Amelioration of breast cancer therapies through normalization of tumor vessels and microenvironment: paradigm shift to improve drug perfusion and nanocarrier permeation.

Breast cancer (BC) is the most commonly diagnosed cancer among women. Chemo-, immune- and photothermal therapies are employed to manage BC. However, the tumor microenvironment (TME) prevents free drugs and nanocarriers (NCs) from entering the tumor premises. Formulation scientists rely on enhanced permeation and retention (EPR) to extravasate NCs in the TME. However, recent research has demonstrated the inconsistent nature of EPR among different patients and tumor types. In addition, angiogenesis, high intra-tumor fluid pressure, desmoplasia, and high cell and extracellular matrix density resist the accumulation of NCs in the TME. In this review, we discuss TME normalization as an approach to improve the penetration of drugs and NCSs in the tumor premises. Strategies such as normalization of tumor vessels, reversal of hypoxia, alleviation of high intra-tumor pressure, and infiltration of lymphocytes for the reversal of therapy failure have been discussed in this manuscript. Strategies to promote the infiltration of anticancer immune cells in the TME after vascular normalization have been discussed. Studies strategizing time points to administer TME-normalizing agents are highlighted. Mechanistic pathways controlling the angiogenesis and normalization processes are discussed along with the studies. This review will provide greater tumor-targeting insights to the formulation scientists.

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.

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.

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.

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.

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.

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.

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.

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.

Sphingosine 1 phosphate lyase inhibition rescues cognition in diabetic mice by promoting anti-inflammatory microglia.

Sphingosine-1-phosphate (S1P) is emerging as a crucial sphingolipid modulating neuroinflammation and cognition. S1P levels in the brain have been found to be decreased in cognitive impairment. S1P lyase (S1PL) is the key enzyme in metabolizing S1P and has been implicated in neuroinflammation. This study evaluated the effect of S1PL inhibition on cognition in type 2 diabetic mice. Fingolimod (0.5 mg/kg and 1 mg/kg) rescued cognition in high-fat diet and streptozotocin-induced diabetic mice, as evident in the Y maze and passive avoidance test. We further evaluated the effect of fingolimod on the activation of microglia in the pre-frontal cortex (PFC) and hippocampus of diabetic mice. Our study revealed that fingolimod inhibited S1PL and promoted anti-inflammatory microglia in both PFC and hippocampus of diabetic mice as it increased Ym-1 and arginase-1. The levels of p53 and apoptotic proteins (Bax and caspase-3) were elevated in the PFC and hippocampus of type 2 diabetic mice which fingolimod reversed. The underlying mechanism promoting anti-inflammatory microglial phenotype was also explored in this study. TIGAR, TP53-associated glycolysis and apoptosis regulator, is known to foster anti-inflammatory microglia and was found to be downregulated in the brain of type 2 diabetic mice. S1PL inhibition decreased the levels of p53 and promoted TIGAR, thereby increasing anti-inflammatory microglial phenotype and inhibiting apoptosis in the brain of diabetic mice. Our study reveals that S1PL inhibition could be beneficial in mitigating cognitive deficits in diabetic mice.

Perspective insights of small molecules, phytoconstituents and biologics in the management of psoriasis: A focus on targeting major inflammatory cytokine pathways.

Psoriasis is an enduring, pruritic and papulosquamous skin ailment that poses a significant burden on public health. It is mainly characterized by hyperkeratosis, acanthosis, parakeratosis, scaly and erythematous plaques. Biomarkers like interleukin-17, interleukin-12 and -23 and tumor necrosis factor-α serve as key drivers of psoriatic pathogenesis. Triggered release of pro-inflammatory cytokines from various up-regulated pathways leads to psoriatic inflammation. Several target moieties like biologics, small molecules and herbal moieties play a fundamental role in the repression of pathogenesis of psoriasis. Biologics and small molecules engaged in the management of psoriasis have been emphasized in detail. An insight into nano-carrier interventions on herbal moieties and clinical aspects of psoriasis are also highlighted. This review emphasizes various pathological targets involved in psoriasis.

