, we attempt to provide extensive overlay of the new targets for RA treatment such as signaling pathways, proteins, and receptors affecting the progression of the disease and its severity. Precise modification in these targets such as suppressing the notch signaling pathway, SIRT 3 protein, Sphingosine-1-phosphate receptor and stimulating the neuronal signals particularly efferent vagus nerve and SIRT 1 protein may offer long term relief and potentially diminish the chronicity. To target or alter the novel molecules and signaling pathway a specific delivery system is required such as liposome, nanoparticles and micelles and many more. Present review paper discusses in detail about novel targets and delivery systems for treating RA.

Plant-Based Approaches for Rheumatoid Arthritis Regulation: Mechanistic Insights on Pathogenesis, Molecular Pathways, and Delivery Systems.

Rheumatoid arthritis (RA) is classified as a chronic inflammatory autoimmune disorder, associated with a varied range of immunological changes, synovial hyperplasia, cartilage destructions, as well as bone erosion. The infiltration of immune-modulatory cells and excessive release of proinflammatory chemokines, cytokines, and growth factors into the inflamed regions are key molecules involved in the progression of RA. Even though many conventional drugs are suggested by a medical practitioner such as DMARDs, NSAIDs, glucocorticoids, etc., to treat RA, but have allied with various side effects. Thus, alternative therapeutics in the form of herbal therapy or phytomedicine has been increasingly explored for this inflammatory disorder of joints. Herbal interventions contribute substantial therapeutic benefits including accessibility, less or no toxicity and affordability. But the major challenge with these natural actives is the need of a tailored approach for treating inflamed tissues by delivering these bioactive agentsat an appropriate dose within the treatment regimen for an extended periodof time. Drug incorporated with wide range of delivery systems such as liposomes, nanoparticles, polymeric micelles, and other nano-vehicles have been developed to achieve this goal. Thus, inclinations of modern treatment are persuaded on the way to herbal therapy or phytomedicines in combination with novel carriers is an alternative approach with less adverse effects. The present review further summarizes the significanceof use of phytocompounds, their target molecules/pathways and, toxicity and challenges associated with phytomolecule-based nanoformulations.

A Review on Molecular Docking As an Interpretative Tool for Molecular Targets in Disease Management.

One of the most often utilized methods for drug discovery is molecular docking. With docking, one may discover new therapeutically relevant molecules by targeting the molecule and predicting the target-ligand interactions as well as different conformation of ligand at various positions. The prediction signifies the effectiveness of the molecule or the developed molecule having different affinity with target. Drug discovery plays an important role in the development of a new drug molecule of different moiety attached to it, which leads us in the management of several diseases. In silico approach led us to identification of numerous diseases caused by virus, fungi, bacteria, protozoa, and other microorganisms that affect human health. By means of computational approach, we can categorize disease symptoms and use the drugs available for such types of warning signs. After the docking process, molecular dynamics computational technique helps in the simulation of the physical movement of atoms and molecules for a fixed period of time, giving a view of the dynamic evaluation of the system. This review is an attempt to illustrate the role of molecular docking in drug development.

Mechanistic insight on the role of iRhom2-TNF-α-BAFF signaling pathway in various autoimmune disorders.

iRhom2 is a crucial cofactor involved in upregulation of TNF receptors (TNFRs) and the pro-inflammatory cytokine tumor necrosis factor (TNF-) from the cell surface by ADAM17. Tumor necrosis factor- α converting enzyme (TACE) is another name given to ADAM17. Many membrane attached biologically active molecules are cleaved by this enzyme which includes TNFRs and the pro-inflammatory cytokine tumor necrosis factor- α. The TNF receptors are of two types TNFR1 and TNFR2. iRhom2 belongs to the pseudo-protease class of rhomboid family, its abundance is observed in the immune cells. Biological activity of ADAM17 is affected in multiple levels by the iRhom2. ADAM17 is trafficked into the Golgi apparatus by the action of iRhom2, where it gets matured proteolytically and is stimulated to perform its function on the cell surface. This process of activation of ADAM17 results in the protection of the organism from the cascade of inflammatory reactions, as this activation blocks the TNF- α mediated secretion responsible for inflammatory responses produced. Present paper illustrates about the iRhom2-TNF-α-BAFF signaling pathway and its correlation with several autoimmune disorders such as Rheumatoid Arthritis, Systemic Lupus Erythematosus, Hemophilia Arthropathy, Alzheimer's disease and Tylosis with esophageal cancer etc.

