BACKGROUND
There is an unmet need for a safer and more effective treatment for obesity. This study assessed the effects of licogliflozin, a dual inhibitor of sodium‐glucose co‐transporter (SGLT) 1/2, ...on body weight, metabolic parameters and incretin hormones in patients with type 2 diabetes mellitus (T2DM) and/or obesity.
METHODS
Patients with obesity (BMI, 35‐50 kg/m2) were enrolled into a 12‐week study (N = 88; licogliflozin 150 mg q.d.). Patients with T2DM were enrolled into a second, two‐part study, comprising a single‐dose cross‐over study (N = 12; 2.5 − 300 mg) and a 14‐day dosing study (N = 30; 15 mg q.d). Primary endpoints included effects on body weight, effects on glucose, safety and tolerability. Secondary endpoints included urinary glucose excretion (UGE24) and pharmacokinetics, while exploratory endpoints assessed the effects on incretin hormones (total GLP‐1, PYY3‐36, and GIP), insulin and glucagon.
RESULTS
Treatment with licogliflozin 150 mg q.d. for 12 weeks in patients with obesity significantly reduced body weight by 5.7% vs placebo (P < 0.001) and improved metabolic parameters such as significantly reduced postprandial glucose excursion (21%; P < 0.001), reduced insulin levels (80%; P < 0.001) and increased glucagon (59%; P < 0.001). In patients with T2DM, a single dose of licogliflozin 300 mg in the morning prior to an oral glucose tolerance test (OGTT) remarkably reduced glucose excursion by 93% (P < 0.001; incremental AUC0‐4h) and suppressed insulin by 90% (P < 0.01; incremental AUC0‐4h). Treatment with licogliflozin 15 mg q.d. for 14 days reduced 24‐hour average glucose levels by 26% (41 mg/dL; P < 0.001) and increased UGE24 to 100 g (P < 0.001) in patients with T2DM. In addition, this treatment regimen significantly increased total GLP‐1 by 54% (P < 0.001) and PYY3‐36 by 67% (P < 0.05) post OGTT vs placebo, while significantly reducing GIP levels by 53% (P < 0.001). Treatment with licogliflozin was generally safe and well tolerated. Diarrhea (increased numbers of loose stool) was the most common adverse event in all studies (90% with licogliflozin vs 25% with placebo in the 12‐week study), while a lower incidence of flatulence, abdominal pain and abdominal distension (25%‐43% with licogliflozin vs 9%‐11% with placebo in the 12‐week study) were among the other gastrointestinal events reported.
CONCLUSION
Licogliflozin treatment (1‐84 days) leads to significant weight loss and favourable changes in a variety of metabolic parameters and incretin hormones. Dual inhibition of SGLT1/2 with licogliflozin in the gut and kidneys is an attractive strategy for treating obesity and diabetes.
In this paper, Ag@Fe
3
O
4
@cellulose nanocrystals (CNC) nanocomposites were synthesized by a facile and green microwave-assisted hydrothermal method. In the procedure, CNC was used as a reducing ...agent for the synthesis of Ag. During the whole synthesis process, there were no additional reducing agents or toxic solvents used. The nanocomposites were characterized by X-ray powder diffraction, scanning electron microscopy, energy-dispersive X-ray spectrum, transmission electron microscopy, thermogravimetric analysis, and differential thermal analysis. In addition, Ag@Fe
3
O
4
@CNC nanocomposites were also synthesized by microwave-assisted method and hydrothermal method. Both the effects of reaction time and synthetic procedures on the reduction process of Ag
+
by CNC were explored. The results showed that Fe
3
O
4
was formed with sphere-like structure and dispersed uniformly. Ag@Fe
3
O
4
@CNC nanocomposites exhibited good adsorption of dye solution, which showed potential applications in water treatment. The antibacterial results showed that Ag@ Fe
3
O
4
@CNC nanocomposites had good antibacterial activities toward both
Staphylococcus aureus
(
S. aureus
) and
Escherichia coli
(
E. coli
). The green and facile strategy reported in this paper may be broadly used in synthesizing other metal nanoparticles, as well as organic–inorganic nanocomposites.
