Complex lipid globules in early-life nutrition improve long-term metabolic phenotype in intra-uterine growth-restricted rats.

Intra-uterine growth restriction (IUGR) is associated with adverse metabolic outcome later in life. Healthy mice challenged with a Western-style diet (WSD) accumulated less body fat when previously fed a diet containing large lipid globules (complex lipid matrix (CLM)). This study was designed to clarify whether an early-life CLM diet mitigates 'programmed' visceral adiposity and associated metabolic sequelae after IUGR. In rats, IUGR was induced either by bilateral uterine vessel ligation (LIG) or sham operation (i.e. intra-uterine stress) of the dam on gestational day 19. Offspring from non-operated (NOP) dams served as controls. Male offspring of all groups were either fed CLM or 'normal matrix' control diet (CTRL) from postnatal days (PND) 15 to 42. Thereafter, animals were challenged with a mild WSD until dissection (PND 98). Fat mass (micro computer-tomograph scan; weight of fat compartments), circulating metabolic markers and expression of 'metabolic' genes (quantitative real-time PCR) were assessed. CLM diet significantly reduced visceral fat mass in LIG at PND 40. At dissection, visceral fat mass, fasted blood glucose, TAG and leptin concentrations were significantly increased in LIG-CTRL v. NOP-CTRL, and significantly decreased in LIG-CLM v. LIG-CTRL. Gene expression levels of leptin (mesenteric fat) and insulin-like growth factor 1 (liver) were significantly reduced in LIG-CLM v. LIG-CTRL. In conclusion, early-life CLM diet mitigated the adverse metabolic phenotype after utero-placental insufficiency. The supramolecular structure of dietary lipids may be a novel aspect of nutrient quality that has to be considered in the context of primary prevention of obesity and metabolic disease in at-risk populations.

Impaired lipid accumulation in the liver of Tsc2-heterozygous mice during liver regeneration.

Tuberin is a negative regulator of mTOR pathway. To investigate the function of tuberin during liver regeneration, we performed 70% hepatectomy on wild-type and Tsc2+/- mice. We found the tuberin phosphorylation correlated with mTOR activation during early liver regeneration in wild-type mice. However, liver regeneration in the Tsc2+/- mice was not enhanced. Instead, the Tsc2+/- livers failed to accumulate lipid bodies, and this was accompanied by increased mortality. These findings suggest that tuberin plays a critical role in liver energy balance by regulating hepatocellular lipid accumulation during early liver regeneration. These effects may influence the role of mTORC1 on cell growth and proliferation.

Naringin in the repair of knee cartilage injury via the TGF-ß/ALK5/Smad2/3 signal transduction pathway combined with an acellular dermal matrix.

Objective: Based on the expression changes in the TGF-ß/ALK5/Smad2/3 signal transduction pathway, the repair of cartilage injury in the rabbit knee joint was investigated and evaluated by oral administration of naringin in combination with acellular dermal matrix implantation. Methods: First, twenty New Zealand white rabbits were randomly divided into five groups: a sham operation group (Sham group), a model group (Mod group), a naringin group (Nar group), an acellular dermal matrix group (ADM group), a naringin â€‹+ â€‹acellular dermal matrix group (Nar/ADM group). After the 12th week, the repaired tissues were assessed for histomorphology and repair content of the repaired site by observing the morphological characteristics of articular cartilage. The International Cartilage Repair Society (ICRS)'s macroscopic evaluation of the cartilage repair scale and the quantitative scoring repair effect of the modified O'Driscoll grading system were used as evaluation criteria. In addition, the structure of the rabbit knee joint was evaluated by micro-CT scan, histological staining (H & E staining, Alcian blue staining, Safranin-O staining) and immunohistochemical staining (TGF-ß2 immunostaining, TGF-ß3 immunostaining, Sox-9 immunostaining). Results: ① The observation of the repair morphology of joint defect tissues showed that the repair effects of the Nar and ADM groups were better than that of the Mod group, and the repair effect of Nar/ADM group was the best (P < 0.05). ② Quantitative scoring of joint defect tissue showed that the Nar/ADM group had the best repair efficacy in the quantitative scores of the above two scales compared with the other groups (P < 0.05). ③ Micro-CT scan showed that the ADM group had obvious repair of the defect structure, while the ADM/Nar group had blurred repair boundaries, and the layers of cartilage and subchondral bone were clear. ④ Histological staining (H & E staining, Alcian blue stain, Safranin-O staining) showed that the ADM group had a better effect on the repair of joint structure at the joint defect, the Nar group had a better effect on the repair of cartilage quality at the joint defect, and the ADM/Nar group had satisfactory results in both of the above aspects. ⑤ Immunohistochemical staining (TGF-ß2 immunostaining, TGF-ß3 immunostaining, Sox-9 immunostaining) revealed that the Nar group showed more abundant expression of the above proteins in articular cartilage defects than the Mod and ADM groups and that the Nar/ADM groups showed extensive TGF-ß2, TGF-ß3 and Sox-9 protein expression, with uniform expression and smooth distribution. Conclusions: Oral administration of naringin, the active ingredient of Rhizoma Drynariae, combined with acellular dermal matrix can achieve better repair effects in both joint structure repair and cartilage quality repair at the defect site when repairing cartilage defects in rabbit knees, and the generation of this effect may be caused by the activation of the TGF-ß/ALK5/Smad2/3 signal transduction pathway by naringin, resulting in the increased expression of TGF-ß2, TGF-ß3, and Sox-9 in cartilage defects. The Translational Potential of this Article: Naringin combined with acellular dermal matrix can facilitate the repair of osteochondral defects and has potential for application in osteochondral tissue engineering.