Mechanistic prospective and pharmacological attributes of quercetin in attenuation of different types of arthritis.

Arthritis is a frequent autoimmune disease with undefined etiology and pathogenesis. Scientific community constantly fascinating quercetin (QUR), as it is the best-known flavonoid among others for curative and preventive properties against a wide range of diseases. Due to its multifaceted activities, the implementation of QUR against various types of arthritis namely, rheumatoid arthritis (RA), osteoarthritis (OA), gouty arthritis (GA) and psoriotic arthritis (PsA) has greatly increased in recent years. Many research evidenced that QUR regulates a wide range of pathways for instance NF-κB, MAK, Wnt/ß-catenine, Notch, etc., that are majorly associated with the inflammatory mechanisms. Besides, the bioavailability of QUR is a major constrain to its therapeutic potential, and drug delivery techniques have experienced significant development to overcome the problem of its limited application. Hence, this review compiled the cutting-edge experiments on versatile effects of QUR on inflammatory diseases like RA, OA, GA and PsA, sources and bioavailability, therapeutic challenges, pharmacokinetics, clinical studies as well as toxicological impacts. The use of QUR in a health context would offer a tearing and potential therapeutic method, supporting the advancement of public health, particularly, of arthritic patients worldwide.

Preclinical study models of psoriasis: State-of-the-art techniques for testing pharmaceutical products in animal and nonanimal models.

Local and systemic treatments exist for psoriasis, but none can do more than control its symptoms because of its numerous unknown mechanisms. The lack of validated testing models or a defined psoriatic phenotypic profile hinders antipsoriatic drug development. Despite their intricacy, immune-mediated diseases have no improved and precise treatment. The treatment actions may now be predicted for psoriasis and other chronic hyperproliferative skin illnesses using animal models. Their findings confirmed that a psoriasis animal model could mimic a few disease conditions. However, their ethical approval concerns and inability to resemble human psoriasis rightly offer to look for more alternatives. Hence, in this article, we have reported various cutting-edge techniques for the preclinical testing of pharmaceutical products for the treatment of psoriasis.

Novel Biotherapeutics Targeting Biomolecular and Cellular Approaches in Diabetic Wound Healing.

Wound healing responses play a major role in chronic inflammation, which affects millions of people around the world. One of the daunting tasks of creating a wound-healing drug is finding equilibrium in the inflammatory cascade. In this study, the molecular and cellular mechanisms to regulate wound healing are explained, and recent research is addressed that demonstrates the molecular and cellular events during diabetic wound healing. Moreover, a range of factors or agents that facilitate wound healing have also been investigated as possible targets for successful treatment. It also summarises the various advances in research findings that have revealed promising molecular targets in the fields of therapy and diagnosis of cellular physiology and pathology of wound healing, such as neuropeptides, substance P, T cell immune response cDNA 7, miRNA, and treprostinil growth factors such as fibroblast growth factor, including thymosin beta 4, and immunomodulators as major therapeutic targets.

COVID-19: clinical presentation and detection methods.

The unending outburst of COVID-19 has reinforced the necessity of SARS-CoV-2 identification approaches for the prevention of infection transmission and the proper care of severe and critical patients. As there is no cure, a prompt and reliable diagnosis of SARS-CoV2 is vital to counter the spread and to provide adequate care and treatment for the infection. Currently, RT-PCR is a gold standard detection method for the qualitative and quantitative detection of viral nucleic acids. Besides, enzyme-linked immunosorbent assay is also a primarily used method for qualitative estimation of viral load. However, almost all the detection methods have their pros and cons in terms of specificity, accuracy, sensitivity, cost, time consumption, the need for sophisticated laboratories, and the requirement of skilled technical experts to carry out the detection tests. Thus, it is suggested to integrate different techniques to enhance the detection efficiency and accurateness for SARS-CoV2. This review focuses on preliminary, pre-confirmatory, and confirmatory methods of detection such as imaging techniques (chest-X-ray and chest- computed tomography), nucleic acid detection methods, serological assay methods, and viral culture and identification methods that are currently being employed to detect the presence of SARS-CoV-2 infection along with recent detection method and applicability for COVID-19.

Novel archetype in psoriasis management bridging molecular dynamics in exploring novel therapies.

