Augmented Transdermal Delivery of Curcumin for the Effective Management of Plaque Psoriasis - Design, Formulation, Characterisation, and In Vivo Studies.

Psoriasis is a recurrent, life-threatening anti-inflammatory condition that affects nearly 1-3% of the global population. It is an autoimmune illness distinguished by hyperplasia of skin cells or fast skin cell development, resulting in abnormally irritating scales and skin patches. Curcumin, as a selective phosphorylase kinase inhibitor, actively suppresses inflammation and keratinocyte proliferation in psoriasis. However, limited solubility in water and poor skin permeability poses a significant hurdle in curcumin's topical effectiveness in psoriasis. The present study focuses on enhancing the solubility and skin permeability of curcumin for better transdermal application. Curcumin-loaded invasomes were formulated, and a factorial design was applied to study the effect of the type of terpenes and their concentrations on the properties of prepared invasomes. A topical gel was formulated using the optimised invasomal formulation which was further evaluated for anti-psoriatic potential in BALB/c mice. The optimised formulation showed 85.84 ± 0.56% entrapment efficiency and a vesicle size of 302.33 ± 1.53 nm. The invasomal gel of the optimised formulation showed a permeation flux of 3 times greater than the plain gel. In vivo studies demonstrated that the invasomal gel of curcumin promoted faster and earlier recovery in psoriatic mice than conventional curcumin gel.

Blood-stage antimalarial activity, favourable metabolic stability and in vivo toxicity of novel piperazine linked 7-chloroquinoline-triazole conjugates.

The persistence of drug resistance poses a significant obstacle to the advancement of efficacious malaria treatments. The remarkable efficacy displayed by 1,2,3-triazole-based compounds against Plasmodium falciparum highlights the potential of triazole conjugates, with diverse pharmacologically active structures, as potential antimalarial agents. We aimed to synthesize 7-dichloroquinoline-triazole conjugates and their structure-activity relationship (SAR) derivatives to investigate their anti-plasmodial activity. Among them, QP11, featuring a m-NO2 substitution, demonstrated efficacy against both chloroquine-sensitive and -resistant parasite strains. QP11 selectively inhibited FP2, a cysteine protease involved in hemoglobin degradation, and showed synergistic effects when combined with chloroquine. Additionally, QP11 hindered hemoglobin degradation and hemozoin formation within the parasite. Metabolic stability studies indicated high stability of QP11, making it a promising antimalarial candidate. In vivo evaluation using a murine malaria model demonstrated QP11's efficacy in eradicating parasite growth without neurotoxicity, presenting it as a promising compound for novel antimalarial development.

Artemisinin resistance in P. falciparum: probing the interacting partners of Kelch13 protein in parasite.

OBJECTIVES: Artemisinin (ART) resistance in Plasmodium is threatening the artemisinin combination therapies-the first line of defence against malaria. ART resistance has been established to be mediated by the Plasmodium Kelch13 (PfK13) protein. For the crucial role of PfK13 in multiple pathways of the Plasmodium life cycle and ART resistance, it is imperative that we investigate its interacting partners. METHODS: We recombinantly expressed PfK13-p (Bric a brac/Poxvirus and zinc finger and propeller domains), generating anti-PfK13-p antibodies to perform co-immunoprecipitation assays and probed PfK13 interacting partners. Surface plasmon resonance and pull-down assays were performed to establish physical interactions of representative proteins with PfK13-p. RESULTS: The co-immunoprecipitation assays identified 17 proteins with distinct functions in the parasite life cycle- protein folding, cellular metabolism, and protein binding and invasion. In addition to the overlap with previously identified proteins, our study identified 10 unique proteins. Fructose-biphosphate aldolase and heat shock protein 70 demonstrated strong biophysical interaction with PfK13-p, with KD values of 6.6 µM and 7.6 µM, respectively. Additionally, Plasmodium merozoite surface protein 1 formed a complex with PfK13-p, which is evident from the pull-down assay. CONCLUSION: This study adds to our knowledge of the PfK13 protein in mediating ART resistance by identifying new PfK13 interacting partners. Three representative proteins-fructose-biphosphate aldolase, heat shock protein 70, and merozoite surface protein 1-demonstrated clear evidence of biophysical interactions with PfK13-p. However, elucidation of the functional relevance of these physical interactions are crucial in context of PfK13 role in ART resistance.

Brain-Derived Neurotropic Factor in Neurodegenerative Disorders.

Globally, neurodegenerative diseases cause a significant degree of disability and distress. Brain-derived neurotrophic factor (BDNF), primarily found in the brain, has a substantial role in the development and maintenance of various nerve roles and is associated with the family of neurotrophins, including neuronal growth factor (NGF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5). BDNF has affinity with tropomyosin receptor kinase B (TrKB), which is found in the brain in large amounts and is expressed in several cells. Several studies have shown that decrease in BDNF causes an imbalance in neuronal functioning and survival. Moreover, BDNF has several important roles, such as improving synaptic plasticity and contributing to long-lasting memory formation. BDNF has been linked to the pathology of the most common neurodegenerative disorders, such as Alzheimer's and Parkinson's disease. This review aims to describe recent efforts to understand the connection between the level of BDNF and neurodegenerative diseases. Several studies have shown that a high level of BDNF is associated with a lower risk for developing a neurodegenerative disease.

