The medical applications of glucagon‐like peptide‐1 receptor (GLP‐1R) agonists is evergrowing in scope, highlighting the urgent need for a comprehensive understanding of the mechanisms through which ...GLP‐1R activation impacts physiology and behaviour. A new area of research aims to elucidate the role GLP‐1R signalling in glia, which play a role in regulating energy balance, glycemic control, neuroinflammation and oxidative stress. Once controversial, existing evidence now suggests that subsets of glia (e.g. microglia, tanycytes and astrocytes) and infiltrating macrophages express GLP‐1Rs. In this review, we discuss the implications of these findings, with particular focus on the effectiveness of both clinically available and novel GLP‐1R agonists for treating metabolic and neurodegenerative diseases, enhancing cognition and combating substance abuse.
LINKED ARTICLES
This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc
Sepsis is a common critical illness in the Intensive care unit(ICU) and its management and treatment has always been a major challenge in critical care medicine. The dysregulated host response to ...infection, causing systemic multi-organ and multi-system damage is the main pathogenesis. Notably, intense stress during sepsis can lead to metabolic disturbances of ions, lipids and energy in the organism. Ferroptosis is an iron-dependent, non-apoptotic cell death distinguished by a disruption of iron metabolism and iron-dependent accumulation of lipid peroxides. Mounting researches have established that ferroptosis has an essential part in anti-inflammatory and sepsis, and drugs targeting ferroptosis-related molecules, such as ferroptosis inhibitors, are gradually proving their effectiveness in sepsis. This paper summarizes and reviews the pathogenesis of ferroptosis, its regulatory network, and its vital involvement in the initiation of sepsis and related organ damage, and finally discusses the possible target drugs provided by the above mechanisms, describes the dilemmas as well as the outlook, in the hope of finding more links between ferroptosis and sepsis and providing new perspectives for the future treatment of sepsis.
The phase III SANDPIPER study assessed taselisib (GDC-0032), a potent, selective PI3K inhibitor, plus fulvestrant in estrogen receptor-positive, HER2-negative, PIK3CA-mutant locally advanced or ...metastatic breast cancer.
Postmenopausal women with disease recurrence/progression during/after an aromatase inhibitor were randomized 2 : 1 to receive taselisib (4 mg; taselisib arm) or placebo (placebo arm) plus fulvestrant (500 mg). Stratification factors were visceral disease, endocrine sensitivity, and geographic region. Patients with PIK3CA-mutant tumors (central cobas® PIK3CA Mutation Test) were randomized separately from those without detectable mutations. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in patients with PIK3CA-mutant tumors. Secondary endpoints included objective response rate, overall survival, clinical benefit rate, duration of objective response, PFS by blinded independent central review (BICR-PFS), safety, and time to deterioration in health-related quality of life.
The PIK3CA-mutant intention-to-treat population comprised 516 patients (placebo arm: n = 176; taselisib arm: n = 340). INV-PFS was significantly improved in the taselisib {7.4 months 95% confidence interval (CI), 7.26-9.07} versus placebo arm (5.4 months 95% CI, 3.68-7.29) (stratified hazard ratio HR 0.70; 95% CI, 0.56-0.89; P = 0.0037) and confirmed by BICR-PFS (HR 0.66). Secondary endpoints, including objective response rate, clinical benefit rate, and duration of objective response, showed consistent improvements in the taselisib arm. Safety was assessed in all randomized patients who received at least one dose of taselisib/placebo or fulvestrant regardless of PIK3CA-mutation status (n = 629). Serious adverse events were lower in the placebo versus taselisib arm (8.9% versus 32.0%). There were more discontinuations (placebo arm: 2.3%; taselisib arm: 16.8%) and dose reductions (placebo arm: 2.3%; taselisib arm: 36.5%) in the taselisib arm.
SANDPIPER met its primary endpoint; however, the combination of taselisib plus fulvestrant has no clinical utility given its safety profile and modest clinical benefit.
•Taselisib, a selective PI3K inhibitor, plus fulvestrant has clinical activity in PIK3CA-mutant, ER-positive breast cancer.•SANDPIPER (NCT02340221) assessed the clinical efficacy of taselisib plus fulvestrant in advanced breast cancer.•Taselisib plus fulvestrant had an expected safety profile, but with more discontinuations than placebo plus fulvestrant.•Taselisib plus fulvestrant versus placebo plus fulvestrant significantly improved progression-free survival.
