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Recent evidence has shown the potential benefits of mitochondria nutrient L carnitine in the treatment and prevention of cancer cachexia.
- Thread starter ginfreely
- Start date
The mitochondria act as engines within your cells, burning these fats to create usable energy. Your body can produce L-carnitine out of the amino acids lysine and methionine ( 2 ). For your body to produce it in sufficient amounts, you also need plenty of vitamin C ( 3 ).
https://www.healthline.com › l-car...
https://www.healthline.com › l-car...
L-Carnitine: Benefits, Side Effects, Sources, and Dosage
Clinical Significance of Carnitine in the Treatment of Cancer: From Traffic to the Regulation
Raheleh Farahzadi,1Mohammad Saeid Hejazi,2,3Ommoleila Molavi,3Elahe Pishgahzadeh,4Soheila Montazersaheb,2and Sevda Jafari5Show more
Academic Editor: Xiangpan Li
Published10 Aug 2023
Abstract
Metabolic reprogramming is a common hallmark of cancer cells. Cancer cells exhibit metabolic flexibility to maintain high proliferation and survival rates. In other words, adaptation of cellular demand is essential for tumorigenesis, since a diverse supply of nutrients is required to accommodate tumor growth and progression. Diversity of carbon substrates fueling cancer cells indicate metabolic heterogeneity, even in tumors sharing the same clinical diagnosis. In addition to the alteration of glucose and amino acid metabolism in cancer cells, there is evidence that cancer cells can alter lipid metabolism. Some tumors rely on fatty acid oxidation (FAO) as the primary energy source; hence, cancer cells overexpress the enzymes involved in FAO. Carnitine is an essential cofactor in the lipid metabolic pathways. It is crucial in facilitating the transport of long-chain fatty acids into the mitochondria for β-oxidation. This role and others played by carnitine, especially its antioxidant function in cellular processes, emphasize the fine regulation of carnitine traffic within tissues and subcellular compartments. The biological activity of carnitine is orchestrated by specific membrane transporters that mediate the transfer of carnitine and its derivatives across the cell membrane. The concerted function of carnitine transporters creates a collaborative network that is relevant to metabolic reprogramming in cancer cells. Here, the molecular mechanisms relevant to the role and expression of carnitine transporters are discussed, providing insights into cancer treatment.https://www.hindawi.com/journals/omcl/2023/9328344/#
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1. Introduction
Carnitine is an amino acid-derived compound found in almost all cells in the body. Carnitine facilitates the transfer of acyl groups across the cell membranes for β-oxidation and ATP production. Carnitine has direct/indirect modulatory effects on several physiological systems, such as the neural system [1]. Although brain cells have low levels of β-oxidation, carnitine is actively transported across the blood–brain barrier and accumulates in neural cells [1]. Approximately 75% of carnitine in the human body is derived from dietary sources, such as animal products such as red meat and dairy products (with high amine content), and 25% is synthesized endogenously from lysine and methionine in the liver and kidneys.Carnitine homeostasis is achieved by a balance between endogenous synthesis, intestinal absorption, and renal reabsorption, indicating that carnitine homeostasis does not simply rely on maintaining a constant level. Various tissues require different amounts of carnitine for survival. For instance, in the testis, carnitine is at the highest level for sperm maturation. Skeletal muscle and myocardium are also carnitine-dependent tissues because fatty acid oxidation (FAO) is the primary energy source for meeting the energy demand [2].
Due to the impermeability of the mitochondrial inner membrane to fatty acyl-CoA thioesters, the specialized transporting system has evolved to transport fatty acids across mitochondrial membranes. Components of this system include carnitine palmitoyltransferase 1 (CPT1) and 2 (CPT2), the carnitine–acylcarnitine carrier (CAC), and the carnitine acetyltransferase (CrAT, also known as CAT). The latter allows the export of the FAO-produced acetyl-CoA as acetylcarnitine from mitochondria to the cytoplasm. Carnitine and acyl groups can be converted to acylcarnitine by carnitine CPTI (also known as CPTA1) in the cytoplasm. In the mitochondrial matrix, CPT2 catalyzes the conversion of acylcarnitines to carnitine and acyl-CoAs. Acyl-CoAs undergo β-oxidation to generate acetyl-CoA that enters the tricarboxylic acid cycle (TCA). In the heart, acylcarnitine may provide an immediate energy source by FAO and the release of carnitine and transfer of the acyl group to CoA for subsequent β-oxidation in the TCA. As a result, maintaining carnitine homeostasis is crucial for cellular metabolism due to its shuttling role in FAO [3].
