Astaxanthin Ameliorates Skeletal Muscle Atrophy in Mice With Cancer Cachexia.

Astaxanthin (AST) is a natural marine carotenoid with a variety of biological activities. This study aimed to demonstrate the possible mechanisms by which AST improves skeletal muscle atrophy in cancer cachexia. In this study, the effects of different doses of AST (30 mg/kg b.w., 60 mg/kg b.w. and 120 mg/kg b.w.) on skeletal muscle functions were explored in mice with cancer cachexia. The results showed that AST (30, 60 and 120 mg/kg b.w.) could effectively protect cachexia mice from body weight and skeletal muscle loss. AST dose-dependently ameliorated the decrease in myofibres cross-sectional area and increased the expression of myosin heavy chain (MHC). AST treatment decreased both the serum and muscle level of IL-6 but not TNF-α in C26 tumor-bearing cachexia mice. Moreover, AST alleviated skeletal muscle atrophy by decreasing the expression of two muscle-specific E3 ligases MAFBx and MuRF-1. AST improved mitochondrial function by downregulating the levels of muscle Fis1, LC3B and Bax, upregulating the levels of muscle Mfn2 and Bcl-2. In conclusion, our study show that AST might be expected to be a nutritional supplement for cancer cachexia patients.

Ursolic acid alleviates cancer cachexia by inhibiting STAT3 signaling pathways in C2C12 myotube and CT26 tumor-bearing mouse model.

Cancer cachexia, a multi-organ disorder resulting from tumor and immune system interactions, prominently features muscle wasting and affects the survival of patients with cancer. Ursolic acid (UA) is known for its antioxidant, anti-inflammatory, and anticancer properties. However, its impact on cancer cachexia remains unexplored. This study aimed to assess the efficacy of UA in addressing muscle atrophy and organ dysfunction in cancer cachexia and reveal the mechanisms involved. UA dose-dependently ameliorated C2C12 myotube atrophy. Mechanistically, it inhibited the expression of muscle-specific RING finger containing protein 1 (MURF1) and the phosphorylation of signal transducer and activator of transcription 3 (STAT3), and upregulated the mRNA or protein levels of myogenic differentiation antigen and myogenin in cultured C2C12 myotubes treated with conditioned medium. In vivo, UA protected CT26 tumor-bearing mice against loss of body weight, as well as increased skeletal muscle and epididymal fat without affecting tumor growth. Additionally, UA increased food intake in CT26 tumor-bearing mice. The mRNA expression of tumor necrosis-α and interleukin 6 was significantly downregulated in the intestine, gastrocnemius, and heart tissues following 38 d UA administration. UA treatment reversed the levels of myocardial function indicators, including creatine kinase, creatine kinase-MB, lactate dehydrogenase, car-dial troponin T, and glutathione. Finally, UA treatment significantly inhibited the expression of MURF1, the phosphorylation of nuclear factor kappa-B p65, and STAT3 in the gastrocnemius muscle and heart tissues of cachexic mice. Our findings suggest that UA is a promising natural compound for developing dietary supplements for cancer cachexia therapy owing to its anti-catabolic effects.

A dose-response meta-analysis of randomized clinical trials investigating the effects of omega-3 supplementation on body weight in patients with cancer cachexia.

BACKGROUND: Cachexia is one of the side effects of cancer diseases that can be reduced weight, and lower overall survival. Weight loss has been associated with adverse outcomes in both cancer patients and patients with benign diseases. There is no definitive treatment for fully reverse cachexia. studies showed higher levels of inflammatory markers in patient with cachectic cancer. Therefore, this study aimed to investigate the dose-response effects of omega-3 as an anti-inflammatory supplement on body weight in patients with cancer cachexia. METHODS: Online databases including PubMed, Scopus, and Web of Science were systematically searched by relevant keywords up to January 2022. Random effect analysis was applied to perform meta-analysis. Subgroup analyses were performed to find heterogeneity sources. Quality assessment was conducted using Revised Cochrane Collaboration's tool II. Trim and fill analysis were also carried out in case of the presence of publication bias. The certainty in the evaluations was assessed by the GRADE approach. RESULTS: Omega-3 supplementation resulted in a significant increase of body weight in patients with cancer cachexia when the age of study participants was ≥67 years and the baseline weight of them was ≤60 kg (WMD = 0.99; 95 % CI: 0.06, 1.92 and WMD = 1.22; 95 % CI: 0.14, 2.30, respectively). Also, there was a non-significant linear relationship between the dosage of omega-3 supplementation and body weight in patients with cancer cachexia. CONCLUSION: Omega-3 supplementation may be a promising agent to increase body weight in patients with cancer cachexia. Also, a non-significant linear relationship between the dosage of omega-3 supplementation and body weight was found in these patients.