Curcumin Loaded Ethosomal Gel for Improved Topical Delivery: Formulation, Characterization and Ex-vivo Studies.

BACKGROUND: Curcumin is a curcuminoid, which is an active constituent of turmeric and is obtained from the rhizomes of Curcuma longa, family Zingiberaceae. Curcumin modulates the activity of various transcription factors and regulates the expression of inflammatory enzymes, cell survival proteins, adhesion molecules and cytokines by binding to a variety of proteins and inhibiting the activity of various kinases. Curcumin falls in the BCS class IV drug, with poor solubility and poor permeability which makes it very challenging to utilize the maximum therapeutic potential of this moiety Objective: The major aim of the study was to enhance transdermal penetration of curcumin via ethosomal gel and to overcome the barriers of poor permeability of transdermal drug delivery. METHODS: Curcumin loaded ethosomes were prepared with varying quantities of ethanol and soya lecithin by the cold method and were optimised based on entrapment efficiency, vesicular size and Ex-vivo studies. Optimised ethosomal formulation was further incorporated into a gel and was evaluated. Ex-vivo studies were performed with the ethosomal gel of curcumin and was compared with simple drug solution. RESULTS: Prepared ethosomal system showed a vesicle size ranging from 211 to 320 nm with spherical, smooth surface and entrapment efficiency of 87 to 91%. Optimised ethosomal system (ET3) was incorporated into gel and was further evaluated. CONCLUSION: The findings of the research work suggested that the ethosomal gel holds excellent potential for transdermal delivery of curcumin.

Autophagic Dysfunction in Dementia: Scope for Development of Potential Remedies.

Dementia is a diverse category of chronic and progressive disorder, which is commonly associated with a loss of memory, difficulty in judgment, impaired language, cognitive impairment, and various other symptoms that affect a person's daily routine life and social life. Dementia affects about 50 million people around the globe. Dementia exists in varied forms and is associated with various neurodegenerative disorders. Alzheimer's disease is the most common form, which accords for about 60% of thecases. Abnormal agglomeration of proteins in the brain has been linked to the pathogenesis of dementia. Autophagy is a necessary protein clearance mechanism, which is dependent on lysosomes. It is a basic physiological process that performs the crucial function of maintaining protein homeostasis within the cells. The autophagic dysfunction in dementia further complicates the disease by hampering the degradation and removing abnormal pathogenic proteins. In order to understand autophagic dysfunction, it is essential to know the genetics of autophagy as well as the mutations This understanding at the genetic level helps definethe relationship between dementia and autophagic dysfunction for developing the potential remedies for the treatment of dementia.

Carbon Nano Tubes: Novel Drug Delivery System in Amelioration of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease is an irreversible, progressive brain disorder manifested with symptoms like loss of memory (known as dementia), personality changes, loss of cognition, impaired movement, confusion, deteriorated planning and thought process. Neurodegeneration in Alzheimer's disease is the result of the deposition of protein beta-amyloid that forms plaques and another protein called tau, forming tangles that prevent the proper functioning of nerve cells in the brain. METHODS: The goal of the review was to comprehensively study the utilization of nanotechnology and the role that carbon nanotubes can play as a drug delivery system for the amelioration of Alzheimer's disease. RESULTS: Nanotechnology is one of the most researched domains of modern science. It contributes significantly to therapeutics by facilitating drug therapy to reach the target sites, which are otherwise difficult to reach with conventional drug delivery systems. Carbon nanotubes are the allotropes of carbon in which several carbon atoms bind with each other to form a cylindrical or a tube-like structure. The carbon nanotubes possess several unique qualities, which confer them with a high potential of being utilized as an efficient drug delivery system. They offer high drug loading and can readily cross the toughest biological barriers like the BBB. Carbon nanotubes also facilitate the passage of drugs to the brain via the olfactory route, which further helps in restoring normal autophagy, thus preventing the elimination of autophagic chemicals. They can carry a vast range of cargos, including drugs, antigens, genetic materials, and biological macromolecules. CONCLUSION: Carbon nanotubes are a highly promising drug delivery system for anti-Alzheimer's drugs. They have the potential of overcoming the various biological barriers like the BBB. However, more extensive research is required so as to set up a firm base for the development of advanced commercial products based on carbon nanotubes for the treatment of Alzheimer's disease.

Targeting metacaspase-3 from Plasmodium falciparum towards antimalarial therapy: A combined approach of in-silico and in-vitro investigation.

