Regioselective Alkynylation and Alkenylation at the More Hindered C-B Bond of 1,2-Bis(Boronic) Esters.

Selective transformations at the more sterically hindered sites of organic molecules represent a frontier in the ability to precisely modify molecules. The lack of effective synthetic methods stands in stark contrast to the large number of encumbered sites encountered in molecules of interest. Here, we demonstrate that 1,2-bis(boronates) undergo selective alkynylation and alkenylation at the more sterically hindered C-B bond. Our preliminary mechanistic studies disclosed that this reaction can proceed through two convergent pathways involving direct coupling of sterically encumbered site versus 1,2-boron migratory coupling. Notably, this method facilitated convenient access to alkenyl and alkynyl boron products, which can be diversified by an array of transformations.

Asymmetric Synthesis of Chiral 1,2-Bis(Boronic) Esters Featuring Acyclic, Non-Adjacent 1,3-Stereocenters.

The construction of acyclic, non-adjacent 1,3-stereogenic centers, prevalent motifs in drugs and bioactive molecules, has been a long-standing synthetic challenge due to acyclic nucleophiles being distant from the chiral environment. In this study, we successfully synthesized highly valuable 1,2-bis(boronic) esters featuring acyclic and nonadjacent 1,3-stereocenters. Notably, this reaction selectively produces migratory coupling products rather than alternative deborylative allylation or direct allylation byproducts. This approach introduces a new activation mode for selective transformations of gem-diborylmethane in asymmetric catalysis. Additionally, we found that other gem-diborylalkanes, previously challenging due to steric hindrance, also successfully participated in this reaction. The incorporation of 1,2-bis(boryl)alkenes facilitated the diversification of the alkenyl and two boron moieties in our target compounds, thereby enabling access to a broad array of versatile molecules. DFT calculations were performed to elucidate the reaction mechanism and shed light on the factors responsible for the observed excellent enantioselectivity and diastereoselectivity. These were determined to arise from ligand-substrate steric repulsions in the syn-addition transition state.

FGF21 prevents neuronal cell ferroptosis after spinal cord injury by activating the FGFR1/ß-Klotho pathway.

Spinal cord injury (SCI) is a kind of traumatic nervous system disease caused by neuronal death, causing symptoms like sensory, motor, and autonomic nerve dysfunction. The recovery of neurological function has always been a intractable problem that has greatly distressed individuals and society. Although the involvement of iron-dependent lipid peroxidation leading to nerve cell ferroptosis in SCI progression has been reported, the underlying mechanisms remain unaddressed. Thus, this study aimed to investigate the potential of recombinant human FGF21 (rhFGF21) in inhibiting ferroptosis of nerve cells and improving limb function after SCI, along with its underlying mechanisms. In vivo animal model showed that FGFR1, p-FGFR1, and ß-Klotho protein gradually increased over time after injury, reaching a peak on the third day. Moreover, rhFGF21 treatment significantly reduced ACSL4, increased GPX4 expression, reduced iron deposition, and inhibited ferroptosis. Meanwhile, rhFGF21 decreased cell apoptosis following acute spinal cord damage. In contrast, FGFR1 inhibitor PD173074 partially reversed the rhFGF21-induced therapeutic effects. Overall, this work revealed that rhFGF21 activates the FGFR1/ß-Klotho pathway to decrease ferroptosis of nerve cells, suggesting that FGF21 could be a new therapeutic target for SCI neurological rehabilitation.

Guanine-rich RNA sequence binding factor 1 regulates neuronal ferroptosis after spinal cord injury in rats via the GPX4 signaling pathway.