Energy preservation for skeletal muscles: Shenqi Fuzheng injection prevents tissue wasting and restores bioenergetic profiles in a mouse model of chemotherapy-induced cachexia.

BACKGROUND: Energy deficiency is the characteristic of chemotherapy-induced cachexia (CIC) which is manifested by muscle wasting. glycolysis, tricarboxylic acid (TCA) cycle, and lipid metabolism are central to muscle bioenergy production, which is vulnerable to chemotherapy during cancer treatment. Recent investigations have spotlighted the potential of Shenqi Fuzheng injection (SQ), a Chinese proprietary medicine comprising Radix Codonopsis and Radix Astragali, in alleviating CIC. However, the specific effects of SQ on muscle energy metabolism remains less explored. PURPOSE AND METHODS: Here, we integrated transcriptomics, spatial metabolomics, gas chromatography-mass spectrometry targeted quantitative analysis, and transmission electron microscopy techniques, combined with Seahorse live-cell metabolic analysis to reveal the changes in genes and pathways related to energy metabolism in the CIC model and SQ's protective effects at molecular and functional levels. RESULTS: Our data showed that chemotherapeutic agents caused glycolysis imbalance, which further leads to metabolic derangements of TCA cycle intermediates. SQ maintained glycolysis balance by facilitating pyruvate fluxing to mitochondria for more efficient bioenergy production, which involved a dual effect on promoting functions of mitochondrial pyruvate dehydrogenase complexes and inhibiting lactate dehydrogenase for lactate production. As a result of the sustained pyruvate level achieved by SQ administration, glycolysis balance was maintained, which further led to the preservation of mitochondrial integrity and function of electron transport chain, thereby, ensuring the normal operation of the TCA cycle and the proper synthesis of adenosine triphosphate (ATP). The above results were further validated using the Seahorse live-cell assay. CONCLUSION: In conclusion, our study highlights SQ as a promising strategy for CIC management, emphasizing its ability to harmonize the homeostasis of the muscle bioenergetic profile. Beyond its therapeutic implications, this study also offers a novel perspective for the development of innovative treatments in the realm of herbal medicine.

Relevance of Dietary Supplement Use in Gastrointestinal-Cancer-Associated Cachexia.

Cancer cachexia is a multi-organ syndrome with unintentional weight loss, sarcopenia, and systemic inflammation. Gastrointestinal (GI) cancer patients are more susceptible to cachexia development due to impaired nutrient absorption and digestion. Given the widespread availability and relatively low cost of dietary supplements, we examined the evidence and effects of fish oil (omega-3 fatty acids), melatonin, probiotics, and green tea for managing symptoms of GI cancer cachexia. A literature review of four specific supplements was conducted using PubMed, Google Scholar, and CINAHL without a date restriction. Of 4621 available literature references, 26 articles were eligible for review. Fish oil decreased C-reactive protein and maintained CD4+ cell count, while melatonin indicated inconsistent findings on managing cachexia, but was well-tolerated. Probiotics decreased serum pro-inflammatory biomarkers and increased the tolerability of chemotherapy by reducing side effects. Green tea preparations and extracts showed a decreased risk of developing various cancers and did not impact tumor growth, survival, or adverse effects. Among these four supplements, probiotics are most promising for further research in preventing systemic inflammation and maintaining adequate absorption of nutrients to prevent the progression of cancer cachexia. Supplements may benefit treatment outcomes in cancer cachexia without side effects while supporting nutritional and therapeutic needs.

