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The basal forebrain (BF) plays a crucial role in cortical activation [1, 2]. However, the exact role of cholinergic BF (ch-BF) neurons in the sleep-wake cycle remains unclear [3, 4]. We demonstrated that photostimulation of ch-BF neurons genetically targeted with channelrhodopsin 2 (ChR2) was sufficient to induce an immediate transition to waking or rapid eye movement (REM) sleep from slow-wave sleep (SWS). Light stimulation was most likely to induce behavioral arousal during SWS, but not during REM sleep, a result in contrast to the previously reported photostimulation of noradrenergic or hypocretin neurons that induces wake transitions from both SWS and REM sleep. Furthermore, the ratio of light-induced transitions from SWS to wakefulness or to REM sleep did not significantly differ from that of natural transitions, suggesting that activation of ch-BF neurons facilitates the transition from SWS but does not change the direction of the transition. Excitation of ch-BF neurons during wakefulness or REM sleep sustained the cortical activation. Stimulation of these neurons for 1 hr induced a delayed increase in the duration of wakefulness in the subsequent inactive period. Our results suggest that activation of ch-BF neurons alone is sufficient to suppress SWS and promote wakefulness and REM sleep.

As a newly approved oral hypoglycaemic agent, the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin, which is derived from the natural product phlorizin can effectively reduce blood glucose. Recent clinical studies have found that dapagliflozin alleviates non-alcoholic fatty liver disease (NAFLD), but the specific mechanism remains to be explored. This study aimed to investigate the underlying mechanism of dapagliflozin in alleviating hepatocyte steatosis in vitro and in vivo. We fed the spontaneous type 2 diabetes mellitus rats with high-fat diets and cultured human normal liver LO2 cells and human hepatocellular carcinoma HepG2 cells with palmitic acid (PA) to induce hepatocellular steatosis. Dapagliflozin attenuated hepatic lipid accumulation both in vitro and in vivo. In Zucker diabetic fatty (ZDF) rats, dapagliflozin reduced hepatic lipid accumulation via promoting phosphorylation of acetyl-CoA carboxylase 1 (ACC1), and upregulating lipid β-oxidation enzyme acyl-CoA oxidase 1 (ACOX1). Furthermore, dapagliflozin increased the expression of the autophagy-related markers LC3B and Beclin1, in parallel with a drop in p62 level. Similar effects were observed in PA-stimulated LO2 cells and HepG2 cells. Dapagliflozin treatment could also significantly activated AMPK and reduced the phosphorylation of mTOR in ZDF rats and PA-stimulated LO2 cells and HepG2 cells. We demonstrated that dapagliflozin ameliorates hepatic steatosis by decreasing lipogenic enzyme, while inducing fatty acid oxidation enzyme and autophagy, which could be associated with AMPK activation. Moreover, our results indicate that dapagliflozin induces autophagy via the AMPK-mTOR pathway. These findings reveal a novel clinical application and functional mechanism of dapagliflozin in the treatment of NAFLD.

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Arm movements modulate leg activity and improve gait efficiency; however, current rehabilitation interventions focus on improving walking through gait-specific training and do not actively involve the arms. The goal of this project was to assess the effect of a rehabilitation strategy involving simultaneous arm and leg cycling on improving walking after incomplete spinal cord injury (iSCI). We investigated the effect of 1) non-gait-specific training and 2) active arm involvement during training on changes in over ground walking capacity. Participants with iSCI were assigned to simultaneous arm-leg cycling (A&L) or legs only cycling (Leg) training paradigms, and cycling movements were assisted with electrical stimulation. Overground walking speed significantly increased by 0.092 ± 0.022 m/s in the Leg group and 0.27 ± 0.072m/s in the A&L group after training. Whereas the increases in the Leg group were similar to those seen after current locomotor training strategies, increases in the A&L group were significantly larger than those in the Leg group. Walking distance also significantly increased by 32.12 ± 8.74 m in the Leg and 91.58 ± 36.24 m in the A&L group. Muscle strength, sensation, and balance improved in both groups; however, the A&L group had significant improvements in most gait measures and had more regulated joint kinematics and muscle activity after training compared with the Leg group. We conclude that electrical stimulation-assisted cycling training can produce significant improvements in walking after SCI. Furthermore, active arm involvement during training can produce greater improvements in walking performance. This strategy may also be effective in people with other neural disorders or diseases. NEW & NOTEWORTHY This work challenges concepts of task-specific training for the rehabilitation of walking and encourages coordinated training of the arms and legs after spinal cord injury. Cycling of the legs produced significant improvements in walking that were similar in magnitude to those reported with gait-specific training. Moreover, active engagement of the arms simultaneously with the legs generated nearly double the improvements obtained by leg training only. The cervico-lumbar networks are critical for the improvement of walking.

