Exploring the role of cathepsin in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease which is marked by leukocytes infiltration inside synovial tissue, joints and also inside synovial fluid which causes progressive destruction of joint cartilage. There are numerous genetical and lifestyle factors, responsible for rheumatoid arthritis. One such factor can be cysteine cathepsins, which act as proteolytic enzymes. These proteolytic enzyme gets activated at acidic pH and are found in lysosomes and are also termed as cysteine proteases. These proteases belong to papain family and have their elucidated role in musculoskeletal disorders. Numerous cathepsins have their targeted role in rheumatoid arthritis. These proteases are secreted through various cell types which includes matrix metalloproteases and papain like cysteine proteases. These proteases can potentially lead to bone and cartilage destruction which causes an immune response in case of inflammatory arthritis.

Understanding the molecular mechanisms and role of autophagy in obesity.

Vital for growth, proliferation, subsistence, and thermogenesis, autophagy is the biological cascade, which confers defence against aging and various pathologies. Current research has demonstrated de novo activity of autophagy in stimulation of biological events. There exists a significant association between autophagy activation and obesity, encompassing expansion of adipocytes which facilitates ß cell activity. The main objective of the manuscript is to enumerate intrinsic role of autophagy in obesity and associated complications. The peer review articles published till date were searched using medical databases like PubMed and MEDLINE for research, primarily in English language. Obesity is characterized by adipocytic hypertrophy and hyperplasia, which leads to imbalance of lipid absorption, free fatty acid release, and mitochondrial activity. Detailed evaluation of obesity progression is necessary for its treatment and related comorbidities. Data collected in regard to etiological sustaining of obesity, has revealed hypothesized energy misbalance and neuro-humoral dysfunction, which is stimulated by autophagy. Autophagy regulates chief salvaging events for protein clustering, excessive triglycerides, and impaired mitochondria which is accompanied by oxidative and genotoxic stress in mammals. Autophagy is a homeostatic event, which regulates biological process by eliminating lethal cells and reprocessing physiological constituents, comprising of proteins and fat. Unquestionably, autophagy impairment is involved in metabolic syndromes, like obesity. According to an individual's metabolic outline, autophagy activation is essential for metabolism and activity of the adipose tissue and to retard metabolic syndrome i.e. obesity. The manuscript summarizes the perception of current knowledge on autophagy stimulation and its effect on the obesity.

Phytochemicals from Plant Foods as Potential Source of Antiviral Agents: An Overview.

To date, the leading causes of mortality and morbidity worldwide include viral infections, such as Ebola, influenza virus, acquired immunodeficiency syndrome (AIDS), severe acute respiratory syndrome (SARS) and recently COVID-19 disease, caused by the SARS-CoV-2 virus. Currently, we can count on a narrow range of antiviral drugs, especially older generation ones like ribavirin and interferon which are effective against viruses in vitro but can often be ineffective in patients. In addition to these, we have antiviral agents for the treatment of herpes virus, influenza virus, HIV and hepatitis virus. Recently, drugs used in the past especially against ebolavirus, such as remdesivir and favipiravir, have been considered for the treatment of COVID-19 disease. However, even if these drugs represent important tools against viral diseases, they are certainly not sufficient to defend us from the multitude of viruses present in the environment. This represents a huge problem, especially considering the unprecedented global threat due to the advancement of COVID-19, which represents a potential risk to the health and life of millions of people. The demand, therefore, for new and effective antiviral drugs is very high. This review focuses on three fundamental points: (1) presents the main threats to human health, reviewing the most widespread viral diseases in the world, thus describing the scenario caused by the disease in question each time and evaluating the specific therapeutic remedies currently available. (2) It comprehensively describes main phytochemical classes, in particular from plant foods, with proven antiviral activities, the viruses potentially treated with the described phytochemicals. (3) Consideration of the various applications of drug delivery systems in order to improve the bioavailability of these compounds or extracts. A PRISMA flow diagram was used for the inclusion of the works. Taking into consideration the recent dramatic events caused by COVID-19 pandemic, the cry of alarm that denounces critical need for new antiviral drugs is extremely strong. For these reasons, a continuous systematic exploration of plant foods and their phytochemicals is necessary for the development of new antiviral agents capable of saving lives and improving their well-being.