The Role of Natural Products in the Improvement of Cancer-Associated Cachexia.

The enormous library of natural products and herbal medicine prescriptions presents endless research avenues. However, the lack of research evidence and trials on cancer-induced cachexia limit the therapeutic potential of natural products. Cancer-induced cachexia is a systemic wasting syndrome characterized by continuous body weight loss with skeletal muscle and adipose tissue atrophy. Cancer cachexia is a problem in itself and reduces the quality of life by lessening the treatment efficacy of anticancer drugs. This review summarizes single natural product extracts for cancer-induced cachexia, not compounds derived from natural products and herbal medicine prescriptions. This article also discusses the effect of natural products on cachexia induced by anticancer drugs and the role of AMPK in cancer-induced cachexia. The article included the mice model used in each experiment to encourage researchers to utilize animal models for research on cancer-induced cachexia in the future.

Astaxanthin Supplementation Assists Sorafenib in Slowing Skeletal Muscle Atrophy in H22 Tumor-Bearing Mice via Reversing Abnormal Glucose Metabolism.

SCOPE: Cachexia, which is often marked by skeletal muscular atrophy, is one of the leading causes of death in cancer patients. Astaxanthin, a carotenoid obtained from marine organisms that can aid in the prevention and treatment of a variety of disorders. In this study, to assess whether astaxanthin ameliorates weight loss and skeletal muscle atrophy in sorafenib-treated hepatocellular carcinoma mice is aimed. METHODS AND RESULTS: H22 mice are treated with 30 mg kg-1  day-1 of sorafenib and 60 mg kg-1  day-1 of astaxanthin by gavage lasted for 18 days. Sorafenib does not delay skeletal muscle atrophy and weight loss, although it does not reduce tumor burden. Astaxanthin dramatically delays weight loss and skeletal muscle atrophy in sorafenib-treating mice, without affecting the food intake. Astaxanthin inhibits the tumor glycolysis, slows down gluconeogenesis, and improves insulin resistance in tumor-bearing mice. Astaxanthin increases glucose competition in skeletal muscle by targeting the PI3K/Akt/GLUT4 signaling pathway, and enhances glucose utilization efficiency in skeletal muscle, thereby slowing skeletal muscle atrophy. CONCLUSION: The findings show the significant potential of astaxanthin as nutritional supplements for cancer patients, as well as the notion that nutritional interventions should be implemented at the initiation of cancer treatment, as instead of waiting until cachexia sets in.

Babao Dan Alleviates Cancer Cachexia in Mice Via Inhibiting IL-6/STAT3 Signaling Pathway.

BACKGROUND: Cancer cachexia is a common but severe condition that causes muscle wasting, body weight loss, and progressive functional impairment, affecting over 50% of cancer patients. Currently, there are no effective treatments that can alleviate cachexia, and hence the discovery of new therapeutics that can effectively prevent or even reverse cancer cachexia is crucial. Babao Dan (BBD) is a Traditional Chinese Medicine (TCM) formula that has been used clinically in combating various cancers, however, its therapeutic potential in alleviating cancer cachexia remains unexplored. Our current study aims to determine the anti-cachectic effects of BBD treatment in alleviating cancer cachexia, as well as determining the underlying mechanisms involved. METHODS: Mouse models of cancer cachexia were induced via implantation of CT26 colon adenocarcinoma cells, and the anti-cachectic effects and mechanisms of BBD were determined via examinations of body weight and muscle mass, as well as serum and muscle markers of cachexia and muscle atrophy. RESULTS: CT26 tumor implantation reduced in the rapid occurrence of cancer cachexia characterized by marked reductions in body weight and muscle mass, functional decrease in muscle function and accelerated deaths. BBD administration not only demonstrated robust anti-cachectic ability via preventing decreases in body weight, muscle mass, and muscle atrophy, but also markedly prolonged survival. The effects of BBD in alleviating cancer cachexia and its associated adverse effects were due to its ability in preventing the activation of IL-6/STAT3 signaling post-CT26 tumor implantation. CONCLUSION: Our findings demonstrated the robust ability of BBD in preventing cancer cachexia and alleviating the main cachexia-induced symptoms as well as prolonging survival via inhibiting activation of IL-6/STAT3 signaling pathway. Therefore, our study demonstrating the strong anti-cachectic effects of BBD in mice may provide a theoretical basis for the use of BBD as a safe and effective drug in the treatment of cancer cachexia.

