Combination Therapy with Gallium Protoporphyrin and Gallium Nitrate Exhibits Enhanced Antimicrobial Activity In Vitro and In Vivo against Methicillin-Resistant Staphylococcus aureus.

There is a major need for the development of new therapeutics to combat antibiotic-resistant Staphylococcus aureus. Recently, gallium (Ga)-based complexes have shown promising antimicrobial effects against various bacteria, including multidrug-resistant organisms, by targeting multiple heme/iron-dependent metabolic pathways. Among these, Ga protoporphyrin (GaPP) inhibits bacterial growth by targeting heme pathways, including aerobic respiration. Ga(NO3)3, an iron mimetic, disrupts elemental iron pathways. Here, we demonstrate the enhanced antimicrobial activity of the combination of GaPP and Ga(NO3)3 against methicillin-resistant S. aureus (MRSA) under iron-limited conditions, including small colony variants (SCV). This therapy demonstrated significant antimicrobial activity without inducing slow-growing SCV. We also observed that the combination of GaPP and Ga(NO3)3 inhibited the MRSA catalase but not above that seen with Ga(NO3)3 alone. Neither GaPP nor Ga(NO3)3 alone or their combination inhibited the dominant superoxide dismutase expressed (SodA) under the iron-limited conditions examined. Intranasal administration of the combination of the two compounds improved drug biodistribution in the lungs compared to intraperitoneal administration. In a murine MRSA lung infection model, we observed a significant increase in survival and decrease in MRSA lung CFUs in mice that received combination therapy with intranasal GaPP and Ga(NO3)3 compared to untreated control or mice receiving GaPP or Ga(NO3)3 alone. No drug-related toxicity was observed as assessed histologically in the spleen, lung, nasal cavity, and kidney for both single and repeated doses of 10 mg Ga /Kg of mice over 13 days. Our results strongly suggest that GaPP and Ga(NO3)3 in combination have excellent synergism and potential to be developed as a novel therapy for infections with S. aureus.

Myristic Acid Supplementation Aggravates High Fat Diet-Induced Adipose Inflammation and Systemic Insulin Resistance in Mice.

Saturated fatty acids (SFAs) are considered to be detrimental to human health. One of the SFAs, myristic acid (MA), is known to exert a hypercholesterolemic effect in mice as well as humans. However, its effects on altering adipose tissue (AT) inflammation and systemic insulin resistance (IR) in obesity are still unclear. Here, we sought to determine the effects of a high fat (HF) diet supplemented with MA on obesity-associated metabolic disorders in mice. Wild-type C57BL/6 mice were fed a HF diet in the presence or absence of 3% MA for 12 weeks. Plasma lipids, plasma adipokines, AT inflammation, systemic IR, glucose homeostasis, and hepatic steatosis were assessed. The body weight and visceral adipose tissue (VAT) mass were significantly higher in mice receiving the HF+MA diet compared to HF diet-fed controls. Plasma total cholesterol levels were marginally increased in HF+MA-fed mice compared to controls. Fasting blood glucose was comparable between HF and HF+MA-fed mice. Interestingly, the plasma insulin and HOMA-IR index, a measure of insulin resistance, were significantly higher in HF+MA-fed mice compared to HF controls. Macrophage and inflammatory markers were significantly elevated in the AT and AT-derived stromal vascular cells upon MA feeding. Moreover, the level of circulating resistin, an adipokine promoting insulin resistance, was significantly higher in HF+MA-fed mice compared with HF controls. The insulin tolerance test revealed that the IR was higher in mice receiving the MA supplementation compared to HF controls. Moreover, the glucose tolerance test showed impairment in systemic glucose homeostasis in MA-fed mice. Analyses of liver samples showed a trend towards an increase in liver TG upon MA feeding. However, markers of oxidative stress and inflammation were reduced in the liver of mice fed an MA diet compared to controls. Taken together, our data suggest that chronic administration of MA in diet exacerbates obesity-associated insulin resistance and this effect is mediated in part, via increased AT inflammation and increased secretion of resistin.

Lauric Acid versus Palmitic Acid: Effects on Adipose Tissue Inflammation, Insulin Resistance, and Non-Alcoholic Fatty Liver Disease in Obesity.