Psoriasis is an autoimmune chronic inflammatory condition of skin affecting 125 million populaces around the globe. It is implicated as a result of multifaceted phenomena involving various cell and subcell activities with the aid of numerous cellular and molecular components including signaling aisle and regulatory proteins owing to the development of such hyperproliferative dermatological conditions. This involves a deeply complex and conflicting pathology owing to genetic and immunological deviations resulting from the unusual presentation of different signaling pathways and regulatory proteins. Explorations of these biomarkers and intervention of molecular and cellular processes in psoriasis are yet to be investigated and could be an exceptional aspect for understanding pathology with successful targeting of disease. In the presented study, we have integrated molecular insights, including signaling molecules, pathways, and proteins implicated in pathogenesis, and we have attempted to link this knowledge to the targeting of these phenomena in order to manage the conditions precisely. Further, therapeutic delivery approaches for targeting distinct layers of skin have also been investigated based on the application of different nanocarriers for successful psoriasis treatment.

Polymers in topical delivery of anti-psoriatic medications and other topical agents in overcoming the barriers of conventional treatment strategies.

In recent decades, topical treatments to dermal disorders have shown ineffectiveness in delivering the medication at a particular location without a suitable drug carrier. Psoriasis treatment is hindered because of the ineffective delivery and efficacy of conventional pharmaceutical treatment. In conventional medication formulation approach, it is difficult to breach the transdermal layer of a skin membrane for topical drugs, i.e. cyclosporine, methotrexate. This problem is further complicated by extreme disease-associated conditions such as hyperkeratosis and irritation. Intending to assure better drug delivery carriers, this review emphasizes the therapeutic efficacy of polymers and their potential to deliver the drug into the deeper layer of the skin membrane. The polymers are essential in structural and physiochemical perspectives as it works as a carrier for the medication. A vast variety of delivery carriers is available nowadays but their applicability in such dermal cases like psoriasis is still lacking due to less knowledge on an appropriate polymer. The current investigation of suitable polymer would assist in brushing our expertise to optimize the advantages of a wide spectrum of polymers to fulfill the topical targeting of psoriasis.

Multifaceted targeting of cationic liposomes via co-delivery of anti-IL-17 siRNA and corticosteroid for topical treatment of psoriasis.

Psoriasis is a chronic autoimmune disorder that affects the skin to alter its structure and physiology and express the phenotypic function of abnormal epidermal cell growth through a cascade of molecular, and cellular intervention. The histological changes in skin include inflammation, scaling, hyperproliferation of epidermis resulting in thickening of the skin, under the influence of altered immunopathogenesis. The zone of activity for the therapeutic targeting of psoriasis is viable epidermis involving various cellular events regulating the whole progression of the disease manifestation. Therefore, therapeutic targeting of psoriasis through the systemic route would be imprecise and associated with numerous side effects. Small interfering RNA (siRNA) molecules have emerged as a powerful class of therapeutics for treating psoriasis. However, successful targeted delivery of necked siRNA into the skin is hampered due to physicochemical features, proneness to enzymatic degradation, and unavailability of effective delivery carriers. The steroidal medications are the most preferred choice among existing conventional topical formulations; however, they also have their drawbacks like poor aqueous solubility, deprived drug penetration across the skin, reduced half-life, dose-dependent side effects, and reduced patient compliance. In the present study, we hypothesize the development of a liposomal gel formulation for co-delivery of siRNA (siRNA against IL-17A) and a steroidal drug (Clobetasol propionate) to target different pathogenic events of psoriasis leading to the accomplishment of synergistic therapeutic effect. Since a sequence of events simultaneously occurs during the pathogenesis of psoriasis, synergistic blends of siRNA and corticosteroid would ensure a multi-targeted treatment that would act through a diverse range of mechanisms, ultimately leading to the enhancement of therapeutic effect. Therefore, exploiting the full therapeutic potential of these therapeutics. Thus, the present work suggests a novel, innovative, and promising idea for accomplishing effective treatment of psoriasis.

Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing.