Cucurbitacin IIb attenuates cancer cachexia induced skeletal muscle atrophy by regulating the IL-6/STAT3/FoxO signaling pathway.

The main features of cancer cachexia include skeletal muscle atrophy, which can significantly reduce the quality of life of patients. Clinical treatment of cancer cachexia is mainly based on nutritional therapy and physical exercise; medication only improves appetite but does not reverse the symptoms of skeletal muscle wasting. In this work, we systematically studied the underlying molecular mechanisms by which cucurbitacin IIb (CuIIb) ameliorates muscle wasting in cancer cachexia both in vitro and in vivo. CuIIb significantly ameliorated the chief features of cancer cachexia in vivo, alleviating weight loss, food intake, muscle wasting, adipose tissue depletion, and organ weight reductions. In vitro, CuIIb (10 and 20 µM) dose-dependently attenuated conditioned medium (CM)-induced C2C12 myotube atrophy. Collectively, our findings demonstrated that CuIIb prevented the upregulation of the E3 ubiquitin ligase muscle atrophy Fbox protein (MAFbx), myosin heavy chain (MyHC), and myogenin (MyoG) and impacted protein synthesis and degradation. In addition, CuIIb decreased the phosphorylation of Tyr705 in STAT3 by regulating the IL-6/STAT3/FoxO pathway to reduce skeletal muscle atrophy in cancer cachexia.

Curcumin treatment suppresses cachexia-associated adipose wasting in mice by blocking the cAMP/PKA/CREB signaling pathway.

BACKGROUND: Cachexia is a multifactorial debilitating syndrome that is responsible for 22% of mortality among cancer patients, and there are no effective therapeutic agents available. Curcumin, a polyphenolic compound derived from the plant turmeric, has been shown to have anti-inflammatory, antioxidant, anti-autophagic, and antitumor activities. However, its function in cancer cachexia remains largely unexplored. PURPOSE: This study aimed to elucidate the mechanisms by which curcumin improves adipose atrophy in cancer cachexia. METHODS: C26 tumor-bearing BALB/c mice and ß3-adrenoceptor agonist CL316243 stimulated BALB/c mice were used to observe the therapeutic effects of curcumin on the lipid degradation of cancer cachexia in vivo. The effects of curcumin in vitro were examined using mature 3T3-L1 adipocytes treated with a conditioned medium of C26 tumor cells or CL316243. RESULTS: Mice with C26 tumors and cachexia were protected from weight loss and adipose atrophy by curcumin (50 mg/kg, i.g.). Curcumin significantly reduced serum levels of free fatty acids and increased triglyceride levels. In addition, curcumin significantly inhibited PKA and CREB activation in the adipose tissue of cancer cachectic mice. Curcumin also ameliorated CL316243-induced adipose atrophy and inhibited hormone-mediated PKA and CREB activation in mice. Moreover, the lipid droplet degradation induced by C26 tumor cell conditioned medium in mature 3T3-L1 adipocytes was ameliorated by curcumin (20 µM) treatment. Curcumin also improved the lipid droplet degradation of mature 3T3-L1 adipocytes induced by CL316243. CONCLUSION: Curcumin might be expected to be a therapeutic supplement for cancer cachexia patients, primarily through inhibiting adipose tissue loss via the cAMP/PKA/CREB signaling pathway.

Saikosaponin D alleviates cancer cachexia by directly inhibiting STAT3.