Stem cells and growth factors-based delivery approaches for chronic wound repair and regeneration: A promise to heal from within.

The sophisticated chain of cellular and molecular episodes during wound healing includes cell migration, cell proliferation, deposition of extracellular matrix, and remodelling and are onerous to replicate. Encapsulation of growth factors (GFs) and Stem cell-based (SCs) has been proclaimed to accelerate healing by transforming every phase associated with wound healing to enhance skin regeneration. Therapeutic application of mesenchymal stem cells (MSCs), embryonic stem cells (ESCs) and induced pluripotent stem cells (PSCs) provides aid in wound fixing, tissue integrity restoration and function of impaired tissue. Several scientific studies have established the essential role GFs in wound healing and their reduced degree in the chronic wound. The overall limitation includes half-life, unfriendly microhabitat abundant with protease, and inadequate delivery approaches results in decreased delivery of effective amounts in a suitable time-based fashion. Advancements in the area of reformative medicine as well as tissue engineering have offered techniques competent of dispensing SCs and GFs in site-oriented manner. The progress in nanotechnology-based approaches attracts researcher to study and evaluate the potential of this SCs and GFs based therapy in chronic wounds. These techniques embrace the polymeric regime viz., nano-formulations, hydrogels, liposomes, scaffolds, nanofibers, metallic nanoparticles, lipid-based nanoparticles and dendrimers that have established better retort through targeting tissues when GFs and SCs are transported via these humans made devices. Assumed the current problems, improvements in delivery approaches and difficulties offered by chronic wounds, we hope to show that encapsulation of SCs and GFs loaded nanoformulations therapies is the rational next step in improving wound care.

Focus on the Multimodal Role of Autophagy in Rheumatoid Arthritis.

Autophagy exerts its dual role in eukaryotic cells and exerts its cytoprotective action through degradation mechanism and by regulating catabolic processes which results in elimination of pathogens. Under suitable conditions, autophagy is associated with recycling of cytoplasmic components which causes regeneration of energy whereas deregulated autophagy exerts its implicated role in development and pathogenesis of auto-immune diseases such as rheumatoid arthritis. The immune, innate, and adaptive responses are regulated through the development, proliferation, and growth of lymphocytes. Such innate and adaptive responses can act as mediator of arthritis; along with this, stimulation of osteoclast-mediated bone resorption takes place via transferring citrullinated peptides towards MHC (major histocompatibility complex) compartments, thereby resulting in degradation of bone. Processes such as apoptosis resistance are also regulated through autophagy. In this review, the current knowledge based on role of autophagy in pathogenesis of rheumatoid arthritis is summarized along with proteins associated.

Understanding the possible role of endocannabinoid system in obesity.

BACKGROUND: Maintenance of weight is essential for sustenance, well-being and to endorse prolonged life. The prevalence of obesity is increasing at an alarming rate globally, due to modern lifestyle and dietary habits. Endocannabinoids are fatty acid derivatives and numerous studies are carried out which focuses and targets their relationship with obesity, via multiple signals which have been recently known for exerting crucial role in regulating energy balance. PURPOSE: This article aims at examining the prospects of endocannabinoids in obesity via directing the role of ECs in stimulating hunger. RESULT: In last few years, irregular stimulation of endocannabinoid system has been suggested as a chief element in the progression of obesity-associated metabolic complications. Certainly, this cascade system comprises of cannabinoid type1 and 2 receptors (CB1R and CB2R) along with their endogenous lipid ligands which are responsible for enhanced feeding behavior as well as lipid metabolism. Significantly, inhibiting CB1R activity might reduce metabolic abnormality linked with obesity. CONCLUSION: Conclusion withdrawn on the basis of supporting scientific data and evidences report that the blockade of cannabinoids can serve as a therapeutic potential for treatment of obesity. Future prospective aims at assessing molecular pathways which contributes towards ECS, elicited weight control and to evaluate how these mechanisms are presently relocated into the production of novel cannabinoid drugs exhibiting enriched care.

