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Histone deacetylases (HDACs) play an important role in the epigenetic regulation of gene expression through their effects on the compact chromatin structure. In clinical studies, several classes of histone deacetylase inhibitors (HDACi) have demonstrated potent anticancer activities with metal complexes. Hence, we synthesized cadmium-proline complexes using both the D- and L-isomers of proline and evaluated their biological activities by observing the efficiency of their inhibition of HDAC activity, ability to reduce the expression of HDAC isoforms in A549 cells and effect on apoptosis. The synthesized compounds were characterized by UV, IR, NMR spectroscopy and elemental analysis. In-vitro cell toxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, and the 50% inhibitory concentration (IC; 2 μM) was obtained at 12 h. The morphological study at nuclear levels was performed by acridine orange/ethidium bromide (AO/EB) and Hoechst staining, and the results showed an association with cell cycle arrest at the G2/M phase. Both cadmium-proline complexes intensely inhibited HDAC activity at 2 μM concentration. Interestingly, Cd[L-proline] was found to be a potent inhibitor for all HDAC isoforms, whereas Cd[D-proline] inhibited only HDAC1 and 2. HDACi are novel chemotherapeutic drugs that induce hyperacetylation of histones H3 and H4, counteracting the aberrant repression of genes, such as insulin-like growth factor-binding protein 3 (IGFBP-3), p53, and p21. ERK/MAPK signaling pathway resulted in the downregulation of the expression of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9), contributing to the inhibition of metastasis in A549 cells. Apoptosis induction was accompanied by the activation of death receptors and their ligands which recruit initiator caspase 8, decrease in mitochondrial membrane potential (ΔΨm), as well as increased Bax/Bcl ratio, followed by activation of caspases 9 and 3. Our finding suggests that Cd[L-proline] complex accelerates epigenetic rearrangement by HDAC inhibition, which may be the key mechanism for its anticancer activity.

Histone deacetylase inhibitors (HDACi) are a small molecule chemotherapeutics that target the chromatin remodeling through the regulation of histone and non-histone proteins. These inhibitors directed against histone deacetylase (HDAC) enzymes have become an important therapeutic tool in oncology; consequently, scientific efforts have fortified the quest for newer and novel HDACi, which forces the design of structurally innovative HDACi. Various urea containing compounds exhibited admirable anticancer activity. On the basis of these observations, we design and synthesize HDAC specific blocker molecules which are specifically besieged towards class I, class II, and class IV HDAC isoforms to enhance the structural assortment for HDACi. Through docking experiments, we identified that the compounds were tightly bound to the isoforms of the HDAC enzymes at their receptor regions. These derivatives potently inhibited the different isoforms, namely, class I, II, and IV of HDACs, by hyperacetylation of lysine residues in A549 cells. The mechanism of apoptosis is evident, regulating tumor suppressor genes and proteins, thereby facilitating the activation of the death receptor pathway by the tumor necrosis factor (TNF) receptor. These derivative facilitated the induction of reactive oxygen species (ROS) generation leading to downregulation of Bcl , and upregulation of Bax expression, thereby dysregulating mitochondrial membrane potential (ΔΨ ) to release cytochrome c, and activation of intrinsic pathway. These compounds downregulate the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) pathway to inhibit cell growth, proliferation, and metastasis through the matrix metalloproteinases (MMPs) MMP2 and MMP9 in A549 cells. These results suggest that our designed urea based derivatives act as epigenetic targeting agents through HDAC inhibition.

In automobiles, the demand for HVAC has been rising for decades and the key variables that affect the thermal comfort in a car were identified as air velocity, temperature, radiant temperature, and relative humidity. Thermal comfort estimation in a vehicle depends on the transient behavior of the cabin space and boundaries. The predicted mean vote (PMV) and predicted percentage of dissatisfied (PPD) are the available methods to describe and optimize thermal comfort in cabin space. In this paper, the cabin thermal comfort of a minivan was analyzed for reduction of energy consumption with the help of experimental and numerical simulation. Using CFD simulation and validation with experimental data, the flow dynamics inside a vehicle cabin is evaluated based on air velocity, temperature, and comfort indices. With some error for the extreme planes, a strong agreement was reached between the experimental values and the CFD model. With the reduction in the air velocity from 2.3 m/s to 1.3 m/s, the average power required to run the blower can be reduced by 43%, providing an advantage of reducing the capacity of the compressor. The higher PPD values were observed on the walls of the cabin and at the outlet of the AC vents.

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