作者: Feehan, Jack ; Tripodi, Nicholas ; Apostolopoulos, Vasso ; Wang, Qian ; Saadati, Saeede ; Lawton, Amy ; Kabthymer, Robel Hussen ; de Courten, Barbora ; Gadanec, Laura Kate

Biological ageing involves a gradual decline in physiological function and resilience, marked by molecular, cellular, and systemic changes across organ systems. Geroscience, an interdisciplinary field, studies these mechanisms and their role in age-related diseases. Genomic instability, inflammation, telomere attrition, and other indicators contribute to conditions like cardiovascular disease and neurodegeneration. Geroscience identifies geroprotectors, such as resveratrol and metformin, targeting ageing pathways to extend the healthspan. Carnosine, a naturally occurring dipeptide (b-alanine and l-histidine), has emerged as a potential geroprotector with antioxidative, anti-inflammatory, and anti-glycating properties. Carnosine's benefits extend to muscle function, exercise performance, and cognitive health, making it a promising therapeutic intervention for healthy ageing and oxidative stress-related pathologies. In this review, we summarize the evidence describing carnosine's effects in promoting healthy ageing, providing new insights into improving geroscience.

2024-11-01·Redox Biology

A quantitative proteomic approach to evaluate the efficacy of carnosine in a murine model of chronic obstructive pulmonary disease (COPD)

Article

作者: Melloni, Elsa ; Carini, Marina ; Vailati, Silvia ; Caponetti, Giovanni ; Gilardoni, Ettore ; Aldini, Giancarlo ; D'Amato, Alfonsina ; Padoani, Gloria ; D’Amato, Alfonsina ; Altomare, Alessandra ; Baron, Giovanna

The aim of the work was to study a dose-dependent effect of inhaled carnosine (10, 50 or 100 mg/kg/day) in mice exposed to cigarette smoke as a model of chronic obstructive pulmonary disease (COPD). A dose-dependent loading of the dipeptide in lung tissue and bronchoalveolar lavage (BAL) was firstly demonstrated by LC-ESI-MS analysis. Cigarette smoke exposure induced a significant lung inflammation and oxidative stress in mice which was dose-dependently reduced by carnosine. Inflammation was firstly evaluated by measuring the cytokines content in the BAL. All the measured cytokines were found significantly higher in the smoke group in respect to control, although the data are affected by a significant variability. Carnosine was found effective only at the highest dose tested and significantly only for keratinocyte-derived cytokine (KC). Due to the high variability of cytokines, a quantitative proteomic approach to better understand the functional effect of carnosine and its molecular mechanisms was used. Proteomic data clearly indicate that smoke exposure had a great impact on lung tissue with 692 proteins differentially expressed above a threshold of 1.5-fold. Protein network analysis identified the activation of some pathways characteristic of COPD, including inflammatory response, fibrosis, induction of immune system by infiltration and migration of leukocyte pathways, altered pathway of calcium metabolism and oxidative stress. Carnosine at the tested dose of 100 mg/kg was found effective in reverting all the pathways evoked by smoke. Only a partial reverse of the dysregulated proteins was evident at low- and mid-tested doses, although, for some specific proteins, indicating an overall dose-dependent effect. Regarding the molecular mechanisms involved, we found that carnosine upregulated some key enzymes related to Nrf2 activation and in particular glutathione peroxidase, reductase, transferase, SOD, thioredoxins, and carbonyl reductase. Such mechanism would explain the antioxidant and anti-inflammatory effects of the dipeptide.

2024-10-18·Skeletal muscle

Metabolic pathways for removing reactive aldehydes are diminished in the skeletal muscle during heart failure.

Article

作者: Chaudhari, Mamata ; Bhatnagar, Aruni ; Zelko, Igor ; Baba, Shahid P ; Hoetker, David ; Brittian, Kenneth ; Nong, Yibing ; Doelling, Benjamin ; Lorkiewicz, Pawel ; Srivastava, Sanjay

Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways. Whether the formation of lipid peroxidation products and metabolic pathways that remove these toxic products are affected during heart failure-associated skeletal muscle wasting has never been studied. Male C57BL/6J mice were subjected to sham and transverse aortic constriction (TAC) surgeries for 4, 8 or 14 weeks. Different skeletal muscle beds were weighed, and the total cross-sectional area of the gastrocnemius muscle was measured via immunohistochemistry. Muscle function and muscle stiffness were measured by a grip strength meter and atomic force microscope, respectively. Atrophic and inflammatory marker levels were measured via qRT‒PCR. The levels of acrolein and HNE-protein adducts, aldehyde-removing enzymes, the histidyl dipeptide-synthesizing enzyme carnosine synthase (CARNS), and amino acid transporters in the gastrocnemius muscle were measured via Western blotting and qRT‒PCR. Histidyl dipeptides and histidyl dipeptide aldehyde conjugates in the Gastrocnemius and soleus muscles were analyzed by LC/MS-MS. Body weight, gastrocnemius muscle and soleus muscle weights and the total cross-sectional area of the gastrocnemius muscle were decreased after 14 weeks of TAC. Heart weight, cardiac function, grip strength and muscle stiffness were decreased in the TAC-operated mice. Expression of the atrophic and inflammatory markers Atrogin1 and TNF-α, respectively, was increased ~ 1.5-2fold in the gastrocnemius muscle after 14 weeks of TAC (p < 0.05 and p = 0.004 vs sham). The formation of HNE and acrolein protein adducts was increased, and the expression of the aldehyde-removing enzyme aldehyde dehydrogenase (ALDH2) was decreased in the gastrocnemius muscle of TAC mice. Carnosine (sham: 5.76 ± 1.3 vs TAC: 4.72 ± 0.7 nmol/mg tissue, p = 0.04) and total histidyl dipeptide levels (carnosine and anserine; sham: 11.97 ± 1.5 vs TAC: 10.13 ± 1.4 nmol/mg tissue, p < 0.05) were decreased in the gastrocnemius muscle of TAC mice. Depletion of histidyl dipeptides diminished the aldehyde removal capacity of the atrophic gastrocnemius muscle. Furthermore, CARNS and TAUT protein expression were decreased in the atrophic gastrocnemius muscle. Our data reveals that reduced expression of ALDH2 and depletion of histidyl dipeptides in the gastrocnemius muscle during heart failure leads to the accumulation of toxic aldehydes and might contribute to muscle wasting.

100 项与 L-carnosine 相关的药物交易

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