Inter and intracellular mitochondrial transfer: Future of mitochondrial transplant therapy in Parkinson's disease.

Parkinson's disease (PD) is marked by the gradual degeneration of dopaminergic neurons and the intracellular build-up of Lewy bodies rich in α-synuclein protein. This impairs various aspects of the mitochondria including the generation of ROS, biogenesis, dynamics, mitophagy etc. Mitochondrial dynamics are regulated through the inter and intracellular movement which impairs mitochondrial trafficking within and between cells. This inter and intracellular mitochondrial movement plays a significant role in maintaining neuronal dynamics in terms of energy and growth. Kinesin, dynein, myosin, Mitochondrial rho GTPase (Miro), and TRAK facilitate the retrograde and anterograde movement of mitochondria. Enzymes such as Kinases along with Calcium (Ca2+), Adenosine triphosphate (ATP) and the genes PINK1 and Parkin are also involved. Extracellular vesicles, gap junctions, and tunneling nanotubes control intercellular movement. The knowledge and understanding of these proteins, enzymes, molecules, and movements have led to the development of mitochondrial transplant as a therapeutic approach for various disorders involving mitochondrial dysfunction such as stroke, ischemia and PD. A better understanding of these pathways plays a crucial role in establishing extracellular mitochondrial transplant therapy for reverting the pathology of PD. Currently, techniques such as mitochondrial coculture, mitopunch and mitoception are being utilized in the pre-clinical stages and should be further explored for translational value. This review highlights how intercellular and intracellular mitochondrial dynamics are affected during mitochondrial dysfunction in PD. The field of mitochondrial transplant therapy in PD is underlined in particular due to recent developments and the potential that it holds in the near future.

Computational and experimental therapeutic efficacy analysis of andrographolide phospholipid complex self-assembled nanoparticles against Neuro2a cells.

BACKGROUND: Neuroblastoma is one of the most common malignancies in childhood, accounts for approximately 7% of all malignancies. Andrographolide (AN) inhibits cancer cells progression via multiple pathways like cell cycle arrest, mitochondrial apoptosis, NF-κß inhibition, and antiangiogenesis mechanism. Despite multiple advantages, application of AN is very limited due to its low aqueous solubility (6.39 ± 0.47 µg/mL), high lipophilicity (log P âˆ¼ 2.632 ± 0.135), and reduced stability owing to pH sensitive lactone ring. OBJECTIVES AND RESULTS: In present investigation, a molecular complex of AN with soya-L-α-phosphatidyl choline (SPC) was synthesized as ANSPC and characterized by FT-IR and1H NMR spectroscopy. Spectral and molecular simulation techniques confirmed the intermolecular interactions between the 14-OH group of AN and the N+(CH3)3part of SPC. In addition, molecular dynamics (MD) simulation was used to determine the degree of interaction between various proteins such as TNF-α, caspase-3, and Bcl-2. Later, ANSPC complex was transformed in to self-assembled soft nanoparticles of size 201.8 ± 1.48 nm with PDI of 0.092 ± 0.004 and zeta potential of -21.7 ± 0.85 mV. The IC50 offree AN (8.319 µg/mL) and the self-assembled soft ANSPC nanoparticles (3.406 µg/mL âˆ¼ 1.2 µg of AN) against Neuro2a cells was estimated with significant (P < 0.05) difference. Interestingly, the self-assembled soft ANSPC nanoparticles showed better endocytosis compared to free AN in Neuro2a cells. In-vitrobiological assays confirmed that self-assembled soft ANSPC nanoparticles induces apoptosis in Neuro2a cells by declining the MMP (Δψm) and increasing the ROS generation. CONCLUSION: Self-assembled soft ANSPC nanoparticles warrant further in-depth antitumor study in xenograft model of neuroblastoma to establish the anticancer potential.

Immune cell-camouflaged surface-engineered nanotherapeutics for cancer management.

