Essential oils for clinical aromatherapy: A comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: Aromatherapy, a holistic healing practice utilizing the aromatic essences of plant-derived essential oils, has gained significant attention for its therapeutic potential in promoting overall well-being. Use of phytoconstituent based essential oil has played a significant role in the evolving therapeutic avenue of aromatherapy as a complementary system of medicine. AIM OF THE STUDY: This comprehensive review article aims to explore the usage of essential oils for aromatherapy, shedding light on their diverse applications, scientific evidence, and safety considerations. Furthermore, the growing interest in using essential oils as complementary therapies in conjunction with conventional medicine is explored, underscoring the significance of collaborative healthcare approaches. MATERIALS AND METHODS: Literature search was performed from databases like PubMed, ScienceDirect, Scopus, and Bentham using keywords like Aromatherapy, Aromatic Plants, Essential oils, Phytotherapy, and complementary medicine. The keywords were used to identify literature with therapeutic and mechanistic details of herbal agents with desired action. RESULTS: The integration of traditional knowledge with modern scientific research has led to a renewed interest in essential oils as valuable tools in contemporary healthcare. Various extraction methods used to obtain essential oils are presented, emphasizing their impact on the oil's chemical composition and therapeutic properties. Additionally, the article scrutinizes the factors influencing the quality and purity of essential oils, elucidating the significance of standardization and certification for safe usage. A comprehensive assessment of the therapeutic effects of essential oils is provided, encompassing their potential as antimicrobial, analgesic, anxiolytic, and anti-inflammatory agents, among others. Clinical trials and preclinical studies are discussed to consolidate the existing evidence on their efficacy in treating diverse health conditions, both physical and psychological. Safety considerations are of paramount importance when employing essential oils, and this review addresses potential adverse effects, contraindications, and best practices to ensure responsible usage. CONCLUSIONS: This comprehensive review provides valuable insights into the exploration of essential oils for aromatherapy, emphasizing their potential as natural and potent remedies for a wide range of ailments. By amalgamating traditional wisdom and modern research, this article aims to encourage further investigation into the therapeutic benefits of essential oils while advocating for their responsible and evidence-based incorporation into healthcare practices.

High mobility group box 1 cytokine targeted topical delivery of resveratrol embedded nanoemulgel for the management of atopic dermatitis.

Resveratrol is a polyphenolic compound showing anti-inflammatory activity by inhibition of high mobility group box 1 cytokine responsible for the activation of nuclear factor-κB pathway in atopic dermatitis. To evaluate the efficacy of resveratrol through topical route we have developed resveratrol-loaded nanoemulgel for the effective management of atopic dermatitis in mice model. The resveratrol-loaded nanoemulsion (0.5%, 0.75% and 1% w/w) was optimized by spontaneous nano-emulsification. The optimized resveratrol-loaded nanoemulsions showed average globule size in the 180-230 nm range and found to be monodispersed. The resveratrol nanoemulgel was prepared with a SEPINEO™ P 600 gel base and propylene glycol. Ex vivo permeation and retention study resulted in significantly higher skin retention of resveratrol from resveratrol-loaded nanoemulgel than free resveratrol-loaded gel. Preclinical efficacy of resveratrol nanoemulgel displayed promising therapeutic outcomes where, western blotting of skin tissues disclosed a significant reduction in the relative expression of high mobility group box 1, the receptor for advanced glycation end products, toll-like receptor-4 and phosphorylated nuclear factor-κB. Further, real-time polymerase chain reaction also disclosed a significant reduction in pro-inflammatory cytokines such as thymic stromal lymphopoietin, interleukin-4, interleukin-13, interleukin-31, tumor necrosis factor-α and interleukin-6. The histopathological examination of skin sections showed improvement in the skin condition. Collectively, the findings from our study showcased the significant improvement in the atopic dermatitis skin condition in mice model after topical application of resveratrol loaded nanoemulgel.

Revamping the corneal permeability and antiglaucoma therapeutic potential of brinzolamide using transniosomes: optimization, in vitro and preclinical evaluation.