Over the past decade, reactive oxygen species (ROS) and free radicals have gained more considerable attention owing to their harmful pathological effects. ROS can trigger oxidative stress and damage various cellular components such as DNA, proteins, and lipids [4]. The body continuously produces ROS during normal physiological processes, which are neutralized by various antioxidant defense mechanisms [5]. Carnitine plays a crucial role in protecting cells from free radicals and the harmful effects of ROS and retards the progression of chronic diseases and aging [6–8]. In addition, carnitine protects the mitochondrial membrane integrity against ROS attack and reduces lipid peroxidation [9]. Carnitine exerts its protective effect against oxidative damage by regulating the function of enzymes involved in the defense system, including superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) [10]. In addition, Nicassio et al. [11] showed that carnitine has the potential to restore age-related alterations in mitochondrial dynamics and function in aged animal models. In this regard, carnitine can normalize age-associated alterations and disorders primarily caused by free radicals.
Several studies have reported the beneficial therapeutic effects of acetylcarnitine in various neurological disorders such as Alzheimer’s disease (AD), Parkinson’s disease, epilepsy, and depression in the elderly [12]. Magi et al. [13] showed that carnitine could ameliorate neuronal damage in glyceraldehyde-induced AD phenotype. Glyceraldehyde is used as a glycolysis inhibitor. According to these results, carnitine improves cell survival in the neurodegenerative context of AD. In addition, carnitine can improve intracellular ATP levels and mitochondrial function and reduce the generation of ROS in mitochondria [13]. In an animal model of liver injury, carnitine blocked the essential pathways involved in nitric oxide synthase activity by inhibiting the nuclear factor-kappa B (NF-κB) and phosphatidylinositol 3-kinase/Akt pathways. These findings indicate the hepatoprotective effects of carnitine [14]. Carnitine has several pleiotropic roles in health and disease (Figure 1). Considering these notions, it is not surprising that carnitine traffic can be altered under other pathological conditions such as cancer.
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So mitochondria nutrients can cross blood brain barrier, no wonder some is said to cause brain cancer. Make sense indeed.
So it’s 75% derived from red meat and dairy, no wonder red meat can cause cancer - I GUESS it’s through these mitochondria nutrients - that also feed cancer. Make sense indeed.
Your red meat beef curtains is cancerous!
See? Everything is connected. Wow I feel like a cancer expert already after 4 months plus of daily postings can put two by two together and draw some intelligent conclusions. I am so proud of myself.
In fact it is scientifically proven cancer cells use methionine which is used to make mitochondria nutrient l-carnitine. So feeding mitochondria nutrients can feed cancer. Make sense indeed.
Everyday I am elevating rising like phoenix while Malaysian Cantonese dogs sons of chickens and sinkie traitor dogs @musclepower @gsbslut @Cottonmouth etc hide in rat hole do evil smear me chicken and think that they can get away from their karma. Pui!
4. Carnitine and Cancer
Patients with cancer were found to be susceptible to carnitine deficiency. The caloric intake of cancer patients is often impaired, while their metabolic demands are increased. Aside from that, pharmacological therapy in cancer patients can interfere with carnitine synthesis, absorption, and excretion [89, 90]. Carnitine deficiency has been reported in chronic illnesses such as cancer [91]. Decreased serum levels of carnitine have been detected in multiple cancers, including endometrial cancer, breast cancer, CML, and pediatric cancer [92–95]. Numerous studies have reported beneficial effects of carnitine in patients with advanced cancer. In a literature review by Radkhouy et al. [96], the beneficial anticancer effect of carnitine was revealed in colon cancer, as evidenced by the prevention of tumor growth. Baci et al. showed that the administration of acetylcarnitine had an angiopreventive effect on prostate cancer cells. Aberrant expression of cytokines/chemokines in prostate cancer can govern progression, invasion, and angiogenesis [97]. High expression of chemokine receptor 4 (CXCR4), an angiogenic factor, is associated with metastatic behavior and poor survival. Acetylcarnitine exerts its anticancer effect by acting on the cytokine/chemokine axis of prostate cancer [98, 99].Cachexia is a multifactorial syndrome characterized by loss of skeletal muscle mass with or without loss of fat mass. This condition cannot be fully compensated by conventional nutritional support, resulting in progressive functional defects in these patients. In a study done by Mitchell et al. [100], it was shown that pancreatic cancer patients exhibit