Coconut oil, rich in medium-chain saturated fatty acids (MCSFA), in particular, lauric acid (LA), is known to exert beneficial metabolic effects. Although LA is the most abundant saturated fatty acid in coconut oil, the specific role of LA in altering obesity-related metabolic disorders remains unknown. Here, we examined the effects of supplementing a high fat (HF) diet with purified LA on obesity-associated metabolic derangements in comparison with palmitic acid (PA), a long-chain saturated fatty acid. Male C57BL/6 mice were fed a control chow diet (CD) or an HF diet supplemented with 3% LA (HF + LA) or PA (HF + PA) for 12 wk. Markers of adipose tissue (AT) inflammation, systemic insulin resistance (IR), and hepatic steatosis, were assessed. The body weight and total fat mass were significantly higher in both HF + LA and HF + PA diet-fed groups compared to CD controls. However, the visceral adipose tissue (VAT) mass was significantly higher (p < 0.001) in HF + LA-fed mice compared to both CD as well as HF + PA-fed mice. Interestingly, markers of AT inflammation were promoted to a lesser extent in HF + LA-fed mice compared to HF + PA-fed mice. Thus, immunohistochemical analysis of VAT showed an increase in MCP-1 and IL-6 staining in HF + PA-fed mice but not in HF + LA-fed mice compared to CD controls. Further, the mRNA levels of macrophage and inflammatory markers were significantly higher in HF + PA-fed mice (p < 0.001) whereas these markers were increased to a lesser extent in HF + LA-fed group. Of note, the insulin tolerance test revealed that IR was significantly increased only in HF + PA-fed mice but not in HF + LA-fed group compared to CD controls. While liver triglycerides were increased significantly in both HF + PA and HF + LA-fed mice, liver weight and plasma markers of liver injury such as alanine aminotransferase and aspartate aminotransferase were increased significantly only in HF + PA-fed mice but not in HF + LA-fed mice. Taken together, our data suggest that although both LA and PA increased AT inflammation, systemic IR, and liver injury, the extent of metabolic derangements caused by LA was less compared to PA in the setting of high fat feeding.

Hereditary vs Familial Pancreatic Cancer: Associated Genetic Syndromes and Clinical Perspective.

Pancreatic ductal adenocarcinoma (PDAC) is a disease marked by high rates of mortality; it is mostly incurable at the time of diagnosis. Only about 7% of patients survive 5 years after diagnosis. Diagnosis at a late stage and rapid progression with minimal response to available treatments are the main reasons for this poor outcome. It is crucial to identify individuals at high risk of developing PDAC so preventive and early detection measures can be employed. Approximately 10% to 15% of PDAC cases have a hereditary or familial basis. In the majority of PDAC cases, no main causative gene has been identified, but several known germline pathogenic mutations have been shown to be related to an increased risk of this cancer. The presence of 2 or more patients with pancreatic cancer within the circle of first-degree relatives, without the presence of a causative germline mutation, is defined as familial pancreatic cancer; this accounts for 4% to 10% of PDAC. Based on the growing evidence supporting the benefit of germline genetic testing in patients with PDAC, both the American Society of Clinical Oncology and the National Comprehensive Cancer Network recently updated their guidelines to include recommendations around genetic testing for patients with pancreatic cancer. However, there is no general consensus on the group of patients and individuals who should be studied and screened. We present a demonstrative case and review the available data on hereditary and familial PDAC.

Hepatic fibrosis persists and progresses despite biochemical improvement in children treated with intravenous fish oil emulsion.

OBJECTIVES: Intestinal failure-associated liver disease (IFALD) is a multifactorial process, which can culminate in cirrhosis and need for transplantation. Fish oil-based lipid emulsions (FOE) reportedly reverse hyperbilirubinemia, but there are little data on their effect on the histopathology of IFALD. METHODS: We blindly examined sequential liver biopsy data on 6 children receiving FOE, with scoring of cholestasis, inflammation, fibrosis, and ductal proliferation based on standardized systems. This information was correlated with biochemical and clinical data to determine any possible relations between biologic and histologic improvement. RESULTS: The median gestational age was 35 weeks, median birth weight 2064 g, and common most reason for intestinal loss was gastroschisis (5/6 children). Median intestinal length was 26 cm beyond the ligament of Treitz and most children had roughly 2 of 3 of their colonic length. It was observed that although hyperbilirubinemia reversed and hepatic synthetic function was preserved across timepoints, fibrosis was persistent in 2 cases, progressive in 3 cases, and regressed in only 1. It remained severe (grade 2 or higher) in 5 of 6 children at last biopsy. Histologic findings of cholestasis improved in all patients and inflammation improved in 5 of 6 children. There were mixed effects on ductal proliferation and steatosis. CONCLUSIONS: In children treated with FOE, reversal of hyperbilirubinemia is not reflected by a similar histologic regression of fibrosis at the timepoints studied. Children with IFALD should have active ongoing treatment and be considered for early referral to an Intestinal Failure Program even with a normalized bilirubin.