Exploring the role of mitochondrial proteins as molecular target in Alzheimer's disease.

Brain is a fully differentiated organ and is sensitive towards oxidative damage of various compounds including lipids, proteins, and DNA that occurs during process of normal aging and is mainly due to its high energy metabolism and reduced activity of anti-oxidative defense mechanism. Mitochondria are dynamic ATP-generating organelles which constitutes cellular functions such as regulation of intracellular calcium, bio-energetic processes, and reduction-oxidation of cells. Such functioning is negatively affected due to the presence of amyloid ß peptide (Aß) which is involved in pathogenesis of Alzheimer disease (AD). Aß interacts with mitochondria and leads to mitochondrial dysfunction. Mitochondrial dysfunction, abnormal interactions, oxidative stress, and mis-folding of synaptic proteins inside nervous system are explored and regarded as primary or initial features in insurgence of pathology (AD and other neurological disease). The major histopathological hallmarks of AD are characterized by presence of these hallmarks intracellularly, its further progression and exacerbation which leads to excessive accumulation of oligomeric as well as fibrillar-ß-amyloid peptides (present extracellularly) and accumulation of neurofibrillary tangles intracellularly. The current review will focus on alterations and variation in mitochondria/mitochondrial DNA (mtDNA) and the rationale for involvement of related abnormalities in pathogenesis of AD.

Exploring the multifocal therapeutic approaches in COVID-19: A ray of hope.

The ongoing global pandemic of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is marked as one of the most challenging infectious diseases in the history of mankind with affliction of ~29,737,453 confirmed cases globally. Looking at the present scenario where there is a parallel increment in curve with time, there is an utmost emergency to discover a perennial solution to this life-threatening virus which has led the Human race in an unusual state of affair. The entire health care fraternity is engaged in endeavouring an ultimate way out to hit this pandemic but no such research made till now has been approved yet, to have the potential to bring an end to this fatal situation. Although a few possible treatment choices exist at the moment yet the requirement to search for a still better therapeutic option remains persistent. Global laboratories are working day and night in search for an effective vaccine, many are undergoing clinical trials but their commercialization is no less than a year away. The present review highlights the current potential therapies viz., vaccines, immunotherapies, convulsant plasma therapies, corticosteroids, antithrombotic, intravenous immunoglobulins, nocturnal oxygen therapy etc. that may prove beneficial in attenuating the pandemic situation. However, comparison and presentation of collective data on the therapeutic advancements in mitigating the pandemic situation needs further clinical investigations in order to prove boon to mankind.

Ubiquitination in rheumatoid arthritis.

Rheumatoid arthritis is a chronic, inflammatory joint disease leading to inflammation of synovial membrane that lines the joints. This inflammation further progresses and results in destruction of joints and surrounding cartilages. The underlying factors can be oxidative stress, pro-inflammatory mediators, imbalance and attenuation between various enzymes and proteins (like nuclear factor erythroid 2 related factor 2/Nrf2 and ubiquitin). Protein degradation pathways comprises of lysosomal, proteasomal pathway, and autophagosome (that are carried out in mammalian cells) are regulated through ubiquitin. Ubiquitin proteasomal system is dominating pathway for carrying out non-lysosomal proteolysis of intracellularly proteins. Fundamental processes including cell cycle progression, process of division, apoptosis, modulation of immune responses and cell trafficking are regulated by process of ubiquitination. Ubiquitin proteasomal pathway (UPP) includes ubiquitin moieties which are covalently attached to proteins and guides them proteasome for degradation. Misfolded, oxidized and damaged proteins which are responsible for critical processes, are major targets of degradation process. Any alteration in this system leads to dysregulated cellular homeostasis; progressively leading to numerous diseases including rheumatoid arthritis. Factors including TAK1, TRAF6 undergo are required for the progression of disease and thus contributes towards pathology of inflammatory disorders such as rheumatoid arthritis. This review will include all linked aspects which contribute its major role in rheumatoid arthritis.