Wound management in diabetic patient is of an extreme clinical and social concern. The delayed and impaired healing makes it more critical for research focus. The research on impaired healing process is proceeding hastily evident by new therapeutic approaches other than conventional such as single growth factor, dual growth factor, skin substitutes, cytokine stimulators, cytokine inhibitors, matrix metalloproteinase inhibitors, gene and stem cell therapy, extracellular matrix and angiogenesis stimulators. Although numerous studies are available that support delayed wound healing in diabetes but detailed mechanistic insight including factors involved and their role still needs to be revealed. This review mainly focuses on the molecular cascades of cytokines (with growth factors) and erstwhile factors responsible for delayed wound healing, molecular targets and recent advancements in complete healing and its cure. Present article briefed recent pioneering information on possible molecular targets and treatment strategies including clinical trials to clinicians and researchers working in similar area.

Understanding the prospective of nano-formulations towards the treatment of psoriasis.

Psoriasis is a consistently recurring, inflammatory, autoimmune disorder of the skin, affecting about 2-5% of the world population. Abundant therapeutic agents are accessible for the treatment of psoriasis. Nevertheless, none of them are entirely secure and effective to treat the disease without compromising patient compliance. Furthermore, already existing drugs are supposed to restrain the ailment and alleviate the sign and symptoms with no complete cure. However, they focus on restraining the disease and alleviating the symptoms without providing an absolute cure. Therefore there remains a vital challenge, to explore a new drug moiety or delivery system which could safely and effectively manage psoriasis without compromising patient compliance. Furthermore, conventional formulations offer reduced benefit/risk ratio of anti-psoriatic drugs, which limits the use of existing conventional formulations. Novel formulations based on nanocarriers are a promising prospect to overcome the limitation of conventional formulations by offering a reduction in dose, dosing frequency, dose-dependent, side effects with enhanced efficacy. Presently nano-formulations have gained widespread application for effective and safe treatment of psoriasis. The present review primarily focuses on conventional therapeutic strategy and recent advances in lipid-based, polymer-based and metallic nano-formulations of a variety of anti-psoriatic drugs. The practicability of various nanocarrier systems including liposomes, nanostructured lipid carriers, ethosomes, solid lipid nanoparticles, nanocapsules, micelles, dendrimers, gold nanoparticles and silver nanoparticles have been discussed in detail. The review also traces related patents to exemplify the role of various nanoparticles in psoriasis treatment. In a nutshell, nano-formulations remain established as a promising modality for treating psoriasis treatment as they propose better penetration, targeted delivery, enhanced safety, and efficacy.

Perspectives of Lipid-Based Drug Carrier Systems for Transdermal Delivery.

Transdermal delivery serves as non-invasive and effortless terminable means for systemic as well as topical drug delivery and finds itself as an option to conventional delivery route. Significant impervious nature of skin is the greatest hurdle for successful delivery of drug molecules to the deeper layers of skin for systemic absorption. Many approaches have been carried out for delivery of a medicament across skin barrier to enhance the efficacy. Among them lipid-based colloidal carriers have gained a unique position for transdermal delivery of drugs and bioactives owing to the presence of epidermal lipids as the chief component within the penetration barrier in high amount. Skin-carrier interaction involves attachment of these carriers to skin with a view to permit exchange of lipid between the outermost layers of the stratum corneum. Based on extensive literature search, although numerous reviews are available on lipid-based systems, but none of them relates exclusively to their transdermal uptake and toxicity. This review specifically focuses on the hurdles of transdermal drug delivery, role of lipid vehicular systems in transdermal drug delivery, uptake pathways, sequential uptake mechanism and cytotoxicity issues of lipid-based carriers which although considered safe, are not completely free from toxicity.

Protein biomarker for psoriasis: A systematic review on their role in the pathomechanism, diagnosis, potential targets and treatment of psoriasis.

Psoriasis is defined as a long-lasting multifactorial inflammatory autoimmune skin condition precisely characterized by delimited, erythematic papules with adherent shiny scales. The conditions are led by hyperproliferative responses of epidermis due to hyperactivation and immature keratinocytes production. The psoriatic skin consists of the thickened epidermal layer, in concurrence with inflammatory exudates in the dermis mainly of dendritic cells, neutrophils, T cells, and macrophages, contributing to the distinct manifestation of psoriatic lesions. It consents to multifaceted and discrete pathology due to the genetic and immunological alteration resulting from abnormal expression of various regulatory and structural proteins. These proteins are associated with various cellular and sub-cellular activities. Therefore, the presence of protein in a pathological cellular environment in the psoriatic lesions as well as in serum could be a great avenue for the insight of pathomechanism, anticipation and diagnosis of psoriasis. Research of protein biomarker in psoriasis is yet a developing realm to be explored by both fundamental and clinical researchers. This review is an attempt to assimilate the current discoveries and revelations of different proteins as a biomarker and their importance in pathogenesis, diagnosis, treatment, and anticipation of both the inflammatory and other dermatological aspects of psoriasis.