Aim: This study aims to explore potential of transniosomes, a hybrid vesicular system, as ocular drug-delivery vehicle. Materials & methods: Thin-film hydration technique was used to fabricate brinzolamide-loaded transniosomes (BRZ-TN) and optimized using Box-Behnken design, further exhaustively characterized for physicochemical evaluations, deformability, drug release, permeation and preclinical evaluations for antiglaucoma activity. Results: The BRZ-TN showed ultradeformability (deformability index: 5.71), exhibiting sustained drug release without irritation (irritancy score: 0) and high permeability compared with the marketed formulation or free drug suspension. The extensive in vivo investigations affirmed effective targeted delivery of transniosomes, with brinzolamide reducing intraocular pressure potentially. Conclusion: Our findings anticipated that BRZ-TN is a promising therapeutic nanocarrier for effectively delivering cargo to targeted sites by crossing corneal barriers.

Exosome-mediated delivery and regulation in neurological disease progression.

Exosomes (EXOs), membranous structures originating from diverse biological sources, have recently seized the attention of researchers due to their theranostic potential for neurological diseases. Released actively by various cells, including stem cells, adipose tissue, and immune cells, EXOs wield substantial regulatory influence over the intricate landscape of neurological complications, exhibiting both positive and negative modulatory effects. In AD, EXOs play a pivotal role in disseminating and breaking down amyloid-ß protein. Moreover, EXOs derived from mesenchymal stem cells showcase a remarkable capacity to mitigate pro-inflammatory phenotypes by regulating miRNAs in neurodegenerative diseases. These vesicles possess the unique ability to traverse the blood-brain barrier, governing the aggregation of mutant huntingtin protein. Understanding the exosomal functions within the CNS holds significant promise for enhancing treatment efficacy in neurological diseases. This review intricately examines the regulatory mechanisms involving EXOs in neurological disease development, highlighting therapeutic prospects and exploring their utility in exosome-based nanomedicine for various neurological complications. Additionally, the review highlights the challenges associated with drug delivery to the brain, emphasizing the complexities inherent in this critical aspect of neurotherapeutics.

Dimethyl Fumarate Exerts a Neuroprotective Effect by Enhancing Mitophagy via the NRF2/BNIP3/PINK1 Axis in the MPP+ Iodide-Induced Parkinson's Disease Mice Model.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder linked to the loss of dopaminergic neurons in the substantia nigra. Mitophagy, mitochondrial selective autophagy, is critical in maintaining mitochondrial and subsequently neuronal homeostasis. Its impairment is strongly implicated in PD and is associated with accelerated neurodegeneration. Objective: To study the positive effect of dimethyl fumarate (DMF) on mitophagy via the NRF2/BNIP3/PINK1 axis activation in PD disease models. Methods: The neuroprotective effect of DMF was explored in in vitro and in vivo PD models. MTT assay was performed to determine the DMF dose followed by JC-1 assay to study its mitoprotective effect in MPP+ exposed SHSY5Y cells. For the in vivo study, C57BL/6 mice were divided into six groups: Normal Control (NC), Disease Control (DC), Sham (Saline i.c.v.), Low Dose (MPP+ iodide+DMF 15 mg/kg), Mid Dose (MPP+ iodide+DMF 30 mg/kg), and High Dose (MPP+ iodide+DMF 60 mg/kg). The neuroprotective effect of DMF was assessed by performing rotarod, open field test, and pole test, and biochemical parameter analysis using immunofluorescence, western blot, and RT-PCR. Results: DMF treatment significantly alleviated the loss of TH positive dopaminergic neurons and enhanced mitophagy by increasing PINK1, Parkin, BNIP3, and LC3 levels in the MPP+ iodide-induced PD mice model. DMF treatment groups showed good locomotor activity and rearing time when compared to the DC group. Conclusions: DMF confers neuroprotection by activating the BNIP3/PINK1/Parkin pathway, enhancing the autophagosome formation via LC3, and improving mitophagy in PD models, and could be a potential therapeutic option in PD.

Understanding molecular mechanisms and miRNA-based targets in diabetes foot ulcers.

