A new labdane diterpenoid from Scoparia dulcis improving pancreatic function against islets cell apoptotic by Bax/Bcl-2/Caspase-3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Scoparia dulcis has been identified as a significant ethnopharmacological substance in the Li, Zhuang, and Dai ethnic groups of China. Traditional medicine use S. dulcis to treat numerous illnesses, most notably diabetes. The considerable antidiabetic properties of this herbal remedy have been established by several clinical investigations and animal experiments. The islet is the intended target of S. dulcis, although the cause of its activity and mechanism for diabetes treatment is unclear. The diterpenoids from S. dulcis have been shown in the literature to have significant hypoglycemic efficacy and to protect islet cells in vitro. Diterpenoids may be the components of this herbal remedy that preserve islets, but further research is needed. AIM OF THE STUDY: This study was projected to investigate the new diterpenoid scoparicol E from S. dulcis and examined its islet-protective effect and the potential mechanism both in vitro and in vivo. METHODS: The structure of the novel diterpenoid scoparicol E was clarified by employing a wide range of spectroscopic methods. Using CCK-8 tests, cytotoxicity and antiapoptotic activity of scoparicol E were detected. Serum biochemical analysis and pathologic examination were performed to study the protective effect of scoparicol E against islet damage. The specific mechanism of action of scoparicol E was investigated through the mitochondrial membrane potential, Annexin V-FITC flow cytometry, and western blotting. RESULTS: Scoparicol E reduced MLD-STZ-induced hyperglycemia in mice and increased insulin and islet apoptosis. Scoparicol E effectively suppressed the Bax/Bcl-2/Caspase-3 pathway, according to the in vivo western blot investigation. Scoparicol E showed significant antiapoptotic action in vitro. We also showed that scoparicol E might prevent islet cells from dying by inhibiting the Bax/Bcl-2/Caspase-3 pathway. The Annexin V-FITC flow cytometry results revealed that MIN6 cell apoptosis was considerably decreased following scoparicol E intervention, showing anti-islet cell apoptosis action. Furthermore, the Caspase-3-mediated apoptosis pathway depends on cytochrome c and the potential of the mitochondrial membrane. Scoparicol E prevented the release of cytochrome c, restored the mitochondrial membrane potential, and prevented MIN6 cell apoptosis. CONCLUSION: We demonstrated the new diterpenoid scoparicol E could protect islet cells apoptosis by modulating the Bax/Bcl-2/Caspase-3 pathway.

New aphidicolane diterpenoids with glucose consumption promoting and cell viability enhancing activities from Scoparia dulcis.

Two new aphidicolane diterpenoids, termed Scopadulinol A (1) and B (2), were obtained from whole plants of Scoparia dulcis. Their structures were elucidated by applying various spectroscopic techniques, including 1D- and 2D-NMR and HR-ESI-MS. The absolute configurations of 1 and 2 were determined by applying the calculated electronic circular dichroism (ECD). In addition, both compounds were tested for their effects on glucose consumption in HL-7702 cells and on palmitic acid (PA) induced viability in MIN6 cells at different concentrations. The results showed that they significantly promoted glucose consumption and attenuated the PA-induced decrease of cell viability. Additionally, 2 was tested to determine whether it could activate AMP-activated protein kinase (AMPK), but it showed no such effect at the tested dosage. These results indicated that the new compounds might promote glucose consumption through other pathways but not by activating AMPK. Collectively, we highlighted the isolation of two new aphidicolane diterpenoids from S. dulcis and found that they could promote glucose consumption and attenuate PA-induced decrease of cell viability.

Compensatory thalamocortical functional hyperconnectivity in type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (T2DM) is associated with brain damage and cognitive decline. Despite the fact that the thalamus involves aspects of cognition and is typically affected in T2DM, existing knowledge of subregion-level thalamic damage and its associations with cognitive performance in T2DM patients is limited. The thalamus was subdivided into 8 subregions in each hemisphere. Resting-state functional and structural MRI data were collected to calculate resting-state functional connectivity (rsFC) and gray matter volume (GMV) of each thalamic subregion in 62 T2DM patients and 50 healthy controls. Compared with controls, T2DM patients showed increased rsFC of the medial pre-frontal thalamus, posterior parietal thalamus, and occipital thalamus with multiple cortical regions. Moreover, these thalamic functional hyperconnectivity were associated with better cognitive performance and lower glucose variability in T2DM patients. However, there were no group differences in GMV for any thalamic subregions. These findings suggest a possible neural compensation mechanism whereby selective thalamocortical functional hyperconnectivity facilitated by better glycemic control help to preserve cognitive ability in T2DM patients, which may ultimately inform intervention and prevention of T2DM-related cognitive decline in real-world clinical settings.

Dry Eye: The Effect of Chi-Ju-Di-Huang-Wan Plus Si Wu Tang and the Underlying Mechanism.