Forkhead box O3 (FOXO3a) is a transcription factor with tumor suppressor functions that plays an important role in prostate cancer. Daidzein, one of the soy isoflavones present in soy-based foods, has been shown to exert anti-tumor effects in vitro and in vivo. We herein investigated the inhibitory effects of S-equol, an isoflavandiol metabolized from daidzein by bacterial flora in the intestines, on the LnCaP, DU145 and PC3 human prostate cancer cell lines. Our results showed that S-equol and R-equol inhibited the growth of all three cell lines. Additional studies revealed that S-equol caused cell cycle arrest in the G2/M phase in PC3 cells by downregulating Cyclin B1 and CDK1 and upregulating CDK inhibitors (p21 and p27), as well as inducing apoptosis by upregulating Fas ligand (FasL) and the expression of proapoptotic Bim. Additionally, S-equol increased the expression of FOXO3a, decreased the expression of p-FOXO3a and enhanced the nuclear stability of FOXO3a. S-equol also decreased the expression of MDM2, which serves as an E3 ubiquitin ligase for p-FOXO3a, thus preventing p-FOXO3a degradation by the proteasome. Mechanistic studies showed that S-equol targeted the Akt/FOXO3a pathway, which is important for prostate cancer cell survival, cell cycle progression and apoptosis. Moreover, treatment with S-equol inhibited the growth of PC3 xenograft tumors in BALB/c nude mice. Overall, the data from the present study demonstrate that S-equol has significant anti-prostate cancer activities in vitro and in vivo, and indicate that its anticancer effects were likely associated with the activation of FOXO3a via an Akt-specific pathway and inhibitory effects on MDM2 expression. The results not only provide a better understanding of the molecular mechanisms of this unique secondary metabolite of a natural anti-cancer compound, but also provide a basis for the development of daidzein and its analogs as novel anticancer agents.

Spinal networks in the cervical and lumbar cord are actively coupled during locomotion to coordinate arm and leg activity. The goals of this project were to investigate the intersegmental cervico-lumbar connectivity during cycling after incomplete spinal cord injury (iSCI), and assess the effect of rehabilitation training on improving reflex modulation mediated by cervico-lumbar pathways. Two studies were conducted. In the first, 22 neurologically intact (NI) people and 10 people with chronic iSCI were recruited. The change in H-reflex amplitude in flexor carpi radialis (FCR) during leg cycling and H-reflex amplitude in soleus (SOL) during arm cycling were investigated. In the second study, two groups of participants with chronic iSCI underwent 12 weeks of cycling training: one performed combined arm and leg cycling (A&L) and the other legs only cycling (Leg). The effect of training paradigm on the amplitude of the SOL H-reflex was assessed. Significant reduction in the amplitude of both FCR and SOL H-reflexes during dynamic cycling of the opposite limbs was found in NI participants, but not in participants with iSCI. Nonetheless, there was a significant reduction in the SOL H-reflex during dynamic arm cycling in iSCI participants after training. Substantial improvements in SOL H-reflex properties were found in the A&L group after training. The results demonstrate that cervico-lumbar modulation during rhythmic movements is disrupted in people with chronic iSCI; however, this modulation is restored after cycling training. Furthermore, involvement of the arms simultaneously with the legs during training may better regulate the leg spinal reflexes.