Synthesis of Nanostructured Lipid Carriers Loaded Chitosan/ Carbopol Hybrid Nanocomposite Gel for Oral Delivery of Artemether and Curcumin.

BACKGROUND: Antimalarial therapy remains the utmost effective means for the management of malarial parasites in the liver and red blood cells. The application of these therapeutic agents is hampered by their improper application, hepato-toxicity caused by their continuous use, and degradation by hepatic enzymes. METHODS: Recent advancements in drug delivery applications have shown potential in improving the pharmacological properties of artemether. Nanostructured lipid carriers (NLCs) loaded chitosan (CH)/Carbopol (CB) hybrid gel was prepared using glycerol monostearate (GMS) as solid lipid and clove oil as a liquid lipid for artemether (ART) and curcumin (CR) for its localized effect on the liver. RESULTS: The smaller particle size (~118 ± 1.0 nm) and high zeta potential (- 41.1 ± 6.46 mV) confirm the formulation and stability of NLCs. On the other hand, the shape and morphology of prepared NLCs and gel showed a spherical and wrinkled surface with a size range of 150-250 nm. The release studies of the NLC's showed a controlled release of artemether (~ 92%) and curcumin (~ 83%) for up to 30 h. Photostability data showed that, approximately, ~86.5 ± 0.3% and ~60 ± 0.9% of nanoencapsulated artemether and curcumin were still detected on exposure to sunlight, respectively. It has been found from the permeation study that 69.8% and 49.1% of the drug was permeated across the mucus membrane in 24 h with a significant increase (P < 0.05) in flux as well as permeability coefficients. CONCLUSION: The overall results showed that prepared CH/CB/NLCs hybrid gel could be a promising vehicle for the effective delivery of ART and CR for the management of malarial parasites. Lay Summary: Antimalarial therapy remains the utmost effective means for the management of malarial parasites in liver and red blood cells. Recent advancements in drug delivery applications have shown potential in improving the pharmacological properties of artemether. Application of these therapeutic agents hampered by their improper application, hepato-toxicity caused by their continuous use and degradation by hepatic enzymes. To manage the above issues, we synthesize nanostructured lipid carriers (NLC's) loaded chitosan (CH)/Carbopol (CB) hybrid gel using glycerol monostearate (GMS) as solid lipid and clove oil as liquid lipid for artemether (ATR) and curcumin (CR) for its local action in liver and the major criteria were to find a protective barrier with hepatoprotective nature of the curcumin.

Mechanistic insights into the role of pyroptosis in rheumatoid arthritis.

Cell death is ascribed as an essential biological process that is fundamental for the development of an organism along with its survival. The procedure comprises of apoptosis and pyroptosis. Pyroptosis is a programmed procedure for cell death which is inflammatory in nature and this pathway gets activated via human caspase-4, human caspase-11 and human caspase-5. The activation of this process leads to release of pro-inflammatory mediators including cytokines, alarmins, IL-18 and IL-1ß. The pro-inflammatory mediators released via interaction of intracellular kinases direct the development of Rheumatoid arthritis. Rheumatoid arthritis is characterized as disorder/disease that is auto-immune and chronic in nature. It involves erosions in marginal bone along with articular cartilage which is responsible for joint destruction. The cytokine along with its complex network is responsible for inflammation. The process of pyroptosis is linked with the destruction of plasma membrane, that releases these mediators and excessive release of these mediators is linked with rheumatoid arthritis.

