Abnormal energy metabolism in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a severe autoimmune disease with significant socioeconomic impact worldwide. Orderly energy metabolism is essential for normal immune function, and disordered energy metabolism is increasingly recognized as an important contributor to the pathogenesis of SLE. Disorders of energy metabolism are characterized by increased reactive oxygen species, ATP deficiency, and abnormal metabolic pathways. Oxygen and mitochondria are critical for the production of ATP, and both mitochondrial dysfunction and hypoxia affect the energy production processes. In addition, several signaling pathways, including mammalian target of rapamycin (mTOR)/adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling and the hypoxia-inducible factor (HIF) pathway also play important regulatory roles in energy metabolism. Furthermore, drugs with clear clinical effects on SLE, such as sirolimus, metformin, and tacrolimus, have been proven to improve the disordered energy metabolism of immune cells, suggesting the potential of targeting energy metabolism for the treatment of SLE. Moreover, several metabolic modulators under investigation are expected to have potential therapeutic effects in SLE. This review aimed to gain insights into the role and mechanism of abnormal energy metabolism in the pathogenesis of SLE, and summarizes the progression of metabolic modulator in the treatment of SLE.

Biochemical Aspects That Lead to Abusive Use of Trimetazidine in Performance Athletes: A Mini-Review.

Trimetazidine (TMZ), used for treating stable angina pectoris, has garnered attention in the realm of sports due to its potential performance-enhancing properties, and the World Anti-Doping Agency (WADA) has classified TMZ on the S4 list of prohibited substances since 2014. The purpose of this narrative mini-review is to emphasize the biochemical aspects underlying the abusive use of TMZ among athletes as a metabolic modulator of cardiac energy metabolism. The myocardium's ability to adapt its energy substrate utilization between glucose and fatty acids is crucial for maintaining cardiac function under various conditions, such as rest, moderate exercise, and intense effort. TMZ acts as a partial inhibitor of fatty acid oxidation by inhibiting 3-ketoacyl-CoA thiolase (KAT), shifting energy production from long-chain fatty acids to glucose, reducing oxygen consumption, improving cardiac function, and enhancing exercise capacity. Furthermore, TMZ modulates pyruvate dehydrogenase (PDH) activity, promoting glucose oxidation while lowering lactate production, and ultimately stabilizing myocardial function. TMZs role in reducing oxidative stress is notable, as it activates antioxidant enzymes like glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD). In conclusion, TMZs biochemical mechanisms make it an attractive but controversial option for athletes seeking a competitive edge.

Evaluation of a Novel Precision Biotic on Enterohepatic Health Markers and Growth Performance of Broiler Chickens under Enteric Challenge.

This study evaluated the supplementation of a precision biotic (PB) on the enterohepatic health markers and growth performance of broiler chickens undergoing an enteric challenge. In the first study, three treatments were used: Unchallenged Control (UC); Challenged Control (CC; dietary challenge and 10× dose of coccidia vaccine); and a challenged group supplemented with PB (1.3 kg/ton). In the second study, three treatments were used: control diet, diet supplemented with Avilamycin (10 ppm), and a diet supplemented with PB (0.9 kg/ton). All the birds were exposed to natural challenge composed by dietary formulation and reused litter from a coccidiosis positive flock. In Trial 1, PB decreased ileal histological damage, increased villi length, and the expression of SLC5A8 in ileal tissue versus CC; it reduced ileal expression of IL-1ß compared to both UC and CC treatments. PB increased the expression of cell cycling gene markers CCNA2 and CDK2 in the ileum compared to CC. In Trial 2, PB improved the growth performance, intestinal lesion scores and intestinal morphology of broiler chickens. These results indicate that birds supplemented with PB are more resilient to enteric challenges, probably by its action in modulating microbiome metabolic pathways related to nitrogen metabolism and protein utilization.

Evaluation of a Precision Biotic on the Growth Performance, Welfare Indicators, Ammonia Output, and Litter Quality of Broiler Chickens.