In today's culture, obesity and overweight are serious issues that have an impact on how quickly diabetes develops and how it causes complications. For the development of more effective therapies, it is crucial to understand the molecular mechanisms underlying the chronic problems of diabetes. The most prominent effects of diabetes are microvascular abnormalities such as retinopathy, nephropathy, and neuropathy, especially diabetes foot ulcers, as well as macrovascular abnormalities such as heart disease and atherosclerosis. MicroRNAs (miRNAs), which are highly conserved endogenous short non-coding RNA molecules, have been implicated in several physiological functions recently, including the earliest stages of the disease. By binding to particular messenger RNAs (mRNAs), which cause mRNA degradation, translation inhibition, or even gene activation, it primarily regulates posttranscriptional gene expression. These molecules exhibit considerable potential as diagnostic biomarkers for disease and are interesting treatment targets. This review will provide an overview of the latest findings on the key functions that miRNAs role in diabetes and its complications, with an emphasis on the various stages of diabetic wound healing.

Quality by design fostered fabrication of cabazitaxel loaded pH-responsive Improved nanotherapeutics against prostate cancer.

Cabazitaxel has been approved for the treatment of prostate cancer since 2010. However, its poor solubility and permeability pitfalls prevent its accumulation at the target site and promote severe adverse effects. About 90% of prostate cancer (PCa) patients suffer from bone metastasis. This advent reports the development of CBZ-loaded pH-responsive polydopamine nanoparticles (CBZ NP) against metastatic PCa cells. Quality by design (QbD) and multivariate analysis tools were employed for the optimization of CBZ NP. Amorphisation of CBZ along with metastatic microenvironment responsive release was observed thereby imparting spatial release and circumventing solubility pitfalls. CBZ NP retained its cytotoxic potential, with a significant increase in quantitative cellular uptake. Apoptotic markers observed from nuclear staining with elevated reactive oxygen species (ROS) and mitochondrial damage revealed by JC-1 staining demonstrated the efficacy of CBZ NP against PC-3 cells with good serum stability and diminished hemolysis. Cell cycle analysis revealed substantial S and G2/M phase arrest with enhancement in apoptosis was observed. Western blot studies revealed an elevation in caspase-1 and suppression in Bcl-2 indicating enhanced apoptosis compared to the control group. Substantial reduction in the diameter of 3D-Tumoroid and enhanced cell proliferation inhibition indicated the efficacy of CBZ NP in PCa. Thus, we conclude that CBZ NP could be a promising Nanotherapeutic approach for PCa.

Experimental Type 2 diabetes and lipotoxicity-associated neuroinflammation involve mitochondrial DNA-mediated cGAS/STING axis: implication of Type-1 interferon response in cognitive impairment.

Type-1 IFN (interferon)-associated innate immune response is increasingly getting attention in neurodegenerative and metabolic diseases like type 2 diabetes (T2DM). However, its significance in T2DM/lipotoxicity-induced neuroglia changes and cognitive impairment is missing. The present study aims to evaluate the involvement of cGAS (cyclic GMP-AMP synthase)-STING (stimulator of interferon gene), IRF3 (interferon regulatory factor-3), TBK (TANK binding kinase)-mediated Type-1 IFN response in the diabetic brain, and lipotoxicity (palmitate-bovine serum albumin conjugate/PA-BSA)-induced changes in cells (neuro2a and BV2). T2DM was induced in C57/BL6 mice by feeding on a high-fat diet (HFD, 60% Kcal) for 16 weeks and injecting a single dose of streptozotocin (100 mg/kg, i.p) in the 12th week. Plasma biochemical parameter analysis, neurobehavioral assessment, protein expression, and quantitative polymerase chain reaction study were carried out to decipher the hypothesis. T2DM-associated metabolic and lipotoxic stress led to mitochondrial impairment causing leakage of mtDNA to the cytoplasm further commencing cGAS activation and its downstream signaling. The diseased hippocampus and cortex showed decreased expression of synaptophysin (p < 0.01) and PSD-95 (p < 0.01, p < 0.05) with increased expression of cGAS (p < 0.001), p-STING (p < 0.001), p-STAT1 (signal transducer and activator of transcription) (p < 0.01), and IFN-ß (p < 0.001) compared to normal control. The IFN-ß/p-STAT1-mediated microglia activation was executed employing a conditioned media approach. C-176, a selective STING inhibitor, alleviated cGAS/p-STING/IFN-ß expression and proinflammatory microglia/M1-associated markers (CD16 expression, CXCL10, TNF-α, IL-1ß mRNA fold change) in the diabetic brain. The present study suggests Type-1IFN response may result in neuroglia dyshomeostasis affecting normal brain function. Alleviating STING signaling has the potential to protect T2DM-associated central ailment.