Spinal cord injury (SCI) can trigger multiple forms of neuronal cell death. Among these, ferroptosis stands out as a particularly important style of cell death due to its iron overload-dependent lipid peroxidative regulatory mechanism. The guanine-rich RNA sequence binding factor 1 (GRSF1) is an RNA-binding protein that has been implicated in cellular senescence, mitochondrial function, oxidative stress, erythropoiesis, and embryonic brain development. However, the function of GRSF1 in neuronal ferroptosis after SCI remains unclear. Here, we established a SCI rat model in vivo and evaluated the function of GRSF1 on neuronal ferroptosis by inhibiting and overexpressing GRSF1. We firstly verified the protein expression of GRSF1 and GPX4 at different time points after SCI. According of changes in expression, we chose 3 d post SCI to assess the effect of GRSF1 on ferroptosis. We found that GRSF1 expression decreased after SCI. In addition, GRSF1 was mainly localized in the cytoplasm of neurons. The results also showed that overexpression of GRSF1 promoted recovery of neurological functional after SCI. Further investigation revealed that GRSF1 might attenuate neuronal ferroptosis by regulating the GPX4 protein expression levels. In summary, our findings indicate that GRSF1 attenuates injury in SCI and reduces neuron ferroptosis and promotes functional recovery via GPX4.

Ir-Catalyzed Enantioselective Synthesis of gem-Diborylalkenes Enabled by 1,2-Boron Shift.

Asymmetric cross-couplings based on 1,2-carbon migration from B-ate complexes have been developed efficiently to access valuable organoboronates. However, enantioselective reactions triggered by 1,2-boron shift have remained to be unaddressed synthetic challenge. Here, Ir-catalyzed asymmetric allylic alkylation enabled by 1,2-boron shift was developed. In this reaction, we disclosed that excellent enantioselectivities were achieved through an interesting dynamic kinetic resolution (DKR) process of allylic carbonates at the elevated temperature. Notably, the highly valuable (bis-boryl)alkenes have enabled an array of diversifications to access versatile molecules. Extensive experimental and computational studies were conducted to elucidate the reaction mechanism of DKR process and clarify the origin of excellent enantioselectivities.

Improved physiological and morphological traits of root synergistically enhanced salinity tolerance in rice under appropriate nitrogen application rate.

Numerous papers studied the relations between nitrogen rate and rice yield in saline soils, whereas the rice root morphological and physiological characteristics mediating nitrogen rates in yield formation under varied salinity levels remain less concerns. Through a field experiment applied with five nitrogen rates (0, 210, 255, 300, 345, and 390 kg ha-1) in saline land, we found that rice yield peaked at 7.7 t ha-1 under 300 kg ha-1 nitrogen, and excessive N was not conductive for increasing yield. To further elucidate its internal physiological mechanism, a pot experiment was designed with three N rates (210 [N1], 300 [N2], 390 [N3] kg ha-1) and three salt concentrations (0 [S0], 1.5 [S1], 3.0 [S2] g kg-1 NaCl). Results showed that the average grain yield was decreased by 19.1 and 51.1% under S1 and S2, respectively, while notably increased by 18.5 and 14.5% under N2 and N3, respectively. Salinity stress significantly inhibited root biomass, root length and surface area, root oxidation capacity (ROC), K+ and K+/Na+ ratio, and nitrogen metabolism-related enzyme activities, whereas root Na+ and antioxidant enzyme activities were notably increased. The mechanism of how insufficient N supply (N1) affected rice yield formation was consistent at different salinity levels, which displayed adverse impacts on root morphological and physiological traits, thereby significantly inhibiting leaf photosynthesis and grain yield of rice. However, the mechanism thorough which excessive N (N3) affected yield formation was quite different under varied salinity levels. Under lower salinity (S0 and S1), no significant differences on root morphological traits and grain yield were observed except the significantly decline in activities of NR and GS between N3 and N2 treatments. Under higher salinity level (S2), the decreased ROC, K+/Na+ ratio due to increased Na+, antioxidant enzyme activities, and NR and GS activities were the main reason leading to undesirable root morphological traits and leaf photosynthesis, which further triggered decreased grain yield under N3 treatment, compared to that under N2 treatment. Overall, our results suggest that improved physiological and morphological traits of root synergistically enhanced salinity tolerance in rice under appropriate nitrogen application rate.