Interleukin 18 accelerates the hepatic cell proliferation in rat liver regeneration after partial hepatectomy.

Interleukin 18 (IL-18) is a proinflammatory cytokine with an ability to accelerate cell proliferation through activating other factors. However, little is yet understood of the role of IL-18 in the regulation of liver regeneration (LR). To study the effect of IL-18 on LR, the gene expression profiles of hepatocytes isolated from rat regenerative liver were determined by Rat Genome 230 2.0 microarray. Next, the synergistic effects of genes associated to IL-18 pathway were analyzed by expression profile function Et. Then, the expression level of IL-18 was examined by RT-PCR and ELISA. Finally, the effect of IL-18 on hepatocyte proliferation was detected by injecting recombinant rat IL-18 (rrIL-18) into rats immediately after partial hepatectomy (PH) and the rate of hepatocyte proliferation was detected by BrdU labeling. The microarray result showed that the expressions of 13 genes of IL-18 pathway and 49 cell proliferation genes regulated by the pathway were significantly altered at transcriptional level. The Et values of three branches of IL-18 pathway, NF-κB, p38 and JNK, were markedly enhanced during the priming and progressing phases of rat LR. The mRNA level of IL-18 was significantly elevated at 2 and 36 h, and its level in plasma was also significantly increased at 2h, and reached the peaks at 12h and 48 h after PH (p<0.05). The number of BrdU positive cells was dramatically increased in rats treated with IL-18 compared to PBS control group (p<0.01). In conclusion, IL-18 promotes rat hepatocyte proliferation in the LR priming and progressing phases after PH.

ß-Amyloid-induced cognitive dysfunction impairs glucose homeostasis by increasing insulin resistance and decreasing ß-cell mass in non-diabetic and diabetic rats.

OBJECTIVE: ß-Amyloid accumulation in the brain may impair glucose homeostasis in both the brain and peripheral tissues. The present study investigated whether ß-amyloid deposition in the hippocampus impairs glucose homeostasis by altering insulin sensitivity, glucose-stimulated insulin secretion or ß-cell mass. METHODS: Male rats were divided into two groups: a non-diabetic sham group and a diabetic partial pancreatectomized (Px) group. Each group was then subdivided into three treatment groups that received intra-CA1 infusions of ß-amyloid (25-35; AMY), ß-amyloid (35-25; RAMY; non-plaque forming), or saline at a rate of 3.6 nmol/day for 14 days. RESULTS: After 4weeks, cognitive function measured by passive avoidance and water maze tests was impaired in non-diabetic rats that received AMY compared with rats that received saline or RAMY. Furthermore, diabetes exacerbated cognitive dysfunction in AMY-infused rats. This was associated with the hyperphosphorylation of tau as a result of attenuated insulin signaling (pAkt→pGSK) through decreased phosphorylation of cAMP responding element binding protein in the hippocampus of non-diabetic and diabetic rats. AMY exacerbated whole-body and hepatic insulin resistance in non-diabetic and diabetic rats. However, AMY potentiated glucose-stimulated insulin secretion in non-diabetic and diabetic rats, but caused decreased ß-cell mass via increased ß-cell apoptosis and decreased ß-cell proliferation. As a result, glucose homeostasis was maintained by potentiating insulin secretion in diabetic rats, but may not be sustainable with further decreases in ß-cell mass. CONCLUSION: Cognitive dysfunction attributable to ß-amyloid accumulation in the hippocampus might be related to disturbed glucose homeostasis due to increased insulin resistance and decreased ß-cell mass.