Sulfo-butyl ether ß-cyclodextrin inclusion complexes of bosutinib: in silico, in vitro and in vivo evaluation in attenuating the fast-fed variability.

Bosutinib (BOS) is a BCS class IV drug that shows low oral bioavailability and high fast-fed variability. Various pharmaceutical formulations have been explored thus far in order to improve its bioavailability while avoiding fast-fed variability. In the present study, we explored cyclodextrin (CD) complexation strategy to overcome the aforementioned disadvantages associated with BOS. CD complexation is a simple, versatile and economic approach that enables formation of inclusion complexes, thereby improving aqueous solubility while nullifying pH-dependent solubility and fast-fed variability for poorly soluble drugs. Initially, we performed molecular dynamics and docking studies to select appropriate CD derivative. The results of in silico studies revealed that sulfo-butyl ether ß-cyclodextrin (SBE-CD) offered superior binding affinity with BOS. Further, Job's plot revealed that 1:1 stoichiometry of BOS and CD resulted in enhancement of BOS solubility up to ~ 132.6-folds. In vitro release studies in bio-relevant media (fasted and fed state simulated gastric and intestinal fluids) revealed higher drug release while overcoming its pH-dependent solubility. In vitro studies on K562 cells demonstrated a 1.83-fold enhancement in cytotoxicity due to enhanced ROS production and G2/M phase arrest.In vivo pharmacokinetic studies in Sprague-Dawley rats revealed insignificant fast-fed variability with AUCfast/fed 0.9493 and Cmaxfast/fed 0.8291 being closer to 1 in comparison with BOS. Hence, we conclude that SBE-CD complexation could be a promising approach in diminishing fast-fed variability of BOS.

Role of F-actin-mediated endocytosis and exercise in mitochondrial transplantation in an experimental Parkinson's disease mouse model.

Dopaminergic neurons gradually deteriorate in Parkinson's Disease (PD), which is characterized by the intracellular accumulation of Lewy bodies that are enriched with α-synuclein protein. Mitochondrial dysfunction is one of the primary contributors to this and is considered as the central player in the pathogenesis of PD. Recently, improving mitochondrial function has been extensively explored as a therapeutic strategy in various preclinical PD models. Mitochondrial transplantation is one such naïve yet highly efficient technique that has been well explored in diseases like diabetes, NAFLD, and cardiac ischemia but not in PD. Here, we compared the effects of transplanting normal allogenic mitochondria to those of transplanting exercise-induced allogenic mitochondria isolated from the liver into the PD mouse model. It is already known that normal Mitochondrial Transplant (MT) reduces the PD pathology, but our research found out that exercise-induced mitochondria were more effective in treating the PD pathology because they had higher respiratory capacities. Additionally, compared to a standard transplant, this therapy significantly boosted the rate of mitochondrial biogenesis and the quantity of mitochondrial subunits in PD mice. Further, we also explored the mechanism of mitochondrial uptake into the cells and found that F-actin plays a key role in the internalization of mitochondria. This study is the first to demonstrate the relevance of exercise-induced allogenic MT and the function of F-actin in the internalization of mitochondria in PD mice.

S1PR2 inhibition mitigates cognitive deficit in diabetic mice by modulating microglial activation via Akt-p53-TIGAR pathway.

