Cerebral ischemia-reperfusion injury (CIRI) refers to a secondary brain injury that occurs when blood supply is restored to ischemic brain tissue and is one of the leading causes of adult disability and mortality. Multiple pathological mechanisms are involved in the progression of CIRI, including neuronal oxidative stress and mitochondrial dysfunction. Isoliquiritigenin (ISL) has been preliminarily reported to have potential neuroprotective effects on rats subjected to cerebral ischemic insult. However, the protective mechanisms of ISL have not been elucidated. This study aims to further investigate the effects of ISL-mediated neuroprotection and elucidate the underlying molecular mechanism. The findings indicate that ISL treatment significantly alleviated middle cerebral artery occlusion (MCAO)-induced cerebral infarction, neurological deficits, histopathological damage, and neuronal apoptosis in mice. In vitro, ISL effectively mitigated the reduction of cell viability, Na⁺-K⁺-ATPase, and MnSOD activities, as well as the degree of DNA damage induced by oxygen-glucose deprivation (OGD) injury in PC12 cells. Mechanistic studies revealed that administration of ISL evidently improved redox homeostasis and restored mitochondrial function via inhibiting oxidative stress injury and ameliorating mitochondrial biogenesis, mitochondrial fusion-fission balance, and mitophagy. Moreover, ISL facilitated the dissociation of Keap1/Nrf2, enhanced the nuclear transfer of Nrf2, and promoted the binding activity of Nrf2 with ARE. Finally, ISL obviously inhibited neuronal apoptosis by activating the Nrf2 pathway and ameliorating mitochondrial dysfunction in mice. Nevertheless, Nrf2 inhibitor brusatol reversed the mitochondrial protective properties and anti-apoptotic effects of ISL both in vivo and in vitro. Overall, our findings revealed that ISL exhibited a profound neuroprotective effect on mice following CIRI insult by reducing oxidative stress and ameliorating mitochondrial dysfunction, which was closely related to the activation of the Nrf2 pathway.

A DNA-encoded library is a collection of small molecules covalently linked to DNA that has unique information about the identity and the structure of each library member. A DNA-encoded chemical library (DEL) is broadly adopted by major pharmaceutical companies and used in numerous drug discovery programs. The application of the DEL technology is advantageous at the initial period of drug discovery because of reduced cost, time, and storage space for the identification of target compounds. The key points for the construction of DELs comprise the development and the selection of the encoding methods, transfer of routine chemical reaction from off-DNA to on-DNA, and exploration of new chemical reactions on DNA. The limitations in the chemical space and the diversity of DEL were reduced gradually by using novel DNA-compatible reactions based on the formation and the cleavage of various bonds. Here, we summarized a series of novel DNA-compatible chemistry reactions for DEL building blocks and analysed the druggability of screened hit molecules via DELs in the past five years.

Spermatogenic dysfunction is one of the major secondary complications of diabetes. L. barbarum polysaccharide (LBP) has long been considered to possess anti-apoptotic activities and antioxidant, anti-inflammatory and fertility-enhancing properties in traditional medical practices in China. The aim of the current study was to seek out scientific evidence to determine if LBP also contributes to the recovery from spermatogenic dysfunction in diabetic individuals. We investigated whether the oral administration of LBP in streptozotocin (STZ)-induced type-1 diabetic male mice would reverse spermatogenic dysfunction and improve histological damage in testes. After the oral administration of LBP (10, 20 or 40 mg kg⁻¹, respectively), sildenafil citrate (5 mg kg⁻¹) or saline for 62 consecutive days, the sperm parameters were analyzed. Macroscopic and microscopic changes in the reproductive organs, including their weight, and photomicroscope and electronmicroscope images were also assessed. In addition, the antioxidant capacity and levels of malondialdehyde in the testes were determined according to the instructions provided with the assay kits and the expression of the apoptosis-related proteins, Caspase-3, Bax and Bcl-2, in the testes was analyzed using western-blot analysis. LBP treatment of diabetic mice considerably recovered the sperm parameters, increased the weight of the reproductive organs, ameliorated their histological appearance and increased antioxidant enzyme activity to different degrees. Moreover, our data also showed a marked decrease in Caspase-3 expression and an increase in the ratio of Bcl-2/Bax 43 after LBP administration (40 mg kg⁻¹) when compared to the diabetic group. These results demonstrate that LBP exerts protective effects on diabetes induced male spermatogenic dysfunction, which is likely to be mediated through increasing antioxidant enzyme activities and inhibiting cell death.