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The epidermal growth factor receptor (EGFR) is highly expressed in many non-small cell lung cancers (NSCLC), necessitating the use of EGFR-tyrosine kinase inhibitors (TKIs) as first-line treatments. Osimertinib (OSM), a third-generation TKI, is routinely used in clinics, but T790M mutations in exon 20 of the EGFR receptor lead to resistance against OSM, necessitating the development of more effective therapeutics. Telmisartan (TLM), OSM, and cell cycle and apoptosis regulatory protein 1 (CARP-1) functional mimetic treatments (CFM4.17) were evaluated in this study against experimental H1975 tumor xenografts to ascertain their anti-cancer effects. Briefly, tumor growth was studied in H1975 xenografts in athymic nude mice, gene and protein expressions were analyzed using next-generation RNA sequencing, proteomics, RT-PCR, and Western blotting. TLM pre-treatment significantly reduced the tumor burden when combined with CFM-4.17 nanoformulation and OSM combination (TLM_CFM-F_OSM) than their respective single treatments or combination of OSM and TLM with CFM 4.17. Data from RNA sequencing and proteomics revealed that TLM_CFM-F_OSM decreased the expression of Lamin B2, STAT3, SOD, NFKB, MMP-1, TGF beta, Sox-2, and PD-L1 proteins while increasing the expression of AMPK proteins, which was also confirmed by RT-PCR, proteomics, and Western blotting. According to our findings, the TLM_CFM-F_OSM combination has a superior anti-cancer effect in the treatment of NSCLC by affecting multiple resistant markers that regulate mitochondrial homeostasis, inflammation, oxidative stress, and apoptosis.

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Retinal organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that mimic the retina’s spatial and temporal differentiation, making them useful as in vitro retinal development models. Retinal organoids can be assembled with brain organoids, the 3D self-assembled aggregates derived from hPSCs containing different cell types and cytoarchitectures that resemble the human embryonic brain. Recent studies have shown the development of optic cups in brain organoids. The cellular components of a developing optic vesicle-containing organoids include primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. The importance of retinal organoids in ocular diseases such as age-related macular degeneration, Stargardt disease, retinitis pigmentosa, and diabetic retinopathy are described in this review. This review highlights current developments in retinal organoid techniques, and their applications in ocular conditions such as disease modeling, gene therapy, drug screening and development. In addition, recent advancements in utilizing extracellular vesicles secreted by retinal organoids for ocular disease treatments are summarized.

The purpose of this study was to investigate the neuroprotective effects of phytocannabinoids, synthetic cannabidiol (CBD) and tetrahydrocannabivarin (THCV) and their combination on taxol induced peripheral neuropathy (PIPN) in mice. Briefly, six groups of C57BL/6J mice (n = 6) were used. PTX (8 mg/kg/day, i.p.) was given to the mice on days 1, 3, 5, and 7 to induce neuropathy. Mice were evaluated for their behavioral parameters and also at the end of the study, DRG collected from the animals were subjected to RNA sequence and westernblot analysis. Further, immunocytochemistry and mitochondrial functional assays were performed on cultured DRGs derived from SD rats. The combination of CBD and THCV improved thermal and mechanical neurobehavioral symptoms in mice by two folds as compared to individual treatments. KEGG (RNA Sequencing) identified P38-MAPK, AMPK, and PI3K-AKT pathways as potential CBD and THCV therapeutic targets. In PTX-treated animals, the expression of p-AMPK, SIRT1, NRF2, HO1, SOD2, and catalase was significantly reduced (p<0.001), whereas the expression of PI3K, p-AKT, p-P38 MAP kinase, BAX, TGF-, NLRP3 inflammasome, and caspase 3 was significantly increased (p<0.001) when compared to control group. In reversing these protein expressions, combination therapy outperformed single therapies. CBD and THCV treatment increased AMPK, Catalase, and Complex I expression while decreasing mitochondrial superoxides in DRG primary cultures. In mice and DRG primary cultures, WAY100135 and rimonabant inhibited the effects of CBD and THCV by blocking 5 HT1A and CB1 receptors. In conclusion, entourage effect of CBD and THCV combination against PIPN appears to protect neurons in mice by modulating 5HT1A and CB1 receptors, respectively.