Objectives: In this pilot study, the effect of 970 mg Chi-Ju-Di-Huang-Wan (CJDHW) plus 30 mg four-substance decoction (Si Wu Tang; CJDHWSWT) was evaluated, in terms of its ability to alleviate dry eye symptoms and its therapeutic mechanism. Methods: This double-masked prospective investigation has recruited dry eye patients who have been randomly selected into two groups, namely treatment (n = 15) versus nontreatment (n = 15). In the treatment group, a daily oral intake of CJDHWSWT plus eye drops systane ultra was given for 90 consecutive days. In the nontreatment group, only defined eye drops were prescribed. The examinations included Schirmer's test, fluorescein-stained superficial punctate keratitis (SPK), artificial tear consumption, tear vascular endothelium growth factor (VEGF) level, and ocular surface disease index. The drug safety tests included liver and kidney functions, and complete blood counts. The candidates were observed during the screening visit and the following three monthly follow-ups. The data were analyzed by unpaired Student's t-test. Results: Compared to no significance in the nontreatment group, CJDHWSWT significantly (p = 0.03) increased the tear secretion after 3 months of intake. Furthermore, in contrast to no significance in the treatment group, there were significant alterations, including (i) increased fluorescein-stained SPK areas (p = 0.03); (ii) increased artificial tear instillation amount (p = 0.03); (iii) elevated tear VEGF protein levels (p = 0.03) in the nontreatment group; and (iv) significant improvement in clinically relevant phenomenon (e.g., reading limit and uncomfortable feeling in windy conditions), after treatment of artificial tear plus oral intake of CJDHWSWT. As shown by the post-treatment normal defined laboratory data, there were no adverse drug effects. Conclusions: This study has supported that CJDHWSWT is safe and effective in relieving dry eye's clinically relevant symptoms/phenomena. CJDHWSWT avoided the tear VEGF upregulation probably induced by dry eye-associated hypoxia/ischemia.

Dendrobium nobile Lindley and its bibenzyl component moscatilin are able to protect retinal cells from ischemia/hypoxia by dowregulating placental growth factor and upregulating Norrie disease protein.

BACKGROUND: Presumably, progression of developmental retinal vascular disorders is mainly driven by persistent ischemia/hypoxia. An investigation into vision-threatening retinal ischemia remains important. Our aim was to evaluate, in relation to retinal ischemia, protective effects and mechanisms of Dendrobium nobile Lindley (DNL) and its bibenzyl component moscatilin. The therapeutic mechanisms included evaluations of levels of placental growth factor (PLGF) and Norrie disease protein (NDP). METHODS: An oxygen glucose deprivation (OGD) model involved cells cultured in DMEM containing 1% O2, 94% N2 and 0 g/L glucose. High intraocular pressure (HIOP)-induced retinal ischemia was created by increasing IOP to 120 mmHg for 60 min in Wistar rats. The methods included electroretinogram (ERG), histopathology, MTT assay and biochemistry. RESULTS: When compared with cells cultured in DMEM containing DMSO (DMSO+DMEM), cells subjected to OGD and pre-administrated with DMSO (DMSO+OGD) showed a significant reduction in the cell viability and NDP expression. Moreover, cells that received OGD and 1 h pre-administration of 0.1 µM moscatilin (Pre-OGD Mos 0.1 µM) showed a significant counteraction of the OGD-induced decreased cell viability. Furthermore, compared with the DMSO+OGD group (44.54 ± 3.15%), there was significant elevated NDP levels in the Pre-OGD Mos 0.1 µM group (108.38 ± 29.33%). Additionally, there were significant ischemic alterations, namely reduced ERG b-wave, less numerous retinal ganglion cells, decreased inner retinal thickness, and reduced/enhanced amacrine's ChAT/Müller's GFAP or vimentin immunolabelings. Moreover, there were significantly increased protein levels of HIF-1α, VEGF, PKM2, RBP2 and, particularly, PLGF (pg/ml; Sham vs. Vehicle: 15.11 ± 1.58 vs. 39.53 ± 5.25). These ischemic effects were significantly altered when 1.0 g/Kg/day DNL (DNL1.0 + I/R or I/R+ DNL1.0) was applied before and/or after ischemia, but not vehicle (Vehicle+I/R). Of novelty and significance, the DNL1.0 action mechanism appears to be similar to that of the anti-PLGF Eylea [PLGF (pg/ml); DNL1.0 vs. Eylea+I/R: 19.93 ± 2.24 vs. 6.44 ± 0.60]. CONCLUSIONS: DNL and moscatilin are able to protect against retinal ischemic/hypoxic changes respectively by downregulating PLGF and upregulating NDP. Progression of developmental retinal vascular disorders such as Norrie disease due to persistent ischemia/hypoxia might be thus prevented.