In this study, a three-dimensional evaluation was performed to explore differences between bone-embedded and soft tissue-covered roots after mandibular third molar (M3M) coronectomy. Patients were ...recruited according to the results of cone-beam computed tomography, 6 months after coronectomy. Completely bone-embedded M3Ms were assigned to group B, while completely soft tissue-covered M3Ms were assigned to group S. Data were recorded using digital software. A total of 213 M3Ms in 181 patients were investigated, of which 170 were assigned to the two study groups. Age was the primary factor influencing root migration (P<0.001). The smaller the degree of angulation of the M3M, the more likely was the root complex to rotate distally (r=−0.37, P<0.001). The depth of the impacted M3M contributed to the regeneration of new bone (P≤0.008). The length of the root complex (odds ratio 0.82, P=0.048) and distance from the root to the alveolar crest (odds ratio 1.23, P=0.026) were two critical factors influencing whether the root complex was bone-embedded. Ensuring that the length of the root complex is <7.6mm and the distance between the root and alveolar crest is ≥5mm were both found to be critical to the remaining root being completely bone-embedded and thus preventing eruption and the need for secondary surgery.
Glaucoma is a progressive neurodegenerative process affecting the retinal ganglion cells (RGCs) and the optic nerve. Oxidative stress has been implicated in glaucoma pathogenesis, and iron is a ...potent generator of oxidative stress. The oral iron chelator deferiprone (DFP) is protective against retinal degenerations associated with oxidative stress. To test whether DFP could be protective in glaucoma, we used microbead injections to induce elevated intraocular pressure (IOP) in a cohort of 3-month old C57BL/6J mice. One eye of each animal was injected with magnetic microbeads resulting in ocular hypertension for >7 weeks while the fellow eye was injected with saline and served as a normotensive internal control. While half of the cohort received oral DFP (1 mg/ml in the drinking water), the other half did not and served as controls. After 8 weeks, Brn3a immunolabeling of flat-mounted retinas was used for manual RGC quantification. Axon counts were obtained from thin sections of optic nerves using the AxonJ plugin for ImageJ. DFP administration was protective against RGC and optic nerve loss in the setting of elevated IOP. These results suggest that iron chelation by DFP may provide glaucoma neuroprotection.
•Oral DFP improved RGC survival in a microbead-induced mouse model of glaucoma.•DFP administration preserved retinal ganglion cells and optic nerve axons in hypertensive glaucomatous eyes.•Iron chelation may be neuroprotective in glaucoma.
By considering the effect of the driving cycle on the energy management strategy (EMS), a fuzzy EMS based on driving cycle recognition is proposed to improve the fuel economy of a parallel hybrid ...electric vehicle. The EMS is composed of driving cycle recognition and a fuzzy torque distribution controller. The current driving cycle is recognized by learning vector quantization in driving cycle recognition. The torque of the engine and the motor is controlled by a fuzzy torque distribution controller based on the required torque of the hybrid powertrain and the battery state of charge. The membership functions and rules of the fuzzy torque distribution controller are optimized simultaneously by using particle swarm optimization. Based on the identification results of driving cycle recognition, the fuzzy torque distribution controller selects the corresponding membership function and rule to control the hybrid powertrain. The simulation research based on ADVISOR demonstrates that this EMS improves fuel economy more effectively than fuzzy EMS without driving cycle recognition.
Summary
Background
Serum vitamin D levels are associated with bone complications in patients with primary biliary cirrhosis (PBC). Increasing evidence suggests a nonskeletal role of vitamin D in ...various autoimmune and liver diseases.
Aim
To investigate the clinical relevance of vitamin D levels in PBC, especially their association with the therapeutic effects of ursodeoxycholic acid (UDCA).
Methods
Consecutive PBC patients were retrospectively reviewed. 25‐hydroxyvitamin D 25(OH)D levels were determined in frozen serum samples collected before initiation of UDCA treatment. Response to UDCA was evaluated by Paris‐I and Barcelona criteria. Logistic regressions were performed to identify the treatment response‐associated parameters.
Results
Among 98 patients, the mean serum 25(OH)D concentration was 17.9 ± 7.6 ng/mL. 25(OH)D levels decreased with increasing histological stage (P = 0.029) and were negatively correlated with bilirubin and alkaline phosphatase levels. After 1 year of UDCA therapy, 31 patients failed to achieve complete response according to Paris‐I criteria. The baseline 25(OH)D level was significantly lower in nonresponders (14.8 ± 6.4 vs. 19.3 ± 7.6 ng/mL, P = 0.005). Vitamin D deficiency at baseline was associated with an increased risk of incomplete response independent of advanced stages (OR = 3.93, 95% CI = 1.02–15.19, P = 0.047). Similar results were obtained when biochemical response was evaluated by Barcelona criteria. Furthermore, 25(OH)D levels were lower in patients who subsequently suffered death or liver transplantation (12.1 ± 4.6 vs. 18.4 ± 7.6 ng/mL, P = 0.023).