Cognitive deficit is one of the challenging complications of type 2 diabetes. Sphingosine 1- phosphate receptors (S1PRs) have been implicated in various neurodegenerative and metabolic disorders. The association of S1PRs and cognition in type 2 diabetes remains elusive. Microglia-mediated neuronal damage could be the thread propagating cognitive deficit. The effects of S1PR2 inhibition on cognition in high-fat diet and streptozotocin-induced diabetic mice were examined in this work. We further assessed microglial activation and putative microglial polarisation routes. Cognitive function loss was observed after four months of diabetes induction in Type 2 diabetes animal model. JTE013, an S1PR2 inhibitor, was used to assess neuroprotection against cognitive decline and neuroinflammation in vitro and in vivo diabetes model. JTE013 (10 mg/kg) improved synaptic plasticity by upregulating psd95 and synaptophysin while reducing cognitive decline and neuroinflammation. It further enhanced anti-inflammatory microglia in the hippocampus and prefrontal cortex (PFC), as evidenced by increased Arg-1, CD206, and YM-1 levels and decreased iNOS, CD16, and MHCII levels. TIGAR, TP53-induced glycolysis and apoptosis regulator, might facilitate the anti-inflammatory microglial phenotype by promoting oxidative phosphorylation and decreasing apoptosis. However, since p53 is a TIGAR suppressor, inhibiting p53 could be beneficial. S1PR2 inhibition increased p-Akt and TIGAR levels and reduced the levels of p53 in the PFC and hippocampus of type 2 diabetic mice, thereby decreasing apoptosis. In vitro, palmitate was used to imitate sphingolipid dysregulation in BV2 cells, followed by conditioned media exposure to Neuro2A cells. JTE013 rescued the palmitate-induced neuronal apoptosis by promoting the anti-inflammatory microglia. In the present study, we demonstrate that the inhibition of S1PR2 improves cognitive function and skews microglia toward anti-inflammatory phenotype in type 2 diabetic mice, thereby promising to be a potential therapy for neuroinflammation.

Quality by design endorsed atorvastatin-loaded nanostructured lipid carriers embedded in pH-responsive gel for melanoma.

AIM: Our aim was to repurpose atorvastatin for melanoma by encapsulating in a nanostructured lipid carrier matrix to promote tumour cell internalisation and skin permeation. pH-responsive chitosan gel was employed to restrict At-NLCs in upper dermal layers. METHODS: We utilised a quality by design approach for encapsulating At within the NLC matrix. Further, cellular uptake and cytotoxicity was evaluated along with pH-responsive release and ex vivo skin permeation. RESULTS: Cytotoxicity assay showed 3.13-fold enhanced cytotoxicity on melanoma cells compared to plain drug with nuclear staining showing apoptotic markers. In vitro, release studies showed 5.9-fold rapid release in chitosan gel matrix at pH 5.5 compared to neutral pH. CONCLUSIONS: At-NLCs prevented precipitation, promoted skin permeation, and SK-MEL 28 cell internalisation. The localisation of NLCs on the upper dermal layer due to electrostatic interactions of skin with chitosan gel diminished the incidence of untoward systemic effects.

Glioblastoma preclinical models: Strengths and weaknesses.

Glioblastoma multiforme is a highly malignant brain tumor with significant intra- and intertumoral heterogeneity known for its aggressive nature and poor prognosis. The complex signaling cascade that regulates this heterogeneity makes targeted drug therapy ineffective. The development of an optimal preclinical model is crucial for the comprehension of molecular heterogeneity and enhancing therapeutic efficacy. The ideal model should establish a relationship between various oncogenes and their corresponding responses. This review presents an analysis of preclinical in vivo and in vitro models that have contributed to the advancement of knowledge in model development. The experimental designs utilized in vivo models consisting of both immunodeficient and immunocompetent mice induced with intracranial glioma. The transgenic model was generated using various techniques, like the viral vector delivery system, transposon system, Cre-LoxP model, and CRISPR-Cas9 approaches. The utilization of the patient-derived xenograft model in glioma research is valuable because it closely replicates the human glioma microenvironment, providing evidence of tumor heterogeneity. The utilization of in vitro techniques in the initial stages of research facilitated the comprehension of molecular interactions. However, these techniques are inadequate in reproducing the interactions between cells and extracellular matrix (ECM). As a result, bioengineered 3D-in vitro models, including spheroids, scaffolds, and brain organoids, were developed to cultivate glioma cells in a three-dimensional environment. These models have enabled researchers to understand the influence of ECM on the invasive nature of tumors. Collectively, these preclinical models effectively depict the molecular pathways and facilitate the evaluation of multiple molecules while tailoring drug therapy.

Fingolimod exerts neuroprotection by regulating S1PR1 mediated BNIP3-PINK1-Parkin dependent mitophagy in rotenone induced mouse model of Parkinson's disease.