A dietary glycan-based precision biotic (Glycan PB) was evaluated on the performance, welfare indicators, and litter characteristics of broiler chickens. In Trial 1, the main effects of Glycan PB dose (0, 250 and 500 g/metric ton (MT)) and xylanase supplementation (0 or 100 g/MT) were tested, as was their interaction. In Trial 2, pens located inside a commercial house were used to test the effect of Glycan PB supplementation (500 g/MT) versus a control diet. In Trial 1, Glycan PB supplementation at 250 and 500 g/MT improved feed conversion ratio (FCR) by 7 and 11 points when compared to diets without Glycan PB (p < 0.001). At 35 d, Glycan PB reduced the pH and ammonia concentration in diets with xylanase. In Trial 1, the supplementation with 500 g of Glycan PB/MT of feed reduced litter scores (p < 0.05). In both trials, 500 g of Glycan PB/MT of feed increased the proportions of birds without footpad lesions (Trial 1: 72.2% vs. 82.7%; p < 0.001; Trial 2: 14 to 27.3% (p = 0.05) or gait defects (Trial 1: 96.1% vs. 98.4%; p < 0.001) and decreased the proportion of birds with footpad lesions (Trial 2: 86% vs. 72.7%; p = 0.05).

A novel microbiome metabolic modulator improves the growth performance of broiler chickens in multiple trials and modulates targeted energy and amino acid metabolic pathways in the cecal metagenome.

A meta-analysis of 19 floor-pen trials (579 replicate pen observations) in diverse geographies, basal diets, seasons, and medication programs was carried out to evaluate the effects of 2 precision glycan microbiome metabolic modulators (MMM1 and MMM2) on the performance of broiler chickens. In each trial, negative-control (NC) diets were compared with either MMM1 (14 trials) or MMM2 (8 trials), supplemented at an intended dose of 500 g/MT from hatch to 31 to 42 d. A dose response of MMM2 was evaluated in 8 trials at doses of 100, 250, 500, and 1,000 g/MT, not all present in each trial. Linear mixed-effect models were constructed for the final BW, cumulative feed intake, feed conversion ratio (FCR) corrected by mortality and BW (cFCR), and mortality, with Treatment as the fixed effect, nested random effects of Trial and Block, and adjustments for heterogeneity of variances. A significance level of P < 0.05 was used. In one of the studies, cecal content samples were collected at 42 d for analysis of microbiome gene abundance. Microbiome metabolic modulator 2 exhibited a reduction of the cFCR of 0.06 g feed/g BW gain compared with the NC and 0.03 g feed/g BW gain compared with MMM1, whereas MMM1 reduced the cFCR by 0.03 g feed/g BW gain compared with NC. Both MMM1 and MMM2 increased the final BW compared with the NC by 43 and 48 g/bird, respectively, with no difference among them. Compared with NC, feed intake was increased by MMM1 (+51 g/bird) and reduced by MMM2 (-74 g/bird). A one-directional dose response of the MMM2 ingredient was observed for the final BW (increasing) and cFCR (decreasing), whereas the feed intake response reached a minimum at 500 g/MT. The metagenomic analysis confirmed an increase in the abundance of genes belonging to the acrylate pathway, which is involved in propionate production, as well as arginine-N-succinyl transferase which is involved in the catabolism of arginine, in response to MMM2. Differential glycan structures of the MMM had an impact on the size and consistency of performance effects in broilers.

The emergence of drug resistance to targeted cancer therapies: Clinical evidence.