Conclusions
25(OH)D level is associated with biochemical and histological features in PBC. Pre‐treatment vitamin D status is independently related to subsequent response to UDCA. Our results suggest that vitamin D status may have important clinical significance in PBC.
Glaucomatous neurodegeneration, a blinding disease affecting millions worldwide, has a need for the exploration of new and effective therapies. Previously, the glucagon-like peptide-1 receptor ...(GLP-1R) agonist NLY01 was shown to reduce microglia/macrophage activation, rescuing retinal ganglion cells after IOP elevation in an animal model of glaucoma. GLP-1R agonist use is also associated with a reduced risk for glaucoma in patients with diabetes. In this study, we demonstrate that several commercially available GLP-1R agonists, administered either systemically or topically, hold protective potential in a mouse model of hypertensive glaucoma. Further, the resulting neuroprotection likely occurs through the same pathways previously shown for NLY01. This work contributes to a growing body of evidence suggesting that GLP-1R agonists represent a viable therapeutic option for glaucoma.
Objectives
We conducted a systematic review and individual participant data meta-analysis of publications reporting the ophthalmologic presentation, clinical exam, and orbital MRI findings in ...patients with giant cell arteritis and ocular manifestations.
Methods
PubMed and Cochrane databases were searched up to January 16, 2022. Publications reporting patient-level data on patients with ophthalmologic symptoms, imaged with orbital MRI, and diagnosed with biopsy-proven giant cell arteritis were included. Demographics, clinical symptoms, exam, lab, imaging, and outcomes data were extracted. The methodological quality and completeness of reporting of case reports were assessed.
Results
Thirty-two studies were included comprising 51 patients (females = 24; median age, 76 years). Vision loss (78%) and headache (45%) were commonly reported visual and cranial symptoms. Ophthalmologic presentation was unilateral (41%) or bilateral (59%). Fundus examination most commonly showed disc edema (64%) and pallor (49%). Average visual acuity was very poor (2.28 logMAR ± 2.18). Diagnoses included anterior (61%) and posterior (16%) ischemic optic neuropathy, central retinal artery occlusion (8%), and orbital infarction syndrome (2%). On MRI, enhancement of the optic nerve sheath (53%), intraconal fat (25%), and optic nerve/chiasm (14%) was most prevalent. Among patients with monocular visual symptoms, 38% showed pathologic enhancement in the asymptomatic orbit. Six of seven cases reported imaging resolution after treatment on follow-up MRIs.
Conclusions
Vision loss, pallid disc edema, and optic nerve sheath enhancement are the most common clinical, fundoscopic, and imaging findings reported in patients diagnosed with giant cell arteritis with ocular manifestations, respectively. MRI may detect subclinical inflammation and ischemia in the asymptomatic eye and may be an adjunct diagnostic tool.
Clinical relevance statement
Brain and orbital MRIs may have diagnostic and prognostic roles in patients with suspected giant cell arteritis who present with ophthalmic symptoms.
Total dissolved gas supersaturation (TDGS) produced by flood flows over a high dam has negative consequences on downstream fish. Reducing the total dissolved gas (TDG) levels and/or providing ...adequate low‐TDGS fish shelter areas remains a challenge. The presence of a low‐TDG‐saturation (LTS) zone at river confluences can protect the fish from harmful high TDG levels, but the effects of confluence hydrodynamics on the TDGS distribution are not well understood. In this study, three‐dimensional (3D) hydrodynamic simulations are performed to understand the influence of flow ratio and junction angle on the TDGS distribution downstream of river confluences. The simulation results show that the TDGS distribution is mainly affected by (a) inflow TDGS that determines the supply, (b) secondary flow that leads to rapid renewal of surface water for degassing, and (c) increased turbulence intensity that promotes dissipation of TDGS. Relationship between the LTS area, the flow ratio and the junction angle is constructed via regression analysis. The regression model is validated against a 3D numerical simulation that is compared to field observations at two river confluences along the Jinshajiang River (China). This study provides scientific basis for potential hydraulic modifications at confluences to enlarge an LTS zone and reduce fish fatality.
Key Points
Field observations and three‐dimensional (3D) numerical simulations of total dissolved gas supersaturation (TDGS) at confluences were conducted
The relationship between low‐TDG‐saturation (LTS) parameters and confluence geometry and inflows was investigated
An regression‐based LTS model of TDGS at confluences was developed and verified with 3D numerical simulations and field observations
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