No abstract

The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, the mechanistic basis of which is unknown. In evaluating cellular energetics and metabolism of t(11;14) and non-t(11;14) MM, we determine that venetoclax-sensitive myeloma has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I and Complex II activities correlate with venetoclax sensitivity. Inhibition of Complex I, using IACS-010759, an orally bioavailable Complex I inhibitor in clinical trials, as well as succinate ubiquinone reductase (SQR) activity of Complex II, using thenoyltrifluoroacetone (TTFA) or introduction of SDHC R72C mutant, independently sensitize resistant MM to venetoclax. We demonstrate that ETC inhibition increases BCL-2 dependence and the 'primed' state via the ATF4-BIM/NOXA axis. Further, SQR activity correlates with venetoclax sensitivity in patient samples irrespective of t(11;14) status. Use of SQR activity in a functional-biomarker informed manner may better select for MM patients responsive to venetoclax therapy.

Highlights d Edited human iPSCs can control SIRT1 expression d Low SIRT1 expression in human iPSC hepatocytes increases fatty acid biosynthesis d Human iPSC-derived livers developed macrosteatosis and inflammatory phenotype d Metabolic profile in human iPSC-derived fatty livers is similar to human NASH livers

The wound healing process is characterized by varied biological and molecular cascades including inflammation, tissue proliferation, and remodeling phase. To augment and maintain these cascades, an all-natural matrix system is proposed. Biocompatible biopolymers, sodium alginate and gelatin, were employed to prepare microfibers via extrusion-gelation into a physical crosslinking solution. Curcumin, an anti-inflammatory, anti-oxidant and wound healing agent, was loaded into the fibers as a natural bioactive compound. Curcumin-loaded composite microfibers and blank microfibers were fabricated using biopolymers such as sodium alginate and gelatin. The formulation batches were coded as A1G9-A10G0 according to the varied concentrations of sodium alginate and gelatin. The molecular transitions within the composite microfibers were characterized using FTIR and were further corroborated using molecular mechanics analysis. In mechanical properties tensile strength and elongation-at-break (extensibility) were ranging between 1.08 ± 0.01 to 3.53 ± 0.41 N/mm 2 and 3.89 ± 0.18 to 0.61 ± 0.03%. The morphological analysis confirmed the formation and fabrication of the microfibers. In addition, physical evaluation including matrix degradation and entrapment efficiency was performed to give a comparative account of various formulations. The water uptake capacity of the blank and curcumin-loaded composite fibers was found to be in the range of 30.77 ± 2.17 to 100.00 ± 5.99 and 22.34 ± 1.11 to 56.34 ± 4.68, respectively. Composite microfibers presented a cumulative release of 85% in 72 h, confirming the prolonged release potential of the composite fibers. The drug release followed an anomalous (non-Fickian) release behavior asserting the role of degradation and diffusion. In an in vivo full-thickness cutaneous wound model, the composite microfibers provided higher degree of contraction 96.89 ± 3.76% as compared to the marketed formulation (Vicco turmeric cream). In conclusion, this all-natural, alginate-gelatin-curcumin composite has the potential to be explored as a cost-effective wound healing platform.