Isoleucine, a branched chain amino acid, plays an important role in the improvement of glucose metabolism as evidenced by the increase of insulin-independent glucose uptake in vitro. This study evaluated the effect of isoleucine on glucose uptake and oxidation in fasted rats and on gluconeogenesis in vivo and in vitro. Oral administration of isoleucine decreased the plasma glucose level by 20% and significantly increased muscle glucose uptake by 71% without significant elevation of the plasma insulin level compared with controls at 60 min after administration. Furthermore, expiratory excretion of 14CO2 from [U-14C]glucose in isoleucine-administered rats was increased by 19% compared with controls. Meanwhile, isoleucine decreased AMP levels in the liver but did not affect hepatic glycogen synthesis. Under insulin-free conditions, isoleucine significantly inhibited glucose production when alanine was used as a glucogenic substrate in isolated hepatocytes. This inhibition by isoleucine was also associated with a decline in mRNA levels for phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase) and a decreased activity of G6Pase in isolated hepatocytes. These findings suggest that a reduction of gluconeogenesis in liver, along with an increase of glucose uptake in the muscle, is also involved in the hypoglycemic effect of isoleucine. In conclusion, isoleucine administration stimulates both glucose uptake in the muscle and whole body glucose oxidation, in addition to depressing gluconeogenesis in the liver, thereby leading to the hypoglycemic effect in rats.

Hypoglycemic effect of isoleucine involves increased muscle glucose uptake and whole body glucose oxidation, and decreased hepatic gluconeogenesis

Study on urine metabolic profiling and pathogenesis of hyperlipidemia.

Childhood obesity is associated with a number of metabolic abnormalities leading to increased cardiovascular risk. Metabolites can be useful as early biomarkers and new targets to promote early intervention beginning in school age. Thus, we aimed to identify metabolomic profiles associated with obesity and obesity-related metabolic traits. We used data from the Obesity Research Study for Mexican children (ORSMEC) in Mexico City and included a case control (n = 1120), cross-sectional (n = 554) and a longitudinal study (n = 301) of 6–12-year-old children. Forty-two metabolites were measured using electrospray MS/MS and multivariate regression models were used to test associations of metabolomic profiles with anthropometric, clinical and biochemical parameters. Principal component analysis showed a serum amino acid signature composed of arginine, leucine/isoleucine, phenylalanine, tyrosine, valine and proline significantly associated with obesity (OR = 1.57; 95%CI 1.45–1.69, P = 3.84 × 10−31) and serum triglycerides (TG) (β = 0.067, P = 4.5 × 10−21). These associations were validated in the cross-sectional study (P < 0.0001). In the longitudinal cohort, the amino acid signature was associated with serum TG and with the risk of hypertriglyceridemia after 2 years (OR = 1.19; 95%CI 1.03-1.39, P = 0.016). This study shows that an amino acid signature significantly associated with childhood obesity, is an independent risk factor of future hypertriglyceridemia in children.

/pdf/an-amino-acid-signature-associated-with-obesity-predicts-2-1ymlexqqlf.pdf

An Amino Acid Signature Associated with Obesity Predicts 2-Year Risk of Hypertriglyceridemia in School-Age Children

This review focuses on the added value provided by a research strategy applying metabolomics analyses to assess phenotypic flexibility in response to different nutritional challenge tests in the framework of metabolic clinical studies. We discuss findings related to the Oral Glucose Tolerance Test (OGTT) and to mixed meals with varying fat contents and food matrix complexities. Overall, the use of challenge tests combined with metabolomics revealed subtle metabolic dysregulations exacerbated during the postprandial period when comparing healthy and at cardiometabolic risk subjects. In healthy subjects, consistent postprandial metabolic shifts driven by insulin action were reported (e.g., a switch from lipid to glucose oxidation for energy fueling) with similarities between OGTT and mixed meals, especially during the first hours following meal ingestion while differences appeared in a wider timeframe. In populations with expected reduced phenotypic flexibility, often associated with increased cardiometabolic risk, a blunted response on most key postprandial pathways was reported. We also discuss the most suitable statistical tools to analyze the dynamic alterations of the postprandial metabolome while accounting for complexity in study designs and data structure. Overall, the in-depth characterization of the postprandial metabolism and associated phenotypic flexibility appears highly promising for a better understanding of the onset of cardiometabolic diseases.