To identify susceptibility loci for schizophrenia, we performed a two-stage genome-wide association study (GWAS) of schizophrenia in the Han Chinese population (GWAS: 746 individuals with ...schizophrenia and 1,599 healthy controls; validation: 4,027 individuals with schizophrenia and 5,603 healthy controls). We identified two susceptibility loci for schizophrenia at 6p21-p22.1 (rs1233710 in an intron of ZKSCAN4, P(combined) = 4.76 × 10(-11), odds ratio (OR) = 0.79; rs1635 in an exon of NKAPL, P(combined) = 6.91 × 10(-12), OR = 0.78; rs2142731 in an intron of PGBD1, P(combined) = 5.14 × 10(-10), OR = 0.79) and 11p11.2 (rs11038167 near the 5' UTR of TSPAN18, P(combined) = 1.09 × 10(-11), OR = 1.29; rs11038172, P(combined) = 7.21 × 10(-10), OR = 1.25; rs835784, P(combined) = 2.73 × 10(-11), OR = 1.27). These results add to previous evidence of susceptibility loci for schizophrenia at 6p21-p22.1 in the Han Chinese population. We found that NKAPL and ZKSCAN4 were expressed in postnatal day 0 (P0) mouse brain. These findings may lead to new insights into the pathogenesis of schizophrenia.
The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory ...pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2−/− mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.
Synopsis
Whether hypoxia and nutrient starvation are coupled to cellular autophagy remains unclear. Here, DNA damage response kinases ATM and CHK2 are shown to trigger autophagy in response to reactive oxygen species (ROS) accumulation, suggesting a novel physiological adaptation pathway toward metabolic stress.
Depletion of CHK2 or ATM impairs oxidative stress‐induced autophagy in MEFs.
CHK2 binds and phosphorylates Beclin1 at Ser90/Ser93, suppressing Beclin1‐Bcl‐2 autophagy regulatory complex formation.
CHK2‐induced autophagy limits intracellular ROS levels by clearing damaged mitochondria.
CHK2‐induced autophagy protects against cell death and tissue damage following cerebral ischemia.
ROS accumulation activates protective autophagy to prevent stress‐induced tissue damage.
As a major active iridoid glycoside from Gardenia jasminoides J. Ellis (Rubiaceae), geniposide possesses various pharmacological activities, including anti-platelet aggregation and anti-inflammatory ...action.
This study explores the effect of geniposide in diabetic wound model by anti-inflammatory action.
Diabetic rodent model in Wistar rats was induced by streptozotocin combined with high-fat feed. The selected rats were divided into control group, the diabetic model group and geniposide subgroups (200, 400 and 500 mg/kg), and orally administrated once daily with saline or geniposide. Wound area and histochemical indicators were measured on day 7 after continuous administration, to assess lesion retraction, inflammatory cells and fibroblasts.
Geniposide notably enhanced lesion retraction by 1.06-1.84 times on day 7 after surgical onset in diabetic rats (p < 0.05). In the pathological experiment by HE staining, geniposide significantly reduced inflammatory cell infiltration and proliferation of fibroblasts in the central lesion regions. In diabetic rats treated with geniposide, the levels of pro-inflammatory factors (tumour necrosis factor-α (TNF-α), interleukin-1β (IL-1β)) and IL-6 were significantly reduced (p < 0.05), followed with the increment of IL-10 in a dose-dependent manner. The IC
50
of geniposide on TNF-α, IL-1β and IL-6 could be calculated as 1.36, 1.02 and 1.23 g/kg, respectively. It assumed that geniposide-induced IL-10 expression contributed to inhibiting the expression of pro-inflammatory factors.
Geniposide promoted diabetic wound healing by anti-inflammation and adjusting blood glucose. Further topical studies are required to evaluate effects on antibacterial activity and skin regeneration.
