Nicotinamide Riboside Promotes Mfn2-mediated Mitochondrial Fusion in Diabetic Hearts through the SIRT1-PGC1α-PPARα Pathway

Background: Myocardial dysfunction is associated with an imbalance in mitochondrial fusion/fission dynamics in patients with diabetes. However, effective strategies to regulate mitochondrial dynamics in the diabetic heart are still lacking. This study investigated whether Nicotinamide riboside (NR) supplementation protects against diabetes-induced cardiac dysfunction by regulating mitochondrial fusion/fission and further explored the underlying mechanisms.Methods: Obese diabetic (db/db) and lean control (db/+) mice were each given NR oral supplementation in this study. NAD+ Content was determined in mice hearts and primary neonatal cardiomyocytes. Cardiac function was detected by echocardiography. Mitochondrial dynamics were analyzed by transmission electron microscopy in vivo and by confocal microscopy in vitro. Results: Here, we show an evident decrease in NAD+ level and mitochondrial fragmentation in the hearts of leptin receptor-deficient diabetic (db/db) mouse model. NR supplementation significantly increased NAD+ content in the diabetic heart tissues. Furthermore, NR treatment increased Mfn2 expression, promoted mitochondrial fusion, suppressed oxidative stress, reduced cardiomyocyte apoptosis and consequently improved cardiac function in db/db mice. In neonatal primary cardiomyocytes cultured in a high-glucose/high-fat medium, NR treatment also promoted mitochondrial fusion, suppressed mitochondria-derived ROS production and reduced cardiomyocyte apoptosis, which were all reversed when Mfn2 was knocked down. Mechanistically, chromatin immunoprecipitation (ChIP) and luciferase report assay analysis revealed that PGC1α and PPARα interdependently regulated Mfn2 transcription by binding to its promoter region. NR treatment elevated NAD+ levels and activated SIRT1, resulting in the deacetylation of PGC1α and promoting the transcription of Mfn2. Furthermore, the inhibition of SIRT1, PGC1α or PPARα blunted the positive effects of NR supplementation on Mfn2 expression and mitochondrial fusion. Conclusion: NR attenuates the development of diabetes-induced cardiac dysfunction by promoting mitochondrial fusion through the SIRT1-PGC1α-PPARα pathway, with PGC1α and PPARα being the interdependent co-regulatory factors for Mfn2. The promotion of mitochondrial fusion via oral supplementation of NR may be a potential strategy for delaying cardiac complications in patients with diabetes.

Drenching Bovine Colostrum, Quercetin or Fructo-Oligosaccharides Has No Effect on Health or Survival of Low Birth Weight Piglets

The introduction of hyperprolific sows has resulted in more low birth weight (LBW) piglets, accompanied by higher mortality. A possible strategy to enhance the resilience and survival of LBW piglets is oral supplementation (drenching) of bioactive substances. This study evaluated the supplementation of bovine colostrum, short-chain fructo-oligosaccharides (scFOS) or quercetin that were dissolved separately in a milk replacer. The study was divided into two sub-experiments. First, the milk replacer was compared with a sham drenched group. Secondly, each dissolved compound was compared with the milk replacer. The LBW piglets, defined as weighing between (mean litter birth weight −1*SD) and (mean litter birth weight −2.5*SD), were randomly allocated to the different treatments and drenched once a day for seven days. On day 1, 3, 9, 24 and 38, piglets were weighed and scored for skin lesions. Blood samples were collected on day 9 and 38 and analyzed to determine glucose, non-esterified fatty acids, urea, immunoglobulin G, insulin-like growth factor 1, and a standard blood panel test. There was no difference between sham drenched piglets and piglets that were drenched with milk replacer regarding any of the parameters. No effect was observed between the milk replacer group and any of the bioactive compounds either, except a higher mortality within the scFOS group. In conclusion, this study showed that drenching the evaluated bioactive compounds, in the used dosages, did not improve LBW piglets’ resilience or survival and more research is required to determine the effect of scFOS on small piglets.

Pre-Digested Protein Enteral Nutritional Supplementation Enhances Recovery of CD4+ T Cells and Repair of Intestinal Barrier in HIV-Infected Immunological Non-Responders

AIDS patients with immune non-response are prone to malnutrition, intestinal barrier damage, thus aggravating chronic immune activation and inflammation. However, nutritional interventions targeting malnutrition may be beneficial to restore immune function, improve clinical outcomes, and reduce mortality remains largely unclear. This work aimed to evaluate the efficacy of a nutritional supplement in HIV-infected immune non-responders (INRs). The subjects received oral supplementation of a pre-digested protein nutrition formula for three months. We show that the CD4+ T and CD8+ T cell counts were significantly increased after supplementation of the pre-digested enteral nutritional supplement. Among all pro-inflammatory cytokines in the serum, only IL-1β level was significantly decreased, while TNF-β was significantly increased (P < 0.05). The levels of intestinal mucosal damage markers, diamine oxidase (DAO), D-lactic acid (D-lactate), and lipopolysaccharide (LPS), decreased significantly (P < 0.05) after the nutritional intervention. Moreover, at month 3 after the intervention, the body weight, body mass index, albumin, and hemoglobin of all subjects were significantly increased (P < 0.05). The correlation analysis demonstrated a significantly negative correlation of CD4+ T cell count with levels of DAO (r = -0.343, P = 0.004), D-lactate (r = -0.250, P = 0.037), respectively, and a significantly positive correlation of IL-1β level with levels of DAO (r = 0.445, P < 0.001), D-lactate (r = 0.523, P < 0.001), and LPS (r = 0.622, P < 0.001). We conclude that the pre-digested enteral nutrition supplement is effective for HIV-infected INRs.

Role of Oral Zinc Supplementation in treatment of Acute Dehydrating Diarrhea in age 6 months to 5 years

Background: Oral Rehydration Salt (ORS) is the standard recommended treatment for acute dehydrating diarrhea but it has very little role in decreasing stool frequency and volume. Current studies recommend oral supplementation of zinc as an adjunct to ORS in treating acute dehydrating diarrhea of children especially those who are at risk of zinc deficiency and malnutrition. Aim: To determine the effect of oral zinc supplementation on duration of acute diarrhea and intake of ORS in children between 6 months and 5 years of age. Settings: Tehsil Head Quarters Hospital, Besham District Shangla, Khyber Pakhtunkhwa from October 2019 to September 2020. Methodology: The study was double blinded Randomized Control Clinical Trial in children aged between 6 months to 5 years of age. A total of 90 children were included in the study. In addition to rehydration, 45 children were given oral zinc (20mg daily) while 45 children were given placebo. Results: All 45(100%) patients in zinc group and 39(86.6%) patients in placebo group recovered after 5 days of treatment. Zinc group had significantly reduced duration of diarrhea (68.3±9.4 vs. 99.8±15.2 hours) and consumed less ORS solution (2.3±0.8 vs. 3.4±1.1 liters) as compared to placebo group. Conclusion: It is concluded from this study that oral zinc supplementation in addition to ORS in treating acute dehydrating diarrhea of children has better effect on the clinical course of disease. Key words: Diarrhea, ORS, Zinc, Dehydration.