/pdf/investigating-the-postprandial-metabolome-after-challenge-lzif2hl9.pdf

Investigating the Postprandial Metabolome after Challenge Tests to Assess Metabolic Flexibility and Dysregulations Associated with Cardiometabolic Diseases

Perturbations in amino acids and metabolic pathways in osteoarthritis patients determined by targeted metabolomics analysis.

Oleanolic acid inhibits mercury chloride induced-liver ferroptosis by regulating ROS/iron overload.

Maternal BPAF exposure impaired synaptic development and caused behavior abnormality in offspring.

Elevated levels of respirable particulate matter (PM) have been strongly linked to disease incidence and mortality in population-based epidemiological studies. Berberine hydrochloride (BBR), an isoquinoline alkaloid found in Coptis chinensis, exhibits antipyretic, anti-inflammatory, and antioxidant properties. However, the protective effects and underlying mechanism of BBR against pulmonary fibrosis remain unclear. This study aimed to investigate the protective effect of BBR on lung tissue damage using a mouse model of PM2.5-induced pulmonary fibrosis. SPF grade C57BL/6 mice were randomly assigned to four groups, each consisting of 10 mice. The mice were pretreated with BBR (50 mg/kg) by gavage for 45 consecutive days. A tracheal drip of PM2.5 suspension (8 mg/kg) was administered once every three days for a total of 15 times to induce lung fibrosis. Moreover, the results demonstrated that PM2.5 was found to inhibit the PPARγ signaling pathway, increase ROS expression, upregulate protein levels of IL-6, IL-1β, TNF-α, as well as regulation of gene expression of STAT3 and SOCS3. Importantly, PM2.5 induced lung fibrosis by promoting collagen deposition, upregulating gene expression of fibrosis markers (TGF-β1, FN, α-SMA, COL-1, and COL-3), and downregulating E-cadherin expression. Remarkably, our findings suggest that these injuries could be reversed by BBR pretreatment. BBR acts as a PPARγ agonist in PM2.5-induced pulmonary fibrosis, activating the PPARγ signaling pathway to mitigate oxidative and inflammatory factor-mediated lung injury. This study provides valuable insights for the future prevention and treatment of pulmonary fibrosis. 

Berberine hydrochloride ameliorates PM2.5-induced pulmonary fibrosis in mice through inhibiting oxidative stress and inflammatory.

OBJECTIVE
To investigate the renal injury induced by cadmium chloride(CdCl_2) and the protective effect of vitamin C(VC) in mice.


METHODS
Forty healthy clean grade male Kunming mice were randomly divided into 4 groups: control group(double distilled water gavage and intraperitoneal injection), VC group(200 mg/kg VC gavage and double distilled water intraperitoneal injection), CdCl_2 group(double distilled water gavage and 2 mg/kg CdCl_2 intraperitoneal injection), VC+CdCl_(2 )group(200 mg/kg VC gavage and 2 mg/kg CdCl_2 intraperitoneal injection). Exposure for 30 days.24 hours after the last exposure, the eyeballs were taken out for blood, and the renal tissue was immediately taken out to calculate kidney coefficient and then separate renal cells. The levels of reactive oxygen species(ROS) were detected by DCFH-DA kit and flow cytometry. Blood urea nitrogen(BUN), serum creatinine(Scr)and β2 microglobulin(β2-MG), cystatin C(Cys C), superoxide dismutase(SOD), glutathione peroxidase(GSH-Px), malondialdehyde(MDA), Caspase3 and Caspase9 kits were used to detect the corresponding indicators respectively. The contents of Cd~(2+) and Zn~(2+) in serum and kidney were detected by graphite furnace atomic absorption spectrometry.