Cancer cachexia is a metabolic syndrome that is characterized by progressive loss of skeletal muscle mass, and effective therapeutics have yet to be developed. Saikosaponin D (SSD), a major bioactive component of Radix Bupleuri, exhibits antiinflammatory, anti-tumor, anti-oxidant, anti-viral, and hepatoprotective effects. In this study, we demonstrated that SSD is a promising agent for the treatment of cancer cachexia. SSD could alleviate TCM-induced myotube atrophy and inhibit the expression of E3 ubiquitin ligases muscle RING-finger containing protein-1 (MuRF1) and muscle atrophy Fbox protein (Atrogin-1/MAFbx) in vitro. Moreover, SSD suppressed the progression of cancer cachexia, with significant improvements in the loss of body weight, gastrocnemius muscle, and tibialis anterior muscle mass in vivo. Mechanism investigations demonstrated that SSD could directly bind to STAT3 and specifically inhibit its phosphorylation as well as its transcriptional activity. Overexpression of STAT3 partially abolished the inhibitory effect of SSD on myotube atrophy, indicating that the therapeutic effect of SSD was attributed to STAT3 inhibition. These findings provide novel strategies for treatment of cancer cachexia by targeting STAT3, and SSD may be a promising drug candidate for cancer cachexia.

Fuzheng Xiaoai Decoction 1 ameliorated cancer cachexia-induced muscle atrophy via Akt-mTOR pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Fuzheng Xiaoai Decoction 1 (FZXAD1) is a clinical experience prescription for the treatment of cancer patients at an advanced stage. FZXAD1 has been used for more than 10 years in the clinic and can effectively improve the deficiency syndrome of cancer patients. However, its mechanisms need further clarification. AIM OF THE STUDY: To check the effects of FZXAD1 in colon 26 (C26) cancer cachexia mice and try to clarify the mechanisms of FZXAD1 in ameliorating cancer cachexia symptoms. MATERIALS AND METHODS: An animal model of cancer cachexia was constructed with male BALB/c mice bearing C26 tumor cells. Food intake, body weight and tumor size were measured daily during the animal experiment. Tissue samples in different groups including tumor and gastrocnemius muscle, were dissected and weighed at the end of the assay. Serum biochemical indicators such as total protein (TP), glucose (GLU) and alkaline phosphatase (ALP) were also detected. Network pharmacology-based analysis predicted the possible targets and signaling pathways involved in the effects of FZXAD1 on cancer cachexia therapy. Western blotting assays of the gastrocnemius muscle tissues from C26 tumor-bearing mice were then used to confirm the predicted possible targets of FZXAD1. RESULTS: The results of animal experiments showed that FZXAD1 could ameliorate cancer cachexia by alleviating the muscle wasting as well as kidney atrophy and increasing the body weight of cancer cachexia mice. AKT1, MTOR, MAPK3, HIF1A and MAPK1 were predicted as the core targets of FZXAD1. Western blotting confirmed the prediction that FZXAD1 increased the expression levels of phosphorylated Akt and mTOR in the muscle tissues. In addition, FZXAD1 treatment obviously ameliorated the increased levels of HIF-1α and phosphorylated Erk1/2 in C26 tumor-bearing mice. CONCLUSION: FZXAD1 effectively ameliorated cancer cachexia in an animal model of mice, which is consistent with its efficacy in the treatment of cancer patients. The mechanisms of FZXAD1 might be mainly based on its alleviating effects on muscle atrophy by activating the Akt-mTOR pathway and thus helping to maintain body weight.

A triple-masked, two-center, randomized parallel clinical trial to assess the superiority of eight weeks of grape seed flour supplementation against placebo for weight loss attenuation during perioperative period in patients with cachexia associated with colorectal cancer: a study protocol.