Original rat model of high kinetic unilateral pulmonary hypertension surgically induced by combined surgery.

OBJECTIVES: The characteristic morphologic lesions observed in the lungs of patients with congenital cardiac anomalies have not been closely modeled in rat shunt-related models, except for the reversible grade 1 changes. The present study reported an original rat model of unilateral pulmonary hypertension surgically induced by combined surgery to reproduce more advanced pulmonary vascular lesions. METHODS: The right pulmonary artery was ligated through a right posterolateral thoracotomy, and a cervical shunt was established 1 week later. The immediate and chronic effects on the pulmonary hemodynamics were evaluated through right heart catheterization immediately after and at 8 and 12 weeks postoperatively. The morphologic changes in pulmonary vasculature were analyzed after staining with hematoxylin-eosin and modified Weigert's method. The right ventricular hypertrophy index was calculated and artery blood gas analysis performed. RESULTS: A pulmonary hypertensive status was successfully induced immediately after cervical surgery and progressively aggravated into a borderline state with disease course advancing. Pulmonary vasculopathy demonstrated a transition from reversibility (muscularization, intimal proliferation of grade 1-2) at 8 weeks to irreversibility (intimal fibrosis, entirely luminal occlusion, grade 3) at 12 weeks postoperatively. Conspicuous right ventricular hypertrophy and decreasing partial arterial pressure of oxygen were also observed. CONCLUSIONS: The present shunt-related model successfully simulated a hypertensive status in pulmonary circulation and reproduced the characteristic transition of pulmonary vasculopathy from reversibility to irreversibility within a relatively short period. Thus, this model could offer an alternative with low mortality and high reproducibility for investigations on the underling mechanisms of shunt-related pulmonary hypertension.

Controladores del tiempo y el envejecimiento: núcleo supraquiasmático y glándula pineal / Aging process entrainment: suprachiasmatic nucleus and pineal gland

El núcleo supraquiasmático (NSQ) es el principal reloj biológico de los mamíferos y sincroniza la actividad de la glándula pineal al ciclo luz-oscuridad a través de una vía polisináptica. El efecto de asa de retroalimentación neuroendocrina se lleva a cabo por la melatonina. El presente trabajo pretende demostrar que la glándula pineal modula la sensibilidad a la luz en el NSQ. Se utilizaron ratas Wistar, y se asignaron a 3 grupos: grupo A (falsa pinealectomía -sham-, sin luz), grupo B (falsa pinealectomía -sham- + luz) y grupo C al cual se le realizó la pinealectomía + luz, después de la manipulación se sacrifican para realizar inmunohistoquímica para c-Fos y al final conteo celular por técnica de estereología. Se obtuvo una reducción del 46,8% del promedio de células inmunorreactivas a c-Fos en el grupo C en comparación del grupo B. Este trabajo muestra que la sensibilidad a la luz está modulada por la actividad de la glándula pineal.

The suprachiasmatic nucleus (SCN) is the main and major biological clock in mammals and is responsible for the synchronization of the pineal gland to the light/darkness cycle through a polysynaptic pathway. The neuroendocrine feedback loop effect is carried out by melatonin. This study was carried out to demonstrate that the pineal gland adjusts the sensibility to light in the suprachiasmatic nucleus. Wistar rats were allocated in 3 groups: Group A (sham pinalectomy, without light), group B (sham pinealectomy + light) and group C which underwent real pinalectomy + light. After the intervention the animals were slain to perform immunohistochemistry for c-Fos and cell counting by stereology technique. A 46.8% average reduction in c-Fos immunoreactive cells was achieved in-group C as compared with group B. The present work shows that sensibility to the light is modulate by the activity of the pineal gland.