Over the years, extensive use of commercially available synthetic pesticides against phytophagous insects has led to their bioaccumulation in the environment causing increased resistance and reduction in soil biodiversity. Further, 90% of the applied pesticides enter the various environmental resources as a result of run-off, exposing the farmers as well as consumers of the agricultural produce to severe health issues. Therefore, growing attention has been given towards the development of alternate environmentally friendly pesticides/insecticides that would aid an efficient pest management system and also prevent chronic exposures leading to diseases. One such strategy is, the use of neem plant’s (Binomial name: Azadirachta indica) active ingredients which exhibit agro-medicinal properties conferring insecticidal as well as immunomodulatory and anti-cancer properties. The most prominent constituent of neem is azadirachtin, which has been established as a pivotal insecticidal ingredient. It acts as an antifeedant, repellent and repugnant agent and induces sterility in insects by preventing oviposition and interrupting sperm production in males. This review discusses, key neem pesticidal components, their active functional ingredients along with recent strategies on employing nanocarriers, to provide controlled release of the active ingredients and to improve their stability and sustainability.

Age-related macular degeneration (AMD) and glaucoma are degenerative conditions of the retina and a significant cause of irreversible blindness in developed countries. Alzheimer’s disease (AD), the most common dementia of the elderly, is often associated with AMD and glaucoma. The cardinal features of AD include extracellular accumulation of amyloid β (Aβ) and intracellular deposits of hyper-phosphorylated tau (p-tau). Neuroinflammation and brain iron dyshomeostasis accompany Aβ and p-tau deposits and, together, lead to progressive neuronal death and dementia. The accumulation of Aβ and iron in drusen, the hallmark of AMD, and Aβ and p-tau in retinal ganglion cells (RGC), the main retinal cell type implicated in glaucoma, and accompanying inflammation suggest overlapping pathology. Visual abnormalities are prominent in AD and are believed to develop before cognitive decline. Some are caused by degeneration of the visual cortex, while others are due to RGC loss or AMD-associated retinal degeneration. Here, we review recent information on Aβ, p-tau, chronic inflammation, and iron dyshomeostasis as common pathogenic mechanisms linking the three degenerative conditions, and iron chelation as a common therapeutic option for these disorders. Additionally discussed is the role of prion protein, infamous for prion disorders, in Aβ-mediated toxicity and, paradoxically, in neuroprotection.

Chloride intracellular channel 3 (CLIC3) drives invasiveness of pancreatic and ovarian cancer by acting in concert with Rab25 to regulate recycling of α5β1 from late endosomes to the plasma membrane. Here we show that in two estrogen receptor (ER)-negative breast cancer cell lines CLIC3 has little influence on integrin recycling, but controls trafficking of the pro-invasive matrix metalloprotease, MT1-MMP. In MDA-MB-231 cells MT1-MMP and CLIC3 are localised primarily to late endosomal/lysosomal compartments located above the plane of adhesion and near the nucleus. MT1-MMP is transferred from these late endosomes to sites of cell-matrix adhesion in a CLIC3-dependent fashion. Correspondingly, CLIC3-knockdown opposes MT1-MMP-dependent invasive processes. These include the disruption of the basement membrane as acini formed from MCF10DCIS.com cells acquire invasive characteristics in 3D culture, and the invasion of MDA-MB-231 cells into Matrigel or organotypic plugs of type I collagen. Consistent with this, expression of CLIC3 predicts poor prognosis in ER-negative breast cancer. The identification of MT1-MMP as a cargo of a CLIC3-regulated pathway that drives invasion highlights the importance of late endosomal sorting and trafficking in breast cancer.

Nanotechnology plays an increasingly important role in the biomedical arena. In particular, magnetic nanoparticles (mNPs) have become important tools in molecular diagnostics, in vivo imaging and improved treatment of disease, with the ultimate aim of producing a more theranostic approach. Due to their small sizes, the nanoparticles can cross most of the biological barriers such as the blood vessels and the blood brain barrier, thus providing ubiquitous access to most tissues. In all biomedical applications maximum nanoparticle uptake into cells is required. Two promising methods employed to this end include functionalization of mNPs with cell-penetrating peptides to promote efficient translocation of cargo into the cell and the use of external magnetic fields for enhanced delivery. This study aimed to compare the effect of both penetratin and a static magnetic field with regards to the cellular uptake of 200 nm magnetic NPs and determine the route of uptake by both methods. Results demonstrated that both techniques increased particle uptake, with penetratin proving more cell specific. Clathrin- medicated endocytosis appeared to be responsible for uptake as shown via PCR and western blot, with Pitstop 2 (known to selectively block clathrin formation) blocking particle uptake. Interestingly, it was further shown that a magnetic field was able to reverse or overcome the blocking, suggesting an alternative route of uptake.

Purpose: Elevated levels of transforming-growth-factor (TGF)-β2 in the trabecular meshwork (TM) and aqueous humor are associated with primary open-angle glaucoma (POAG). The underlying mechanism includes alteration of extracellular matrix homeostasis through Smad-dependent and independent signaling. Smad4, an essential co-Smad, upregulates hepcidin, the master regulator of iron homeostasis. Here, we explored whether TGF-β2 upregulates hepcidin, implicating iron in the pathogenesis of POAG. Methods: Primary human TM cells and human and bovine ex vivo anterior segment organ cultures were exposed to bioactive TGF-β2, hepcidin, heparin (a hepcidin antagonist), or N-acetyl carnosine (an antioxidant), and the change in the expression of hepcidin, ferroportin, ferritin, and TGF-β2 was evaluated by semiquantitative RT-PCR, Western blotting, and immunohistochemistry. Increase in reactive oxygen species (ROS) was quantified with dihydroethidium, an ROS-sensitive dye. Results: Primary human TM cells and bovine TM tissue synthesize hepcidin locally, which is upregulated by bioactive TGF-β2. Hepcidin downregulates ferroportin, its downstream target, increasing ferritin and iron-catalyzed ROS. This causes reciprocal upregulation of TGF-β2 at the transcriptional and translational levels. Heparin downregulates hepcidin, and reduces TGF-β2-mediated increase in ferritin and ROS. Notably, both heparin and N-acetyl carnosine reduce TGF-β2-mediated reciprocal upregulation of TGF-β2. Conclusions: The above observations suggest that TGF-β2 and hepcidin form a self-sustained feed-forward loop through iron-catalyzed ROS. This loop is partially disrupted by a hepcidin antagonist and an anti-oxidant, implicating iron and ROS in TGF-β2-mediated POAG. We propose that modification of currently available hepcidin antagonists for ocular use may prove beneficial for the therapeutic management of TGF-β2-associated POAG.