Malaria is a global challenge, and its infection is propagated through Plasmodium falciparum, an obligate human parasite. The genome of P. falciparum encodes many proteases that play significant roles in their survival and pathogenesis thus being considered as attractive drug targets. P. falciparum metacaspase-3 (PfMCA3) is one such protease and a validated drug target to control malarial infection. First, we modeled the three-dimensional structure of PfMCA3 and predicted its ligand-binding pocket. The structural features of PfMCA3 were used for virtual screening followed by docking and molecular dynamics (MD) simulation studies to identify potent inhibitors. We used an in-house library of 513 compounds for screening to identify lead molecule fits well in the active site pocket of PfMCA3. The binding affinity and mechanism were investigated by combined docking and MD simulation studies. Docking studies reveal that the selected compounds are forming enough number of non-covalent interactions to the PfMCA3. In the enzyme inhibition assay, one of the selected compounds, H6 was found with appreciable inhibitory potential. MD simulation studies further support the binding of compound H6 with PfMCA3 and formation of a stable complex throughout the simulation trajectory. Taken together, we proposed that compound H6 is a promising lead scaffold that can be further exploited as a potential inhibitor of PfMCA3 for therapeutic management of malarial infection.Communicated by Ramaswamy H. Sarma.

Liposomes: Novel Drug Delivery Approach for Targeting Parkinson's Disease.

Parkinson's disease is one of the most severe progressive neurodegenerative disorders, having a mortifying effect on the health of millions of people around the globe. The neural cells producing dopamine in the substantia nigra of the brain die out. This leads to symptoms like hypokinesia, rigidity, bradykinesia, and rest tremor. Parkinsonism cannot be cured, but the symptoms can be reduced with the intervention of medicinal drugs, surgical treatments, and physical therapies. Delivering drugs to the brain for treating Parkinson's disease is very challenging. The blood-brain barrier acts as a highly selective semi-permeable barrier, which refrains the drug from reaching the brain. Conventional drug delivery systems used for Parkinson's disease do not readily cross the blood barrier and further lead to several side-effects. Recent advancements in drug delivery technologies have facilitated drug delivery to the brain without flooding the bloodstream and by directly targeting the neurons. In the era of Nanotherapeutics, liposomes are an efficient drug delivery option for brain targeting. Liposomes facilitate the passage of drugs across the blood-brain barrier, enhances the efficacy of the drugs, and minimize the side effects related to it. The review aims at providing a broad updated view of the liposomes, which can be used for targeting Parkinson's disease.

Applications of Exosomes in Targeted Drug Delivery for the Treatment of Parkinson's Disease: A Review of Recent Advances and Clinical Challenges.

Parkinson's disease (PD) is one of the most prevalent and severe neurodegenerative disease affecting more than 6.1 million people globally. It is characterized by age-related progressive deterioration of neurological functions caused by neuronal damage or neuronal death. During PD, the dopamineproducing cells in the substantia nigra region of the brain degenerate, which leads to symptoms like resting tremors and rigidity. Treatment of PD is very challenging due to the blood-brain barrier, which restricts the drug from reaching the brain. Conventional drug delivery systems possess a limited capacity to cross the blood barrier, leading to low bioavailability and high toxicity (due to off-site drug release). Therefore, it becomes necessary to accelerate the development of novel drug delivery systems, including nanoparticles, microemulsions, matrix systems, solid dispersions, liposomes, and solid lipid nanoparticles for the treatment of PD. Exosomes are biological lipid bilayer membrane vesicles produced by nearly all mammalian cells. The characteristics of vesicles are unique to their cell of origin and are primarily involved in intracellular communication. Exosomes, due to their nanoscale size, could easily permeate across the central nervous system, which makes them ideal for targeting the neurons in the substantia nigra. Exosomes could be efficient drug carrier systems for brain targeting, which can increase the efficacy of the drug and minimize the side effects. The review aims at providing a broad updated view of exosomes and their application in the treatment of PD.

Metacaspase-3 of Plasmodium falciparum: An atypical trypsin-like serine protease.

Metacaspases are clan CD cysteine peptidases found in plants, fungi and protozoa that possess a conserved Peptidase_C14 domain, homologous to the human caspases and a catalytic His/Cys dyad. Earlier reports have indicated the role of metacaspases in cell death; however, metacaspases of human malaria parasite remains poorly understood. In this study, we aimed to functionally characterize a novel malarial protease, P. falciparum metacaspase-3 (PfMCA3). Unlike other clan CD peptidases, PfMCA3 has an atypical active site serine (Ser1865) residue in place of canonical cysteine and it phylogenetically forms a distinct branch across the species. To investigate whether this domain retains catalytic activity, we expressed, purified and refolded the Peptidase_C14 domain of PfMCA3 which was found to express in all asexual stages. PfMCA3 exhibited trypsin-like serine protease activity with ser1865 acting as catalytic residue to cleave trypsin oligopeptide substrate. PfMCA3 is inhibited by trypsin-like serine protease inhibitors. Our study found that PfMCA3 enzymatic activity was abrogated when catalytic serine1865 (S1865A) was mutated. Moreover, PfMCA3 was found to be inactive against caspase substrate. Overall, our study characterizes a novel metacaspase of P. falciparum, different from human caspases and not responsible for the caspase-like activity, therefore, could be considered as a potential chemotherapeutic target.