Hyperhomocysteinemia inhibits tibial fracture healing in rats through PI3K/AKT signaling pathway.

To explore the influence of hyperhomocysteinemia (hHcys) on the tibial fracture healing in rats and its effect on the phosphatidylinositol 3-hydroxy kinase (PI3K)/protein kinase B (AKT) signaling pathway. A total of 36 Sprague-Dawley rats were randomly divided into sham group (n=12), tibial fracture group (n=12) and hHcys + fracture group (n=12). The rats in tibial fracture group underwent the tibial fracture surgery, while the model of tibial fracture and hHcys was established in hHcys + fracture group. The level of plasma homocysteine (Hcy) in each group was analyzed using the full-automatic biochemical analyzer, the fracture stress biomechanical measurement was performed, and the ultimate bending strength and torque were calculated. Moreover, the protein expressions of PI3K and phosphorylated (p)-AKT in tibial tissues were detected using western blotting, the messenger ribonucleic acid (mRNA) levels of Bcl-2 associated X protein (Bax) and caspase-3 were detected using quantitative polymerase chain reaction (qPCR), the apoptosis was detected via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and the expressions of inflammatory factors were detected via immunohistochemistry. Compared with sham group, tibial fracture group and hHcys + fracture group had a significantly increased level of plasma Hcy, significantly decreased ultimate bending strength and torque, obviously decreased relative protein expressions of PI3K and p-AKT, increased mRNA levels of Bax and caspase-3 and an increased expression of pro-inflammatory factor tumor necrosis factor-α (TNF-α). Compared with tibial fracture group, hHcys + fracture group had a higher level of plasma Hcy, lower ultimate bending strength and torque, lower relative protein expressions of PI3K and p-AKT, higher mRNA levels of Bax and caspase-3, a higher apoptosis rate and a higher expression of TNF-α. hHcys blocks the downstream apoptotic signal transduction, promotes apoptosis and inflammatory response, and affects fracture healing through affecting the PI3K/AKT signaling pathway.

Integrative identification of unexpected kinase-inhibitor interactions in the MAPK-mediated proliferation and differentiation of Mc3T3-E1 osteoblasts.

Kinase-targeted therapy is a new and promising approach to disease treatment. However, some kinase inhibitors have been observed to cause an off-target adverse risk for skeletal system by influencing the growth of osteoblasts. It is known that the proliferation and differentiation of osteoblasts are essentially regulated by MAPK signaling pathway, and many off-target events are considered to influence this pathway. Here, the unexpected MAPK-inhibitor interactions in mouse MC3T3-E1 osteoblastic cells were investigated in detail using an integrative protocol. With bioinformatics analysis we successfully profiled a systematic noncognate interaction spectrum for off-target kinase inhibitors against mouse MAPK kinases, from which 13 potential MAPK-inhibitor interactions were identified. The inhibitors Nilotinib, Dasatinib and Bosutinib were suggested as promising candidates; their cytotoxicity on MC3T3-E1 and inhibitory activity against MAPK kinase were tested at cellular and molecular levels, respectively. We also tested two known MAPK inhibitors SP600125 and SB203580 as positive controls. Consequently, the Dasatinib was found to have high off-target risk for unexpectedly targeting osteoblast MAPK signaling pathway.

Influence of N-acetyl cysteine (NAC) and 2-methylene-1,3-dioxepane (MDO) on the properties of polymethyl methacrylate (PMMA) bone cement.

