Combined untargeted and targeted lipidomics approaches reveal potential biomarkers in type 2 diabetes mellitus cynomolgus monkeys.

BACKGROUND: The significantly increasing incidence of type 2 diabetes mellitus (T2DM) over the last few decades triggers the demands of T2DM animal models to explore the pathogenesis, prevention, and therapy of the disease. The altered lipid metabolism may play an important role in the pathogenesis and progression of T2DM. However, the characterization of molecular lipid species in fasting serum related to T2DM cynomolgus monkeys is still underrecognized. METHODS: Untargeted and targeted LC-mass spectrometry (MS)/MS-based lipidomics approaches were applied to characterize and compare the fasting serum lipidomic profiles of T2DM cynomolgus monkeys and the healthy controls. RESULTS: Multivariate analysis revealed that 196 and 64 lipid molecules differentially expressed in serum samples using untargeted and targeted lipidomics as the comparison between the disease group and healthy group, respectively. Furthermore, the comparative analysis of differential serum lipid metabolites obtained by untargeted and targeted lipidomics approaches, four common serum lipid species (phosphatidylcholine [18:0_22:4], lysophosphatidylcholine [14:0], phosphatidylethanolamine [PE] [16:1_18:2], and PE [18:0_22:4]) were identified as potential biomarkers and all of which were found to be downregulated. By analyzing the metabolic pathway, glycerophospholipid metabolism was associated with the pathogenesis of T2DM cynomolgus monkeys. CONCLUSION: The study found that four downregulated serum lipid species could serve as novel potential biomarkers of T2DM cynomolgus monkeys. Glycerophospholipid metabolism was filtered out as the potential therapeutic target pathway of T2DM progression. Our results showed that the identified biomarkers may offer a novel tool for tracking disease progression and response to therapeutic interventions.

Quantitative Proteomic Analysis of Serum Reveals MST1 as a Potential Candidate Biomarker in Spontaneously Diabetic Cynomolgus Monkeys.

The prevalence of type 2 diabetes (T2DM) is increasing globally, creating essential demands for T2DM animal models for the study of disease pathogenesis, prevention, and therapy. A non-human primate model such as cynomolgus monkeys can develop T2DM spontaneously in an age-dependent way similar to humans. In this study, a data-independent acquisition-based quantitative proteomics strategy was employed to investigate the serum proteomic profiles of spontaneously diabetic cynomolgus monkeys compared with healthy controls. The results revealed significant differences in protein abundances. A total of 95 differentially expressed proteins (DEPs) were quantitatively identified in the current study, among which 31 and 64 proteins were significantly upregulated and downregulated, respectively. Bioinformatic analysis revealed that carbohydrate digestion and absorption was the top enriched pathway by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Protein-protein interaction network analysis demonstrated that MST1 was identified as the most connected protein in the network and could be considered as the hub protein. MST1 was significantly and inversely associated with FSG and HbA1c. Furthermore, recent lines of evidence also indicate that MST1 acts as a crucial regulator in regulating hepatic gluconeogenesis to maintain metabolic homeostasis while simultaneously suppressing the inflammatory processes. In conclusion, our study provides novel insights into serum proteome changes in spontaneously diabetic cynomolgus monkeys and points out that the dysregulation of several DEPs may play an important role in the pathogenesis of T2DM.

Preliminary serum and fecal metabolomics study of spontaneously diabetic cynomolgus monkeys based on LC-MS/MS.

BACKGROUND: Using untargeted metabolomics techniques, the goal of the study is to differentially screen serum and feces metabolite profiles of spontaneously diabetic and healthy cynomolgus monkeys, to explore potential serum and fecal biomarkers and analyze affected metabolic pathways. METHODS: We adopted the diagnostic criteria for T2DM recommended by ADA for humans: FSG ≥7.0 mmol/L (126 mg/dl) and HbA1c ≥ 6.5%. The serum and feces samples from three diagnosed spontaneously T2DM cynomolgus monkeys and 11 age-matched healthy controls were enrolled in the study. We employed LC-MS/MS-based untargeted metabolomic methods to reveal the differential metabolite profiles of serum and feces samples between the two groups and to analyze the affected metabolic pathways in MetaboAnalyst 5.0 based on KEGG library. RESULTS: Six and 44 differential metabolites were identified in serum and feces samples, respectively, and the corresponding affected commonly metabolic pathways involved several metabolic ways, such as arginine biosynthesis, pantothenate and CoA biosynthesis, alanine, aspartate and glutamate metabolism, valine, leucine and isoleucine biosynthesis, and histidine metabolism. CONCLUSION: The differential potential serum and feces biomarkers obtained from the LC-MS/MS based untargeted metabolomic may help to explain the potential pathophysiological mechanisms of T2DM and offer pivotal information for the early diagnosis and treatment of DM.