For many decades classical anti-tumor therapies included chemotherapy, radiation and surgery; however, in the last two decades, following the identification of the genomic drivers and main hallmarks of cancer, the introduction of therapies that target specific tumor-promoting oncogenic or non-oncogenic pathways, has revolutionized cancer therapeutics. Despite the significant progress in cancer therapy, clinical oncologists are often facing the primary impediment of anticancer drug resistance, as many cancer patients display either intrinsic chemoresistance from the very beginning of the therapy or after initial responses and upon repeated drug treatment cycles, acquired drug resistance develops and thus relapse emerges, resulting in increased mortality. Our attempts to understand the molecular basis underlying these drug resistance phenotypes in pre-clinical models and patient specimens revealed the extreme plasticity and adaptive pathways employed by tumor cells, being under sustained stress and extensive genomic/proteomic instability due to the applied therapeutic regimens. Subsequent efforts have yielded more effective inhibitors and combinatorial approaches (e.g. the use of specific pharmacologic inhibitors with immunotherapy) that exhibit synergistic effects against tumor cells, hence enhancing therapeutic indices. Furthermore, new advanced methodologies that allow for the early detection of genetic/epigenetic alterations that lead to drug chemoresistance and prospective validation of biomarkers which identify patients that will benefit from certain drug classes, have started to improve the clinical outcome. This review discusses emerging principles of drug resistance to cancer therapies targeting a wide array of oncogenic kinases, along with hedgehog pathway and the proteasome and apoptotic inducers, as well as epigenetic and metabolic modulators. We further discuss mechanisms of resistance to monoclonal antibodies, immunomodulators and immune checkpoint inhibitors, potential biomarkers of drug response/drug resistance, along with possible new therapeutic avenues for the clinicians to combat devastating drug resistant malignancies. It is foreseen that these topics will be major areas of focused multidisciplinary translational research in the years to come.

8-(3-phenylpropyl)-1,3,7-triethylxanthine is a synthetic caffeine substitute with stronger metabolic modulator activity.

Caffeine is one of the most worldwide consumed methylxanthines. It is well-known for its thermogenic and cell metabolism modulating effects. Based on methylxanthines' chemical structure, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (PTX) is a novel adenosine antagonist with higher receptor affinity than caffeine. Therefore, we hypothesized that PTX metabolic effects could be stronger than those of caffeine. For that purpose, murine 3T3-L1 cells were cultured in the presence of increasing doses of PTX or caffeine (0.1, 1, 10 and 100 µM) for 24 h. Cytotoxicity was evaluated by reduction of tetrazolium salt (MTT) and lactate dehydrogenase (LDH) release. Cell metabolites released to the culture medium were identified and quantified by proton nuclear magnetic resonance (1H NMR). Cellular oxidative profile was also evaluated. Our results showed that PTX displayed no signs of cytotoxicity at all studied concentrations. When compared with caffeine, PTX increased glucose, pyruvate, and glutamine consumption, as well as lactate, alanine, and acetate production. Additionally, PTX decreased protein oxidation, thus protecting against oxidative stress-induced damage. These results illustrate that PTX is a stronger and less cytotoxic caffeine substitute with potential applications as metabolic modulator and a good candidate for novel drug design.

Major themes for 2010 in cardiothoracic and vascular anesthesia.

Significant variability in transfusion practice persists despite guidelines. Although the lysine analogues are effective antifibrinolytics, safety concerns exist with high doses tranexamic acid. Despite recombinant activated factor VII promising results in massive bleeding after cardiac surgery, it significantly increases arterial thromboembolic risk. Aortic valve repair may evolve to standard of care. Transcatheter aortic valve implantation is an established therapy for aortic stenosis. The cardiovascular anesthesiologist features prominently in the new guidelines for thoracic aortic disease. Although intense angiotensin blockade improves outcomes in heart failure, it might aggravate the maintenance of perioperative systemic vascular tone. Ultrafiltration is an alternative to diuresis for volume overload in heart failure. Management of heart failure titrated to brain natriuretic peptide activity reduces mortality. A major surgical advance has been the significant outcome improvement achieved with continuous-flow left ventricular assist devices. Advanced liver disease is a significant predictor for perioperative bleeding, transfusion and mortality after ventricular assist device insertion. Acquired von Willebrand syndrome is not only common in patients with these devices but often aggravating bleeding and transfusion in this setting. Metabolic myocardial modulation with perhexilene significantly enhances effort tolerance in hypertrophic cardiomyopathy. A landmark report has highlighted future priorities in this disease. Pediatric cardiac surgical trials have revealed the importance of perioperative cerebral oxygen saturation monitoring and the Sano shunt. Advances in pediatric-specific ventricular assist devices will likely revolutionize pediatric heart failure. Recent reports have highlighted the priorities for future perioperative trials and for training models in pediatric cardiac anesthesia.