An association between spinal kyphosis and gastroesophageal reflux disease (GERD) was reported in recent years. However, it remains unclear whether spinal kyphosis affects gastric motility. We evaluated the changes in myoelectrical activity measured by electrogastrography (EGG) in elderly osteoporosis patients. A total of 18 patients scheduled for the treatment of osteoporosis were included in this study. They were analyzed by recording EGG to assess myoelectrical activity and heart rate variability (HRV) to evaluate the autonomic nervous system function before and after meals. Dominant power (DP) representing the strength of gastric electrical activity and dominant frequency (DF) representing its frequency were analyzed in blocks with a 5-minute duration. We divided the patients into 2 groups, thoracolumbar kyphosis (TLK) and non-TLK groups, and compared them. There were no significant differences between the 2 groups in background data. In the non-TLK group, DPs post 0–5 min were significantly higher than those during pre 5–0 min in channels 1 and 3 (P < 0.05 and P < 0.01). DF deviation in the TLK group was significantly higher than that in the non-TLK group at 10 to 15 postprandial minutes (P < 0.05). Low frequency/high frequency activity measured by HRV, reflecting the activity of the sympathetic nervous system, in the TLK group was significantly lower than that in the non-TLK group while eating (P < 0.01). The EGG of patients with spinal kyphotic deformity showed a similar change to that of patients with GERD; the spinal kyphotic deformity itself may affect gastric electrical activity.
The effect of non-viable lactic acid bacteria on gastrointestinal physiology and dysfunction remains still unclear. Previous clinical trials have reported that Lactobacillus gasseri CP2305 (CP2305) exerts stress-relieving and anti-flatulent effects regardless of cell viability. In this study, we investigated the effect of viable and non-viable CP2305 cells on electrical field stimulation (EFS)-evoked increases in short-circuit current (Isc) using the Ussing chamber technique. In mucosal-submucosal preparations of rats, both viable and non-viable CP2305 cells significantly and acutely inhibited the EFS-evoked increases in Isc in the middle and distal colon and rectum but not in proximal colon. The inhibition of EFS-evoked Isc differed from strain to strain. Peripheral injection of corticotropin releasing factor (CRF) is known to mimic diarrhea symptoms in rats. Therefore, we examined the chronic effects of CP2305 cells on CRF-induced diarrhea in the rat model. Treatment with viable and non-viable CP2305 cells significantly improved CRF-induced diarrhea in the rat model. However, the treatment did not affect the fecal pellet output. These findings suggest that CP2305 has an important role in gastrointestinal physiology and dysfunction.
Caloric restriction (CR) is a major contributor to good health and longevity. CR mimetics (CRMs) are a group of plant-derived compounds capable of inducing the benefits of CR. Since a longevity gene, SIRT1, inhibits T-cell activation and SIRT1 loss results in increased T-cell activation, we hypothesized that compounds capable of activating SIRT1 signaling can inhibit T-cell activation and function as CRMs. Thus we propose, in the present study, the application of a T-cell activation-inhibitory assay to screen candidate CRMs. Well-known CRMs, such as resveratrol, butein, and fisetin, suppressed the anti-CD3/CD28 antibody-induced activation of mouse spleen T-cells. We next randomly assessed 68 plant-derived compounds for screening novel candidate CRMs using this bioassay and found that all four compounds showing IC50 values <5 μM, such as curcumin, α-mangostin, nobiletin, and heptamethoxyflavone, have beneficial functions for health such as anti-inflammatory effect. These results suggest that the T-cell activation-inhibitory assay can be used to screen candidate CRMs.
Recently, the first series of small molecule inhibitors of PD-1/PD-L1 were reported by Bristol-Myers Squibb (BMS), which were developed using a homogeneous time-resolved fluorescence (HTRF)-based screening investigation of the PD-1/PD-L1 interaction. Additional crystallographic and biophysical studies showed that these compounds inhibited the interaction of PD-1/PD-L1 by inducing the dimerization of PD-L1, in which each dimer binds one molecule of the stabilizer at its interface. However, the immunological mechanism of the antitumor effect of these compounds remains to be elucidated. In the present study, we focused on BMS-202 (a representative of the BMS compounds) and investigated its antitumor activity using in vitro and in vivo experiments. BMS-202 inhibited the proliferation of strongly PD-L1-positive SCC-3 cells (IC50 15 μM) and anti-CD3 antibody-activated Jurkat cells (IC50 10 μM) in vitro. Additionally, BMS-202 had no regulatory effect on the PD-1 or PD-L1 expression level on the cell surface of these cells. In an in vivo study using humanized MHC-double knockout (dKO) NOG mice, BMS-202 showed a clear antitumor effect compared with the controls; however, a direct cytotoxic effect was revealed to be involved in the antitumor mechanism, as there was no lymphocyte accumulation in the tumor site. These results suggest that the antitumor effect of BMS-202 might be partly mediated by a direct off-target cytotoxic effect in addition to the immune response-based mechanism. Also, the humanized dKO NOG mouse model used in this study was shown to be a useful tool for the screening of small molecule inhibitors of PD-1/PD-L1 binding that can inhibit tumor growth via an immune-response-mediated mechanism.
Psychological stress is thought to be a risk factor for the onset or accelerate the progression of Parkinson’s disease. The main aim of this study is to explore the causative effect of confrontational housing (CH), a paradigm developed as an animal model of psychosocial stress, in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. When mice were housed confrontationally for 24 h, they displayed increased anxiety like-behavior in the light/dark box test. Administration of MPTP after CH for 24 h caused severe damage of striatal dopaminergic neurons as indicated by decreases in dopamine transporter and tyrosine hydroxylase proteins and an increase of glial fibrillary acidic protein levels compared to CH alone. The dose of MPTP used this study slightly affected these protein levels in the striatum of control mice, but they did not significantly change. Our results indicate that the striatal dopaminergic neurons are vulnerable to environmental risk factors that presumably have neurotoxin-like properties under psychological stress condition.