Preparation and optimization of chitosan-gelatin films for sustained delivery of lupeol for wound healing.

Lupeol entrapped chitosan-gelatin hydrogel (LCGH) films were prepared by solution cast method by blending chitosan and gelatin solution using glycerol as plasticizer, followed by crosslinking with glutaraldehyde. LCGH films were characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), equilibrium water content (EWC), Water vapor transmission rate (WVTR) and in vitro release studies. SEM confirmed presence of the uniform porous network of both blank and LCGH films. The incorporation of lupeol in hydrogel was confirmed FTIR and DSC. The LCGH film was smooth, flexible, non-brittle and showed excellent swelling ability. EWC (85.40%) and WVTR (2228±31.8) met the condition of ideal wound dressing. The biological activity of lupeol was assessed by antioxidant and antibacterial assay. Antioxidant assay confirmed that lupeol and LCGH film have excellent antioxidant properties by scavenging both radicals at steady increasing rate which increases with time due to steady release of lupeol. Antibacterial activity of lupeol in LCGH film was found to be retained as assessed by disc diffusion method. Cell viability was evaluated by MTT assay with NIH/3T3 fibroblast cells. The MTT assay showed that the CGH film evidently offered acceptable cell viability and non-toxicity. These observations depicted that chitosan/gelatin hydrogel film can be an ideal delivery system for sustained released of lupeol and LCGH film for enhanced wound healing.

Rationalized Insights on Causes of Rheumatoid Arthritis in the Elderly and Women: Special Emphasis on Treatment Strategies.

Rheumatoid arthritis (RA) is an autoimmune disorder distinguished by synovial inflammation followed by destruction of joint. The pathogenesis of arthritis involves immune imbalance of the endogenous system. Causative factors include immune imbalance, oxidative stress, genetics, and environment. Continued effort has been made to treat RA via chemical, enzymatic, genetic, and hormonal approaches. RA has been reported more in the aged and in women. Arthritis necessitates lifelong administration of drugs to maintain quality of life. The major challenges of treatment are the side effects associated with these drugs. Novel approaches and targets have been explored as alternative measures to relieve pain in RA sufferers. Customary treatment strategies have limited therapeutic capability with episodes of associated side effects. Thus, revolutionary advances in novel RA-targeted drug delivery strategies are needed for efficient therapies and to meet the demand for treatment. The current review summarizes the pathogenesis of RA, its causative factors, and therapeutic approaches. These approaches are discussed with regard to mode of action, pharmacokinetics, marketed products, side effects of individual RA drugs, recent developments, modifications in the delivery of various drugs through targeted ligands, novel drug carriers as vesicular, particulate, self assembled, cellular, ceramic systems, and future prospects.

Influence of selected variables on fabrication of Triamcinolone acetonide loaded solid lipid nanoparticles for topical treatment of dermal disorders.

Aim of the study was to develop solid lipid nanoparticles (SLN) of triamcinolone acetonide (TA) and to study the effect of various process variables in order to optimize the formulation for effective delivery. Drug loaded SLNs were successfully prepared and characterized by TEM, XRD and DSC study. Process variables like surfactant concentration, drug concentration, lipid concentration etc. showed significant effect on the particle size and entrapment efficiency. SLNs exhibited prolonged drug release following Higuchi release kinetics (R(2) = 0.9909). In vitro skin distribution study demonstrated systemic escape of drug from TA loaded SLNs which might eliminate side effects associated with systemic exposure.

Ceramic nanoparticles: Recompense, cellular uptake and toxicity concerns.

Over the past few years, nanoparticles and their role in drug delivery have been the centre of attraction as new drug delivery systems. Various forms of nanosystems have been designed, such as nanoclays, scaffolds and nanotubes, having numerous applications in areas such as drug loading, target cell uptake, bioassay and imaging. The present study discusses various types of nanoparticles, with special emphasis on ceramic nanocarriers. Ceramic materials have high mechanical strength, good body response and low or non-existing biodegradability. In this article, the various aspects concerning ceramic nanoparticles, such as their advantages over other systems, their cellular uptake and toxicity concerns are discussed in detail.