RESULTS
The levels of kidney coefficient and BUN, Scr, β2-MG were 1.36±0.10, (19.34±0.63)mmol/L, (61.30±2.04)mmol/L and(1.02±0.10)g/mL respectively in CdCl_(2 )group, which were higher than those in the control group and VC group(P<0.05). The levels of the above four indexes in VC+CdCl_(2 )group were 1.09±0.10, (9.65±0.50)mmol/L, (41.85±1.27)mmol/L and(0.61±0.01)g/mL respectively, which were lower than those in CdCl_2 group(P<0.05). CdCl_2 exposure resulted in unclear glomerular contour, swelling of renal tubules, interstitial hyperemia, and exfoliated epithelial cells in the lumen. VC pretreatment could improve the above changes. The levels of Cd~(2+) in serum and renal tissue of mice in CdCl_2 group were(4.36±0.07)μg/L, (18.6±1.95)μg/g respectively, which were higher than that of control group and VC group(P<0.05), in VC+CdCl_2 group, the level were(2.12±0.06)μg/L and(2.18±0.09)μg/g, they were lower than that of CdCl_2 group(P<0.05). The level of serum Zn~(2+ )in CdCl_2 group was(11.35±1.03)μg/L, that was lower than control group(P<0.05). The level of serum Zn~(2+) in VC+CdCl_2 group was(26.98±3.13)μg/L, which was higher than that of CdCl_2 group(P<0.05). The levels of ROS, MDA, Caspase3 and Caspase9 in kidney tissue of mice in CdCl_2 group were(1.86±0.13), (4.78±0.15)nmol/mg, 1.50±0.24 and 1.69±0.17 respectively, which were higher than those in control group(P<0.05). And the level of GSH-Px was(261.3±23.36)U/mg, it was lower than that in control group(P<0.05). Compared with the CdCl_2 group, the levels of ROS, MDA, Caspase3 and Caspase9 in VC+CdCl_2 group decreased, and the level of GSH-Px increased, the difference was statistically significant(P<0.05).


CONCLUSION
CdCl_2 exposure can lead to oxidative stress, damage of glomerulus and renal tubules, imbalance of zinc ion homeostasis, and damage of renal function. VC pretreatment can reduce the damage caused by CdCl_2 to a certain extent.

[Renal injury induced by cadmium chloride and the protective effect of vitamin C in mice].

OBJECTIVE
To investigate the damage of rat alveolar type II epithelial cells(RLE-6 TN) caused by air fine particulate matter(PM_(2.5)) and its related mechanism.


METHODS
PM_(2.5) in the atmosphere of Weifang City in 2020 was collected and cell culture medium was used to prepare particulate suspension. RLE-6 TN cells were exposed to different concentrations(25, 50, 100, 200, 400 μg/mL) of particulate matter suspensions for 24 h. The morphological changes of RLE-6 TN cells were observed under inverted microscope, and the cell viability was determined by MTT method. The concentration of lactate dehydrogenase(LDH) in cell supernatant was determined by microplate method. DCFH-DA, Annexin V-FITC/PI, JC-1 probe and laser confocal fluorescence intensity were used to determine the levels of reactive oxygen species(ROS), apoptosis and mitochondrial membrane potential. Total superoxide dismutase(T-SOD), glutathione(GSH) and malondialdehyde(MDA) contents and activity levels in cells were determined by colorimetric method. Caspase-3 and Caspase-9 kit were used to detect the relative expression activity of apoptosis proteins.


RESULTS
PM_(2.5) could lead to morphological changes of RLE-6 TN cells, enlarged cell space and decreased cell viability. Compared with the control group, there were statistically significant differences in each dose group(P<0.05). LDH concentration in the supernatant of ≥50 μg/mL infected group increased, and LDH concentration was ≥(377.82±29.84), which was significantly different from that of the control group(278.51±23.76)(P<0.05). The result of laser confocal detection of ROS showed that the intracellular green fluorescence increased gradually in the ≥50 μg/mL group, and the relative fluorescence intensity was ≥(2.77±0.18), which was statistically significant compared with the control group(P<0.05). The level of apoptosis was significantly increased compared with the control group(P<0.05). The level of mitochondrial membrane potential decreased gradually, and the level of mitochondrial membrane potential in the ≥25 μg/mL group was ≤(4.22±0.45), which was statistically different from that in the control group(6.16±0.49)(P<0.05). PM_(2.5) could reduce the levels of T-SOD and GSH, and the levels of T-SOD and GSH in ≥50 μg/mL exposed group were ≤(14.67±0.49) and ≤(433.29±39.24), respectively, significantly lower than those in control group((16.58±0.60) and(542.90±45.06))(P<0.05). MDA level increased with the increase of PM_(2.5) concentration. Compared with the control group(1.15±0.19), MDA level in ≥50 μg/mL exposed group was ≥(1.72±0.13), with statistical significance(P<0.05). The activity levels of Caspase-3 and Caspase-9 increased in ≥100 μg/mL group, and the activity levels were ≥(1.62±0.27) and ≥(1.23±0.06), respectively, compared with the control group, the differences were statistically significant(P<0.05).


CONCLUSION
Exposure to a certain concentration of PM_(2.5) can induce oxidative stress of rat alveolar type II epithelial cells, reduce the membrane potential, and eventually lead to cell apoptosis.

[Air fine particulate matter induced alveolar type Ⅱ epithelial cell injury in rats].

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