Preeclampsia is a severe pregnancy-related disorder, and patients usually present with high circulating inflammatory factor levels and excessive activation of the nuclear factor-κB (NF-κB) pathway. ...Administration of aspirin (ASP) is effective for preventing preeclampsia, and thus, we propose that ASP might affect placental function by regulating the NF-κB pathway. Systemic lipopolysaccharide (LPS) (20 µg/kg) was used to induce preeclampsia-like pregnant mouse model, and low-dose ASP (15.2mg/kg) was administrated. Here, we report significantly increased circulatory expression levels of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-6, and soluble Fms-related tyrosine kinase-1 in LPS-treated pregnant mice, accompanied by kidney and placental dysfunction. Low-dose ASP treatment significantly reversed the preeclampsia-like phenotype, lowering hypertension, decreasing proteinuria, and ameliorating fetal growth retardation. Moreover, the excessive activation of NF-κB signaling in mice placentae induced by LPS was significantly reduced by ASP. In JEG-3 cells, LPS activated the NF-κB signaling pathway by upregulating the expression of cyclooxygenase-2 (COX-2) and related inflammatory factors, whereas the invasion ability of JEG-3 cells was weakened. However, ASP administration impeded NF-κB signaling activation, downregulated COX-2 and inflammatory factor expression, and rescued trophoblast invasion. This study provides new evidence that low-dose ASP is beneficial for preeclampsia prevention by inhibiting NF-κB and its downstream signaling pathways in trophoblast cells. Summary Sentence Low-dose ASP is beneficial for preventing LPS-induced preeclampsia by inhibiting NF-κB and downstream signaling pathways in trophoblast cells.
Ischemic stroke is a common type of stroke with a high mortality and morbidity rate. Preventing and controlling cerebral ischemic injury is particularly important. Forsythiaside A (FA) has been ...reported to have anti‑inflammatory and antioxidant activities. The aim of the present study was to explore the impact of FA on middle cerebral artery occlusion (MCAO)‑induced cerebral ischemic injury in rats. The results indicated that FA markedly increased the percent survival and decreased the neurological deficit score in rats with cerebral ischemic injury. Furthermore, cell apoptosis was significantly inhibited by FA administration, which was accompanied by decreased caspase‑3 and caspase‑9 expression. A marked increase in the expression levels of nuclear factor‑erythroid 2‑related factor 2 (Nrf2), NAD(P)H quinone dehydrogenase 1 and glutathione‑s‑transferase was detected in FA‑treated rats. In addition, treatment with FA reduced malonaldehyde expression, and enhanced the expression of superoxide dismutase and glutathione. Furthermore, endoplasmic reticulum (ER) stress was vastly alleviated by FA treatment, as evidenced by the increased expression of B‑cell lymphoma 2, apoptosis regulator and the downregulated expression of phosphorylated (phospho)‑protein kinase RNA‑like ER kinase (PERK)/PERK, phospho‑inositol‑requiring enzyme 1 (IRE1α)/IRE1α and CCAAT‑enhancer‑binding proteins homologous protein. Taken together, the present study demonstrated that FA attenuated cerebral ischemic damage via mediation of the activation of Nrf2 and ER stress pathways. These data may provide ideas for novel treatment strategies of cerebral ischemic damage.
A scale-invariant chiral effective Lagrangian is constructed for octet pions and a dilaton figuring, as Nambu-Goldstone bosons, with vector mesons incorporated as hidden gauge fields. The Lagrangian ...is built to the next-to-leading order in chiral-scale counting without baryon fields and then to leading order including baryons. The resulting theory is hidden scale symmetric and local symmetric. We also discuss some possible applications of the present Lagrangian.
The inhibitory effects of the main inhibitors formed during acid pretreatment of corn stalk were studied through ethanol fermentations of model substrates and hydrolysates from corn stalk by alcohol ...yeast. Experimental results showed that the tested inhibitors had no significant effect on ethanol fermentations when they were added separately at a concentration according to analysis results from hydrolysate of corn stalk. However, when they were added as a mixture, the inhibitory effects became obvious. With the increase of concentration, there was a delay in ethanol productivity. But complete inhibition was observed at 5.0 g L
−1
furfural, 10.0 g L
−1
acetic acid, 7.0 g L
−1
ferulic acid, and 7.0 g L
−1
p
-coumaric acid, respectively. The inhibitory effect decreased in the order: furfural > acetic acid > ferulic acid >
p
-coumaric acid > HMF. These results suggest that a high concentration of inhibitor has a strong negative influence on ethanol fermentation, but the inhibiting abilities of various inhibitors are different.
The inhibitory effects of the main inhibitors formed during acid pretreatment of corn stalk were studied through ethanol fermentations of model substrates and hydrolysates from corn stalk by alcohol yeast.
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