cachexia at the time of diagnosis. Patients with cancer cachexia are resistant to dietary interventions; however, carnitine supplementation could improve the quality of life and body mass. Impairment of FAO can be attributed to the reduced activity of CPTI and CPTII in the liver. CPTI and CPTII play a vital role in the development of cancer cachexia. Accumulating evidence has revealed the importance of carnitine molecules in fatty acid metabolism. In cancer cachectic mice, Liu et al. [101] found a decreased levels of serum-free carnitine and acetylcarnitine with downregulated mRNA levels of CPTI and CPTII. In addition, a hepatic reduction in CPTI activity was detected. According to their results, oral administration of carnitine at a dose of 18 mg/kg significantly restored CPT activity and downregulated the serum levels of interleukin-6 (IL-6) and TNF-αin animal models. With this respect, it can be assumed that carnitine-mediated amelioration is associated with CPT regulation in the liver [101]. In a cachectic mouse model of colon cancer, Jiang et al. [102] showed that oral administration of carnitine at a dose of 9 mg/kg/day ameliorated the cachexia parameters. Carnitine can also decrease the elevated serum levels of IL-6 and TNF-α in cancer cachectic mice [102]. Data from a similar recent study have indicated the potential benefits of carnitine in cancer therapy. Their findings revealed that carnitine improved cancer cachexia in an animal model through the Akt/FOXO3/MaFbx and p70S6K pathways. Carnitine also decreased IL-1 and IL-6 serum levels, which are responsible for the progression of cancer-associated cachexia [63]. In addition, it has been shown that carnitine administration can alleviate disorders of lipid metabolism. Beyond this, carnitine can decrease the serum levels of hepatic enzymes, including aspartate aminotransferase (AST), alanine aminotransferase (ALT), and triglyceride (TG), which are significantly elevated during irregular feeding in cancer patients [103].
Metabolic reprogramming and increased ATP demand are well-established hallmarks of cancers [104]. FAO plays a crucial role in providing ATP, NADH, FADH2, and NADPH, thus providing survival benefits to cancer cells. CPTI is a rate-limiting FAO enzyme that contributes to cancer metabolic adaptation, and its overexpression can fuel tumor growth in numerous tumor types [105]. CPTI can crosstalk with various cellular signaling pathways involved in cancer pathogenesis. In this regard, inhibition of CPTI may suppress cancer development [106]. From these studies, it can be inferred that carnitine has a beneficial impact on the management of cancer symptoms.
As discussed earlier, cancer cells require more energy than normal cells. In other words, energy demand increases with tumor aggressiveness and malignancy [107]. Normal cells meet their energy requirements through TCA and oxidative phosphorylation in the mitochondria (Figure 3) [108]. Under aerobic conditions, normal cells meet their energy demands through glycolysis in the cytosol, followed by oxidative phosphorylation within the mitochondria. Cancer cells alter their metabolism to support growth, survival, proliferation, and long-term maintenance [109]. Indeed, cancer cells prefer to obtain energy from glycolysis even in the abundance of oxygen, a phenomenon referred to as the “Warburg effect.” Glycolysis is much faster (100 times) than oxidative phosphorylation, even though the energy production is much lower. These events occur in the cytosol, even in the presence of functional mitochondria and abundant oxygen. Cancer cells bypass the mitochondrial respiratory chain, which synthesizes ATP. Such metabolic reprogramming has been observed in various cancer types. [110–112]. In addition to aerobic glycolysis, cancer cells can also stimulate fatty acid biosynthesis and glutamine consumption. Glutamine is considered the second crucial growth-supporting substrate in cancer cells. During metabolic adaptation, most cancer cells utilize glucose and glutamine as their primary carbon sources [113]. In cancer cells, mitochondrial function is not entirely impaired, and oxidative phosphorylation and TCA are still functioning [114]. In addition, there is increasing evidence that some cancers exhibit dual capacities for glycolysis and oxygen-consuming metabolism. Notably, metabolic flexibility exists in diverse cancers and cancers of the same type but at various stages. Metabolic plasticity can promote cancer cells growth, invasion, and metastatic behavior [16].
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And these Cantonese criminal dogs sons of chickens think they are so fucking smart when their lies kena busted in one Gansiokbin thread just move to another Gansiokbin thread and these Cantonese cancer dogs repeat lies to harm me can feel like winner call me loser liao. Knnbccb 真是贱！ 一边拿我好处，一边说谎害给他好处的人。根本就是恩将仇报，忘恩负义的狗。Getting Cantonese cancer is definitely called their RETRIBUTION PUI!
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