China is facing serious experimental monkey shortage during the COVID-19 lockdown.

This report aims to analyze the experimental monkey shortage generated by the COVID-19 lockdown. The supply capability of the monkey breeding farms is insufficient to meet demand, and the sales prices have skyrocketed since 2018. The contradiction will be further aggravated with import prohibition although the countermeasures suggested.

Microwave ablation versus parathyroidectomy for severe secondary hyperparathyroidism in patients on hemodialysis: a retrospective multicenter study.

BACKGROUND: Microwave ablation is effective for severe secondary hyperparathyroidism, but the difference in efficacy between microwave ablation and parathyroidectomy remains unclear. In this multicenter retrospective cohort study, we compared the long-term clinical efficacy of microwave ablation and parathyroidectomy for severe secondary hyperparathyroidism undergoing hemodialysis. MATERIALS AND METHODS: The patients were divided into microwave ablation and parathyroidectomy groups. The primary endpoint was the proportion of patients with intact parathyroid hormone (iPTH) concentrations within the target range (100-600 pg/mL) during the efficacy assessment phase. The secondary endpoints were (i) differences in iPTH concentrations over time between the two groups, and (ii) decreases in iPTH concentrations over time in the two groups. RESULTS: Microwave ablation was performed in 47/92 patients and parathyroidectomy in 45/92. Primary endpoint: iPTH concentrations within the target range were achieved during the efficacy assessment phase in 26/47 patients (55.3%) and in 14/45 (31.1%) patients in the microwave ablation and parathyroidectomy groups, respectively (p = .02). Secondary endpoints: (i) Mean iPTH concentrations during the efficacy assessment phase were significantly higher in the microwave ablation versus parathyroidectomy groups (649 ± 519 pg/mL versus 136 ± 228 pg/mL, respectively; p < .01). (ii) Mean decrease in iPTH concentration from baseline was 725 ± 605 pg/mL versus 1369 ± 478 pg/mL in the MWA versus parathyroidectomy groups, respectively (p < .01). CONCLUSIONS: Ultrasound-guided percutaneous microwave ablation provides higher iPTH target-achieving rates than parathyroidectomy in patients with severe secondary hyperparathyroidism undergoing hemodialysis.

The Faster-Onset Antidepressant Effects of Hypidone Hydrochloride (YL-0919) in Monkeys Subjected to Chronic Unpredictable Stress.

Given the limited monkey models of depression available to date, as well as the procedural complexity and time investments that they involve, the ability to test the efficacy and time course of antidepressants in monkey models is greatly restricted. The present study attempted to build a simple and feasible monkey model of depression with chronic unpredictable stress (CUS) and evaluate the antidepressant effect and onset time of fluoxetine hydrochloride (FLX) and the new drug hypidone hydrochloride (YL-0919), a potent and selective 5-HT reuptake inhibitor, 5-HT1A receptor partial agonist and 5-HT6 receptor full agonist. Female cynomolgus monkeys with low social status in their colonies were selected and subjected to CUS for 8 weeks by means of food and water deprivation, space restriction, loud noise, strobe light, and intimidation with fake snakes. Huddling, self-clasping, locomotion and environmental exploration were monitored to evaluate behavioral changes. In addition, the window-opening test was used to evaluate the exploratory interest of the monkeys. The present results revealed that CUS-exposed monkeys displayed significant depression-like behaviors, including significant decreases in exploratory interest, locomotion, and exploration as well as significant increases in huddling and self-clasping behavior and the level of fecal cortisol after 8 weeks of CUS. Treatment with FLX (2.4 mg/kg, i. g.) or YL-0919 (1.2 mg/kg, i. g.) markedly reversed the depression-like behaviors caused by CUS, producing significant antidepressant effects. YL-0919 (once daily for 9 days) had a faster-onset antidepressant effect, compared with FLX (once daily for 17 days). In summary, the present study first established a CUS model using female cynomolgus monkeys with low social status and then successfully evaluated the onset time of 5-HTergic antidepressants. The results suggested that monkeys exposed to CUS displayed significant depression-like behaviors, and both FLX and YL-0919 produced antidepressant effects in this model. Moreover, YL-0919 appeared to act faster than FLX. The present study provides a promising prospect for the evaluation of fast-onset antidepressant drugs based on a CUS monkey model.