The motor impairments brought on by the loss of dopaminergic neurons in the substantia nigra are the most well-known symptoms of Parkinson's disease (PD). It is believed that dopaminergic neurons are especially vulnerable to mitochondrial malfunction. For the maintenance of mitochondrial integrity, selective autophagic removal of dysfunctional mitochondria via mitophagy primarily regulated by PINK1/Parkin pathway is essential. Moreover, newer studies also implicate the role of phospholipid metabolism, such as that of Sphingosine-1-phosphate (S1P) as a contributor to PD. S1P receptors have been reported to influence mitochondrial function in neurodegenerative diseases. Fingolimod (FTY720), an S1P receptor-1 modulator has been proven effective in PD but its regulation of mitophagy in PD is still elusive. In this study, the neuroprotective effect of FTY720 by modulating mitophagy, has been explored against rotenone (ROT) induced neurotoxicity in in-vivo. The animals were randomly divided into 5 groups namely, Normal Control (NC); Disease control (DC): ROT (1.5 mg/kg); Low dose (LD): ROT + FTY720 (0.5 mg/kg); High dose (HD): ROT + FTY720 (1 mg/kg) and Vehicle control (VC): 1 % DMSO. ROT was administered through i.p. and FTY720 through p.o. for 21 days. At the end of the study, various neurobehavioral studies (rotarod test and actimeter), western blot techniques, and immunofluorescence studies were performed. FTY720 restored the neurobehavioural functions and protein expression of PINK1, Parkin and BNIP3 in ROT-induced PD mice. The results obtained in our study suggest that FTY720 has a neuroprotective effect in ROT-induced mice model of PD via PINK1-Parkin mediated mitophagy.

Development of trisubstituted thiophene-3-arboxamide selenide derivatives as novel EGFR kinase inhibitors with cytotoxic activity.

Overexpression of EGFR is one of the eminent oncogenic drivers detected in the development of several human cancers. The increasing incidences of mutation-based resistance in the tyrosine kinase domain call upon the need for the development of a newer class of small-molecule TK inhibitors. Accordingly, a new series of symmetrical trisubstituted thiophene-3-carboxamide selenide derivatives was developed via the hybridization of complementary pharmacophores. Most of the compounds showed a modest to excellent antiproliferative action at 20 µM concentration. The utmost antiproliferative activity was portrayed by compound 16e on the selected cancer cell lines with IC50 < 9 µM, the lowest being 3.20 ± 0.12 µM in the HCT116 cell line. Further, it also displayed an impressive EGFR kinase inhibition with an IC50 value of 94.44 ± 2.22 nM concentration. As a corollary of the reported EGFR inhibition, the nature, energy, and stability of the binding interactions were contemplated via in silico studies.

Colloidal therapeutics in the management of traumatic brain injury: Portray of biomarkers and drug-targets, preclinical and clinical pieces of evidence and future prospects.

Complexity associated with the aberrant physiology of traumatic brain injury (TBI) makes its therapeutic targeting vulnerable. The underlying mechanisms of pathophysiology of TBI are yet to be completely illustrated. Primary injury in TBI is associated with contusions and axonal shearing whereas excitotoxicity, mitochondrial dysfunction, free radicals generation, and neuroinflammation are considered under secondary injury. MicroRNAs, proinflammatory cytokines, and Glial fibrillary acidic protein (GFAP) recently emerged as biomarkers in TBI. In addition, several approved therapeutic entities have been explored to target existing and newly identified drug-targets in TBI. However, drug delivery in TBI is hampered due to disruption of blood-brain barrier (BBB) in secondary TBI, as well as inadequate drug-targeting and retention effect. Colloidal therapeutics appeared helpful in providing enhanced drug availability to the brain owing to definite targeting strategies. Moreover, immense efforts have been put together to achieve increased bioavailability of therapeutics to TBI by devising effective targeting strategies. The potential of colloidal therapeutics to efficiently deliver drugs at the site of injury and down-regulate the mediators of TBI are serving as novel policies in the management of TBI. Therefore, in present manuscript, we have illuminated a myriad of molecular-targets currently identified and recognized in TBI. Moreover, particular emphasis is given to frame armamentarium of repurpose drugs which could be utilized to block molecular targets in TBI in addition to drug delivery barriers. The critical role of colloidal therapeutics such as liposomes, nanoparticles, dendrimers, and exosomes in drug delivery to TBI through invasive and non-invasive routes has also been highlighted.

