Histone deacetylase 6 (HDAC6) plays a key role in a variety of neurological disorders, which makes it attractive drug target for the treatment of Alzheimer’s disease, Parkinson’s disease, and memory/learning impairment. The selectivity of HDAC6 inhibitors (sHDAC6Is) are widely considered to be susceptible to the sizes of their Cap group and the physicochemical properties of their linker or zinc-binding group, which makes the discovery of new sHDAC6Is extremely difficult. With the discovery of the distinct selectivity between Trichostatin A (TSA) enantiomers, the chirality residing in the connective units between TSA’s Cap and linker shows a great impact on its selectivity. However, the mechanism underlining (S)-TSA’s selectivity is still elusive, and the way chirality switches the selective (S)-TSA to nonselective (R)-TSA is unknown. In this study, multiple computational approaches were collectively applied to explore, validate, and differentiate the binding modes of two TSA enantiomers in HDACs (especially the HDAC6) at atomic level. First, two nonconservative residues (G200/M205 and Y197/F202 in HDAC1/6) in loop3 and four conservative residues deep inside the hydrophobic binding pocket were discovered as the decisive residues of (S)-TSA’s selectivity toward HDAC6. Then, a novel mechanism underlying the selectivity of (S)-TSA toward HDAC6 was proposed, which was composed of the trigger by two nonconservative residues F202 and M205 in HDAC6 and a subsequently improved fit of (S)-TSA deep inside HDAC6’s hydrophobic binding pocket. TSA enantiomers were used as a molecular probe to explore the mechanism underlying sHDAC6Is’ selectivity in this study. Because of their decisive roles in (S)-TSA’s selectivity to HDAC6, both F202 and M205 in HDAC6 should be especially considered in the discovery of novel sHDAC6Is.

Extensive studies have revealed that cognitive processing was impaired after anesthesia and surgery, particularly for the elderly patients. However, most of the existing studies focused on the general cognitive deficits (e.g., delayed neuro-cognitive recovery and POCD). Although diagnosis of social abilities has been used in various clinical fields, few studies have investigated the potential deficit on social cognition after anesthesia and surgery. The current study examined whether there was any social cognitive dysfunction after anesthesia and surgery. We achieved this by taking biological motion (BM) as the stimuli of interest, the perception of which has been taken as the hallmark of social cognition. The elderly patients (aged ≥ 60 years) were required to judge whether an upright BM stimulus appeared among the dynamic noises to test their social cognition, as well as do a Mini-Mental State Examination to test their general cognition. The two tests were performed at both 1-day before and 7-day after the surgery. Results showed that 31.25% of patients exhibited BM perception deficit after anesthesia and surgery relative to before anesthesia and surgery, implying that social cognitive dysfunction existed. Meanwhile, social cognitive dysfunction was independent from delayed neurocognitive recovery.

Accumulated spinal axial loading provided by a custom-made hot plate accelerated mice lumbar disc and especially endplate degeneration. However, this method requires further development to establish a lumbar disc degeneration model.

The abnormal expression of histone deacetylase 8 (HDAC8) has been reported to associate with various cancer entities (colon, breast cancer, pancreas, etc.) as well as parasitic diseases, making HDAC8 gradually develop into an attractive and potential therapeutic target. Among the various design strategies of selective HDAC8 inhibitors (modification of Cap, Linker, or zinc binding group regions), the optimization of Cap region has aroused great interest among the researchers. However, the detailed information underlying how the modification of Cap region influences the inhibitory activities is still unclear, and in this study, compounds 2c, 3g, and 3n were selected to explore the differences in binding mechanisms brought by Cap modifications via various computational approaches at the atomic level. Five residues (Y293, H167, D254, D165, and M261) have a large difference in energy contributions to the constructed systems, and the subpocket formed by Y293 and M261 could interact with Cap groups, triggering the differences in the energy contributions of the residues (H167, D254, and D165) located in metal-catalytic center. In summary, the compounds 2c, 3g, and 3n were selected as molecular probes to explore the binding mechanism, and the residues (Y293 and M261) forming the subpocket should be paid special attention in the design and synthesis of novel selective HDAC8 inhibitors. K E Y W O R D S