Nanocarriers (NCs) have shown potential in delivering hydrophobic cytotoxic drugs and tumor-specific targeting. However, the inability to penetrate the tumor microenvironment and entrapment by macrophages has limited their clinical translation. Various cell-based drug delivery systems have been explored for their ability to improve circulation half-life and tumor accumulation capabilities. Tumors are characterized by high inflammation, which aids in tumor progression and metastasis. Immune cells show natural tumor tropism and penetration inside the tumor microenvironment (TME) and are a topic of great interest in cancer drug delivery. However, the TME is immunosuppressive and can polarize immune cells to pro-tumor. Thus, the use of immune cell membrane-coated NCs has gained popularity. Such carriers display immune cell-specific surface receptors for tumor-specific accumulation but lack cell machinery. The lack of immune cell machinery makes them unaffected by the immunosuppressive TME, meanwhile maintaining the inherent tumor tropism. In this review, we discuss the molecular mechanism behind the movement of various immune cells toward TME, the preparation and characterization of membrane-coated NCs, and the efficacy of immune cell-mimicking NCs in tumor therapy. Regulatory guidelines and the bottlenecks in clinical translation are also highlighted. STATEMENT OF SIGNIFICANCE: Nanocarriers have been explored for the site-specific delivery of chemotherapeutics. However, low systemic circulation half-life, extensive entrapment by macrophages, and poor accumulation inside the tumor microenvironment prevent the clinical translation of conventional nanotherapeutics. Immune cells possess the natural tropism towards the tumor along the chemokine gradient. Hence, coating the nanocarriers with immune cell-derived membranes can improve the accumulation of nanocarriers inside the tumor. Moreover, coating with membranes derived autologous immune cells will prevent engulfment by the macrophages.

Emerging insights of peptide-based nanotherapeutics for effective management of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, prevalent, immune-mediated, inflammatory, joint disorder affecting millions of people worldwide. Despite current treatment options, many patients remain unable to achieve remission and suffer from comorbidities. Because of several comorbidities as well as its chronic nature, it diminishes the quality of patients' life and intensifies socioeconomic cargo. Consolidating peptides with immensely effective drug delivery systems has the ability to alleviate adverse effects associated with conventional treatments. Peptides are widely used as targeting moieties for the delivery of nanotherapeutics. The use of novel peptide-based nanotherapeutics may open up new avenues for improving efficacy by promoting drug accumulation in inflamed joints and reducing off-target cytotoxicity. Peptide therapeutics have grabbed significant attention due to their advantages over small drug molecules as well as complex targeting moieties. In light of this, the market for peptide-based medications is growing exponentially. Peptides can provide the versatility required for the successful delivery of drugs due to their structural diversity and their capability to lead drugs at the site of inflammation while maintaining optimum therapeutic efficacy. This comprehensive review aims to provide an enhanced understanding of recent advancements in the arena of peptide-based nanotherapeutics to strengthen targeted delivery for the effective management of rheumatoid arthritis. Additionally, various peptides having therapeutic roles in rheumatoid arthritis are summarized along with regulatory considerations for peptides.

Neuroprotective Effect of Phloretin in Rotenone-Induced Mice Model of Parkinson's Disease: Modulating mTOR-NRF2-p62 Mediated Autophagy-Oxidative Stress Crosstalk.

BACKGROUND: Parkinson's disease (PD) is an age-related progressive multifactorial, neurodegenerative disease. The autophagy and Keap1-Nrf2 axis system are both implicated in the oxidative-stress response, metabolic stress, and innate immunity, and their dysregulation is associated with pathogenic processes in PD. Phloretin (PLT) is a phenolic compound reported possessing anti-inflammatory and antioxidant activities. OBJECTIVE: To evaluate the neuroprotective potential of PLT in PD via modulating the autophagy-antioxidant axisMethods:The neuroprotective effect of PLT was evaluated in vitro using rotenone (ROT) exposed SH-SY5Y cell line and in vivo using ROT administered C57BL/6 mice. Mice were administered with PLT (50 and 100 mg/kg, p.o.) concomitantly with ROT (1 mg/kg, i.p) for 3 weeks. Locomotive activity and anxiety behaviors were assessed using rotarod and open field tests respectively. Further apoptosis (Cytochrome-C, Bax), α-Synuclein (α-SYN), tyrosine hydroxylase (TH), antioxidant proteins (nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1) and autophagic (mTOR, Atg5,7, p62, Beclin,LC3B-I/II) protein activity were evaluated both in in vitro and in vivo. RESULTS: PLT improved locomotive activity and anxiety-like behavior in mice. Further PLT diminished apoptotic cell death, α-SYN expression and improved the expression of TH, antioxidant, and autophagic regulating protein. CONCLUSION: Taken together, present data deciphers that the PLT effectively improves motor and non-motor symptoms via modulating the mTOR/NRF2/p62 pathway-mediated feedback loop. Hence, PLT could emerge as a prospective disease-modifying drug for PD management.