The properties of polymethyl methacrylate (PMMA) bone cement make it a popular bone filling material. However, its disadvantages, such as lack of biodegradability and osteogenesis, restrict its clinical application. Studies have indicated the osteogenic properties of N-acetyl cysteine (NAC) and the biodegradability of 2-methylene-1,3-dioxepane/methyl methacrylate-based (MDO/MMA) copolymers. In this study, we developed bioactive PMMA cements through modification with fixed concentrations of NAC and different proportions of MDO. The purpose of this study was to compare the mechanical properties, morphology, NAC release, biocompatibility, degradability and mineralization capability of modified bone cements with those of conventional cement. The specific-modified specimens (NAC-p (5% MDO-co-MMA)) exhibited a lower bending modulus but had little effect on compressive strength. This material was morphologically compact and nonporous, similar to conventional PMMA bone cement. NAC could be released from NAC-p (5% MDO-co-MMA) continuously and appropriately. NAC-p (5% MDO-co-MMA) was biologically safe and showed satisfactory tissue compatibility. Ester was introduced into the polymer, which reinforced the degradation properties of NAC-p (5% MDO-co-MMA). NAC-p (5% MDO-co-MMA) enhanced the mineralization capability of osteoblastic cells.

Epimedium protects steroid-induced avascular necrosis of femoral head in rats by inhibiting autophagy.

The effect of epimedium extracting solution on bone mineral density (BMD) of steroid-induced avascular necrosis of femoral head (SANFH) in rats was evaluated to further explore its function mechanism. Twenty-four Sprague-Dawley (SD) rats (male/female: 1/1) were randomly divided into three groups: the control (n=8), the glucocorticoid (n=8) and the epimedium (n=8) group. Rats in the glucocorticoid and the epimedium group were injected with prednisolone acetate injection in gluteal muscles with 15 mg/kg/day twice a week. The epimedium group was given 10 ml/kg ephedra extracting solution containing crude drug with the concentration of 1.5 g/ml daily by gavage. After 6 weeks, all the experimental rats were sacrificed and materials were extracted. The expression of autophagy-related proteins were detected by observing the bone of the femoral head. After comparison of the control group with the model group in BMD, it was found that there were significant differences (P<0.05). There were no significant differences between the control and the epimedium group (P>0.05). Neither between the glucocorticoid and the epimedium group (P<0.05). Epimedium extracting solution can significantly enhance the BMD of femoral heads, prevent osteoporosis and lead to collapse, increase the expression of apoptotic and protective proteins and reduce the expression of autophagy-related proteins, thus providing a preliminary theoretical study for the prevention and treatment of SANFH.

Effect of interleukin-6 polymorphism on fracture risk.

BACKGROUND: Interleukin-6 (IL6) -174C/G polymorphism was suggested to be associated with fracture risk. However, the results were inconsistent. Thus, we did a meta-analysis. METHODS: Reported studies were searched from online electronic databases of Pubmed, EMBASE, Chinese National Knowledge Infrastructure (CNKI). The odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to assess the association between IL6 -174C/G polymorphism and fracture risk. RESULTS: Six studies evaluated the association between IL6 -174C/G polymorphism and fracture risk. A significant association was found between IL6 -174C/G polymorphism and fracture risk (OR=1.25; 95% CI, 1.10-1.43; P=0.0008). In the subgroup analysis of gender, we found that women with IL6 -174C/G polymorphism had an increased fracture risk (OR=1.25; 95% CI, 1.07-1.46; P=0.005). In the subgroup analysis of type of fracture, we found that IL6 -174C/G polymorphism was significantly associated with wrist fracture (OR=1.25; 95% CI, 1.07-1.47; P=0.006) and osteoporotic fracture (OR=1.60; 95% CI, 1.12-2.28; P=0.009). However, no significant association was found between IL6 -174C/G polymorphism and hip fracture (OR=1.05; 95% CI, 0.89-1.24; P=0.53) and stress fracture (OR=1.25; 95% CI, 0.97-1.61; P=0.08). CONCLUSION: This meta-analysis suggested that the IL6 -174C/G polymorphism was associated with wrist and osteoporotic fracture risk.