Role of Nrf2 in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis comprises the roots of 19th century and is an autoimmune and chronic inflammatory disorder leading to progressive joint destruction. This erosive joint damage is linked with infiltration of leukocytes along with inflammatory destruction and blood cell formation within the synovial membrane, deprivation of cartilage and bone that leads to incapacitative pain. The changes in synovium include its proliferation that leads to pannus formation and this ultimately leads to the invasion and erosions causing the destruction of joints. It is also defined as the destructive or chronic disease with a longer time duration that takes articular consideration as a feature. OBJECTIVE: The factors that can lead to RA includes inflammatory cascades, increased levels of (TNF-α) tumor necrosis factor α, IL-1b and IL-17 (interleukins) along with reduced levels of Nrf2 factors (nuclear factor-erythroid 2-related factor-2). Nrf2 binds effectively to antioxidant response elements (ARE) that mainly encodes majority of the phase II antioxidant enzymes as well as stress receptive proteins including glutathione S-transferase (GSH), heme oxygenase-1 (HO-1), peroxiredoxin I, all these act by cellular defense mechanism and removes the cytotoxic electrophiles along with the ROS that is reactive oxygen species. Nrf2 also responds to the inflammatory stimulus and protect the tissues from the inflammatory tissues.

Inulin as a Delivery Vehicle for Targeting Colon-Specific Cancer.

Natural polysaccharides, as well as biopolymers, are now days widely developed for targeting colon cancer using various drug delivery systems. Currently, healing conformations are being explored that can efficiently play a multipurpose role. Owing to the capability of extravagance colonic diseases with the least adverse effects, biopolymers for site specific colon delivery have developed an increased curiosity over the past decades. Inulin (INU) was explored for its probable application as an entrapment material concerning its degradation by enzymes in the colonic microflora and its drug release behavior in a sustained and controlled manner. INU is a polysaccharide and it consists of 2 to 1 linkage having an extensive array of beneficial uses such as a carrier for delivery of therapeutic agents as an indicative/investigative utensil or as a dietary fiber with added well-being aids. In the main, limited research, as well as information, is available on the delivery of therapeutic agents using inulin specifically for colon cancer because of its capability to subsist in the stomach's acidic medium. This exceptional steadiness and robustness properties are exploited in numerous patterns to target drugs securely for the management of colonic cancer, where they effectively act and kills colonic tumor cells easily. In this review article, recent efforts and inulin-based nano-technological approaches for colon cancer targeting are presented and discussed.

Synthesis of physically crosslinked PVA/Chitosan loaded silver nanoparticles hydrogels with tunable mechanical properties and antibacterial effects.

Limitation of antibacterial activity, low water vapour, oxygen permeation and mechanical strength are the disadvantages of existing wound dressings. The present research is focused on synthesis of Polyvinyl alcohol (PVA) and Chitosan (CH) hydrogels using freeze thaw process. The formation of AgNPs and PVA/CH hydrogels was confirmed by UV spectroscopy, particle size, morphology, spectral analysis, swelling studies, and in-vitro drug release studies. The particle size of AgNPs was found to be in the range of 20-35 nm with an intense peak at 430 nm. The results of spectral peaks showed that PVA/CH blend maintains characteristics peak of -OH and -NH in the spectrum with higher intensity. The morphology and tensile strength of hydrogels showed a wrinkled surface with an increase in force and extension values from 0.49 to 11.15 N and 45 to 129 mm, respectively. A controlled release of 84.3% (28 h) of Ocimum sanctum extract was noticed from hydrogel discs which scavenges 69.2% of free radicals as compared to raw extract 82.5% (16 h) which scavenges 63.1% of free radicals, respectively. The results of zone of inhibition (ZOI) against gram +ve and gram -ve bacteria was found to be 9.3 mm and 6.3 mm, respectively.