Narsimha Reddy Penthala

Chronic, low-grade inflammation has been implicated in aging and age-dependent conditions, including Alzheimer’s disease, cardiomyopathy, and cancer. One of the age-associated processes underlying chronic inflammation is protein aggregation, which is implicated in neuroinflammation and a broad spectrum of neurodegenerative diseases such as Alzheimer’s, Huntington’s, and Parkinson’s diseases. We screened a panel of bioactive thiadiazolidinones (TDZDs) from our in-house library for rescue of protein aggregation in human-cell and C. elegans models of neurodegeneration. Among the tested TDZD analogs, PNR886 and PNR962 were most effective, significantly reducing both the number and intensity of Alzheimer-like tau and amyloid aggregates in human cell-culture models of pathogenic aggregation. A C. elegans strain expressing human Aβ_1–42 in muscle, leading to AD-like amyloidopathy, developed fewer and smaller aggregates after PNR886 or PNR962 treatment. Moreover, age-progressive paralysis was reduced 90% by PNR886 and 75% by PNR962, and “healthspan” (the median duration of spontaneous motility) was extended 29% and 62%, respectively. These TDZD analogs also extended wild-type C. elegans lifespan by 15–30% (p < 0.001), placing them among the most effective life-extension drugs. Because the lead drug in this family, TDZD-8, inhibits GSK3β, we used molecular-dynamic tools to assess whether these analogs may also target GSK3β. In silico modeling predicted that PNR886 or PNR962 would bind to the same allosteric pocket of inactive GSK3β as TDZD-8, employing the same pharmacophore but attaching with greater avidity. PNR886 and PNR962 are thus compelling candidate drugs for treatment of tau- and amyloid-associated neurodegenerative diseases such as AD, potentially also reducing all-cause mortality.

Glioblastoma (GBM) is highly resistant to treatment and invasion into the surrounding brain is a cancer hallmark that leads to recurrence despite surgical resection. With the emergence of precision medicine, patient-derived 3D systems are considered potentially robust GBM preclinical models. In this study, we screened a library of 22 anti-invasive compounds (i.e., NF-kB, GSK-3-B, COX-2, and tubulin inhibitors) using glioblastoma U-251 MG cell spheroids. We evaluated toxicity and invasion inhibition using a 3D Matrigel invasion assay. We next selected three compounds that inhibited invasion and screened them in patient-derived glioblastoma organoids (GBOs). We developed a platform using available macros for FIJI/ImageJ to quantify invasion from the outer margin of organoids. Our data demonstrated that a high-throughput invasion screening can be done using both an established cell line and patient-derived 3D model systems. Tubulin inhibitor compounds had the best efficacy with U-251 MG cells, however, in ex vivo patient organoids the results were highly variable. Our results indicate that the efficacy of compounds is highly related to patient intra and inter-tumor heterogeneity. These results indicate that such models can be used to evaluate personal oncology therapeutic strategies.

A series of novel hybrid 8-hydroxyquinoline-indole derivatives (7a–7e, 12a–12b and 18a–18h) were synthesized and screened for inhibitory activity against self-induced and metal-ion induced Aβ_1–42 aggregation as potential treatments for Alzheimer’s disease (AD). In vitro studies identified the most inhibitory compounds against self-induced Aβ_1–42 aggregation as 18c, 18d and 18f (EC₅₀ = 1.72, 1.48 and 1.08 µM, respectively) compared to the known anti-amyloid drug, clioquinol (1, EC₅₀ = 9.95 µM). The fluorescence of thioflavin T-stained amyloid formed by Aβ_1–42 aggregation in the presence of Cu²⁺ or Zn²⁺ ions was also dramatically decreased by treatment with 18c, 18d and 18f. The most potent hybrid compound 18f afforded 82.3% and 88.3% inhibition, respectively, against Cu²⁺- induced and Zn²⁺- induced Aβ_1–42 aggregation. Compounds 18c, 18d and 18f were shown to be effective in reducing protein aggregation in HEK-tau and SY5Y-APP_Sw cells. Molecular docking studies with the most active compounds performed against Aβ_1–42 peptide indicated that the potent inhibitory activity of 18d and 18f were predicted to be due to hydrogen bonding interactions, π–π stacking interactions and π–cation interactions with Aβ_1–42, which may inhibit both self-aggregation as well as metal ion binding to Aβ_1–42 to favor the inhibition of Aβ_1–42 aggregation.

The 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) oxidation of cellulose, when mediated with Oxone^® (KHSO₅), can be performed simply and under mild conditions. Furthermore, the products of the reaction can be isolated into two major components: Oxone^®-mediated TEMPO-oxidized cellulose nanomaterials Form I and Form II (OTO-CNM Form I and Form II). This study focuses on the characterization of the properties of OTO-CNMs. Nanoparticle-sized cellulose fibers of 5 and 16 nm, respectively, were confirmed through electron microscopy. Infrared spectroscopy showed that the most carboxylation presented in Form II. Conductometric titration showed a two-fold increase in carboxylation from Form I (800 mmol/kg) to Form II (1600 mmol/kg). OTO-CNMs showed cellulose crystallinity in the range of 64–68% and crystallite sizes of 1.4–3.3 nm, as shown through XRD. OTO-CNMs show controlled variability in hydrophilicity with contact angles ranging from 16 to 32°, within or below the 26–47° reported in the literature for TEMPO-oxidized CNMs. Newly discovered OTO-CNM Form II shows enhanced hydrophilic properties as well as unique crystallinity and chemical functionalization in the field of bio-sourced material and nanocomposites.