Tumor-promoting aftermath post-chemotherapy: A focus on breast cancer.

Chemotherapy is an important tool for the management of solid tumors including breast cancers (BC). Its neo-adjuvant and adjuvant use is important for shrinking tumor size and neutralizing the disseminated cancer cells. Initial chemotherapy administration often leads to a reduction in tumor size and pathological complete response. However, chemotherapy-induced tumor-free survival is not durable in BC patients. Chemotherapy is the prominent treatment for the management of triple-negative BC (TNBC), the most aggressive subtype of the BC. Various factors such as the emergence of multidrug resistance (MDR), the appearance of dormant and tolerant clones, and remodeling of the tumor microenvironment (TME) in response to chemotherapy-induced stress are responsible for tumor relapse. In current review, the authors have highlighted various cytokines and growth factors, and underlying signaling pathways such as NF-κB and PI3k/AkT, responsible for the emergence of chemo-resistance and metastasis in the TME. The present review potentially explores the role of epithelial-mesenchymal transition (EMT) in eliciting metastasis and providing stem-like phenotypes to the BC cells. The appearance of drug-tolerant sub-populations such as persister cells and BC stem cells has been discussed with mechanistic pathways. Through the current review, authors have significantly explained the mechanistic pathways of the chemotherapy-induced transformation of the tumor microenvironment (TME) constituents responsible for tumor progression. Potential therapeutic targets have been highlighted.

Tuning Mesoporous Silica Nanoparticles in Novel Avenues of Cancer Therapy.

The global menace of cancer has led to an increased death toll in recent years. The constant evolution of cancer therapeutics with novel delivery systems has paved the way for translation of innovative therapeutics from bench to bedside. This review explains the significance of mesoporous silica nanoparticles (MSNs) as delivery vehicles with particular emphasis on cancer therapy, including novel opportunities for biomimetic therapeutics and vaccine delivery. Parameters governing MSN synthesis, therapeutic agent loading characteristics, along with tuning of MSN toward cancer cell specificity have been explained. The advent of MSN in nanotheranostics and its potential in forming nanocomposites for imaging purposes have been illustrated. Additionally, various hurdles encountered during the bench to bedside translation have been explained along with potential avenues to circumvent them. This also opens up new horizons in drug delivery, which could be useful to researchers in the years to come.

Advancements in redox-sensitive micelles as nanotheranostics: A new horizon in cancer management.

World Health Organisation (WHO) delineated cancer as one of the foremost reasons for mortality with 10 million deaths in the year 2020. Early diagnosis and effective drug delivery are of utmost importance in cancer management. The entrapment of both bio-imaging dyes and drugs will open novel avenues in the area of tumor theranostics. Elevated levels of reactive oxygen species (ROS) and glutathione (GSH) are the characteristic features of the tumor microenvironment (TME). Researchers have taken advantage of these specific TME features in recent years to develop micelle-based theranostic nanosystems. This review focuses on the advantages of redox-sensitive micelles (RSMs) and supramolecular self-assemblies for tumor theranostics. Key chemical linkers employed for the tumor-specific release of the cargo have been discussed. In vitro characterisation techniques used for the characterization of RSMs have been deliberated. Potential bottlenecks that may present themselves in the bench-to-bedside translation of this technology and the regulatory considerations have been deliberated.