Prolonged deficits of associative motor learning in cynomolgus monkeys after long-term administration of phencyclidine.

Phencyclidine (PCP) is a potent drug of abuse that induces sustained schizophrenia-like symptoms in humans by blocking neurotransmission at N-methyl-d-aspartate (NMDA)-type glutamate receptors. Alterations in NMDA receptor function have been linked to numerous behavioral deficits and cognitive dysfunction. Classical eye-blink conditioning (EBC), including delay (dEBC) and trace (tEBC) paradigms, provides an effective means to study the neurobiology of associative motor learning in rodents, mammals and primates. To assess whether administration of low-dosage PCP for extended periods has prolonged effect to alter associative motor learning, in this study 19 adult cynomolgus monkeys were administered PCP (0.3mg/kg, intramuscularly) or saline twice a day for 14days. Twelve-fifteen months after PCP or saline injection, monkeys received dEBC, tEBC, or pseudo-paired training for 6 or 12 successive daily sessions, respectively. The results of this study show that percentage of conditioned response (CR) in dEBC increased as a function of training sessions in both PCP-treated and control monkeys and there was no significant CR% difference between the two groups. However, the CR timing in dEBC of PCP-treated monkeys was significantly impaired, as manifested by shorter CR peak latencies than those of the control group. PCP-treated animals showed significantly lower percentage of CR in tEBC compared to controls. PCP-treated animals were also more sensitive to outside stimuli in tEBC because the UR peak latency of PCP-treated group was significantly lower than the control group. These results indicated that cynomolgus monkeys manifested prolonged deficits in associative motor learning after long-term administration of phencyclidine.

Dose-Dependent Changes in Auditory Sensory Gating in the Prefrontal Cortex of the Cynomolgus Monkey.

BACKGROUND Sensory gating, often described as the ability to filter out irrelevant information that is repeated in close temporal proximity, is essential for the selection, processing, and storage of more salient information. This study aimed to test the effect of sensory gating under anesthesia in the prefrontal cortex (PFC) of monkeys following injection of bromocriptine, haloperidol, and phencyclidine (PCP). MATERIAL AND METHODS We used an auditory evoked potential that can be elicited by sound to examine sensory gating during treatment with haloperidol, bromocriptine, and PCP in the PFC in the cynomolgus monkey. Scalp electrodes were located in the bilateral PFC and bilateral temporal, bilateral parietal, and occipital lobes. Administration of bromocriptine (0.313 mg/kg, 0.625 mg/kg, and 1.25 mg/kg), haloperidol (0.001 mg/kg, 0.01 mg/kg, and 0.05 mg/kg), and the N-methyl-D-aspartic acid receptor antagonist PCP (0.3 mg/kg) influenced sensory gating. RESULTS We demonstrated the following: (1) Administration of mid-dose bromocriptine disrupted sensory gating (N100) in the right temporal lobe, while neither low-dose nor high-dose bromocriptine impaired gating. (2) Low-dose haloperidol impaired gating in the right prefrontal cortex. Mid-dose haloperidol disrupted sensory gating in left occipital lobe. High-dose haloperidol had no obvious effect on sensory gating. (3) Gating was impaired by PCP in the left parietal lobe. CONCLUSIONS Our studies showed that information processing was regulated by the dopaminergic system, which might play an important role in the PFC. The dopaminergic system influenced sensory gating in a dose- and region-dependent pattern, which might modulate the different stages that receive further processing due to novel information.