Quality by design endorsed fabrication of Ibrutinib-loaded human serum albumin nanoparticles for the management of leukemia.

Ibrutinib (IB), a BCS class II drug suffers from limited aqueous solubility, short half-life and extensive first-pass metabolism. In this project, we aim to recruit the desirable properties of human serum albumin (HSA) as a biocompatible drug carrier to circumvent nanoparticle-associated drawbacks. Quality by design and multivariate analysis was used for the optimization of IB-NPs. Cell culture studies performed on the K562 cell line revealed that the Ibrutinib-loaded HSA NPs demonstrated improved cytotoxicity, drug uptake, and reactive oxygen species generation in the leukemic K562 cells. Cell cycle analysis revealed G2/M phase retention of the leukemia cells. In vitro protein corona and hemolysis studies revealed superior hematological stability compared to the free drug which showed greater than 40 % hemolysis. In vitro drug release studies showed prolonged release profile till 48 h. Pharmacokinetic studies demonstrated a 2.31-fold increase in AUC and an increase in half-life from 0.43 h to 2.887 h with a tremendous reduction in clearance and elimination rate indicating prolonged systemic circulation which is desirable in leukemia. Hence, we conclude that IB-loaded albumin nanoparticles could be a promising approach for the management of leukemia.

Involvement of miRNA on epigenetics landscape of Parkinson's disease: From pathogenesis to therapeutics.

The development of novel therapeutics for the effective management of Parkinson's disease (PD) is undertaken seriously by the scientific community as the burden of PD continues to increase. Several molecular pathways are being explored to identify novel therapeutic targets. Epigenetics is strongly implicated in several neurodegenerative diseases (NDDs) including PD. Several epigenetic mechanisms were found to dysregulated in various studies. These mechanisms are regulated by several miRNAs which are associated with a variety of pathogenic mechanisms in PD. This concept is extensively investigated in several cancers but not well documented in PD. Identifying the miRNAs with dual role i.e., regulation of epigenetic mechanisms as well as modulation of proteins implicated in the pathogenesis of PD could pave way for the development of novel therapeutics to target them. These miRNAs could also serve as potential biomarkers and can be useful in the early diagnosis or assessment of disease severity. In this article we would like to discuss about various epigenetic changes operating in PD and how miRNAs are involved in the regulation of these mechanisms and their potential to be novel therapeutic targets in PD.

Dimethyl fumarate ameliorates parkinsonian pathology by modulating autophagy and apoptosis via Nrf2-TIGAR-LAMP2/Cathepsin D axis.

Mounting evidence suggests a role for oxidative stress and accumulation of dysfunctional organelle and misfolded proteins in PD. Autophagosomes mediate the clearance of these cytoplasmic proteins via delivery to lysosomes to form autophagolysosomes, followed by degradation of the protein by lysosomal enzymes. In PD, autophagolysosome accumulation occurs initiating a plethora of events resulting in neuronal death by apoptosis. This study evaluated the effect of Dimethylfumarate (DMF), an Nrf2 activator in the rotenone-induced mouse PD model. In PD mice, there was decreased expression of LAMP2 and LC3, which resulted in inhibition of autophagic flux and increased expression of cathepsin D, which mediated apoptosis. The role of Nrf2 activation in alleviating oxidative stress is well known. Our study elucidated the novel mechanism underlying the neuroprotective effect of DMF. The loss of dopaminergic neurons induced by rotenone was lessened to a significant extent by pre-treatment with DMF. DMF promoted autophagosome formation and inhibited apoptosis by removing the inhibitory effect of p53 on TIGAR. TIGAR expression upregulated LAMP2 expression and downregulated Cathepsin D, promoting autophagy and inhibiting apoptosis. Thus, it was proved that DMF confers neuroprotection against rotenone-induced dopaminergic neurodegeneration and could be used as a potential therapeutic agent for PD and its progression.