Background: Progressive, involuntary weight and lean mass loss in cancer are linked to cachexia, a prevalent syndrome in gastrointestinal malignancies that impacts quality of life, survival and postoperative complications. Its pathophysiology is complex and believed to involve proinflammatory cytokine-mediated systemic inflammation resulting from tumor-host interaction, oxidative stress, abnormal metabolism and neuroendocrine changes. Therapeutic options for cachexia remain extremely limited, highlighting the need for clinical research targeting new interventions. Thus, this study primarily assesses the effects of grape-seed flour (GSF), rich in polyphenols and fibers, for attenuating perioperative weight loss in colorectal cancer. Methods: This is a dual-center, triple-masked, placebo-controlled, parallel-group, phase II, randomized clinical trial designed to investigate GSF supplementation in subjects with pre- or cachexia associated with colorectal cancer during the perioperative period. Eighty-two participants will receive 8g of GSF or cornstarch (control) for 8 weeks. Assessments are scheduled around surgery: pre-intervention (4 weeks prior), day before, first week after, and post-intervention (4 weeks later). The primary endpoint is the difference in body weight mean change from baseline to week 8. The secondary endpoints describe the harms from 8-week supplementation and assess its superiority to improve body composition, post-surgical complications, quality of life, anorexia, fatigue, gastrointestinal symptoms, and handgrip strength. The study will also explore its effects on gut bacteria activity and composition, systemic inflammation, and muscle metabolism. Discussion: The current trial addresses a gap within the field of cancer cachexia, specifically focusing on the potential role of a nutritional intervention during the acute treatment phase. GSF is expected to modulate inflammation and oxidative stress, both involved in muscle and intestinal dysfunction. The research findings hold substantial implications for enhancing the understanding about cachexia pathophysiology and may offer a new clinical approach to managing cachexia at a critical point in treatment, directly impacting clinical outcomes. Trial registration: The Brazilian Registry of Clinical Trials (ReBEC), RBR-5p6nv8b; UTN: U1111-1285-9594. Prospectively registered on February 07, 2023.

Phytochemicals: A potential therapeutic intervention for the prevention and treatment of cachexia.

Cachexia, a multifactorial and often irreversible wasting syndrome, is often associated with the final phase of several chronic disorders. Although cachexia is characterized by skeletal muscle wasting and adipose tissue loss, it is a syndrome affecting different organs, which ultimately results in systemic complications and impaired quality of life. The pathogenesis and underlying molecular mechanisms of cachexia are not fully understood, and currently there are no effective standard treatments or approved drug therapies to completely reverse cachexia. Moreover, adequate nutritional interventions alone cannot significantly improve cachexia. Other approaches to ameliorate cachexia are urgently needed, and thus, the role of medicinal plants has received considerable importance in this respect due to their beneficial health properties. Increasing evidence indicates great potential of medicinal plants and their phytochemicals as an alternative and promising treatment strategy to reduce the symptoms of many diseases including cachexia. This article reviews the current status of cachexia, the molecular mechanisms of primary events driving cachexia, and state-of-the-art knowledge that reports the preventive and therapeutic activities of multiple families of phytochemical compounds and their pharmacological mode of action, which may hold promise as an alternative treatment modality for the management of cachexia. Based on our review of various in vitro and in vivo models of cachexia, we would conclude that phytochemicals may have therapeutic potential to attenuate cachexia, although clinical trials are required to unequivocally confirm this premise.

Omega-3 polyunsaterated fatty acids improve quality of life and survival, but not body weight in cancer cachexia: A systematic review and meta-analysis of controlled trials.

Several clinical trials have reported that patients with cancer cachexia can benefit from n-3 polyunsaturated fatty acids (n-3 PUFAs) supplements; however, the results have been conflicting. This systematic review and meta-analysis aimed to evaluate the effect of n-3 PUFAs on cancer cachexia. A search of the PubMed, Embase, and Cochrane Library databases was performed to identify the included randomized controlled trials. Trials including patients with cancer cachexia who were administered a course of n-3 PUFAs were included. A meta-analysis on body weight, lean body weight, proinflammatory factors, quality of life, and median duration of survival was conducted. A total of 12 randomized controlled trials with 1184 patients were included. No effect on body weight (standard mean difference [SMD], 0.10; 95% CI, -0.06 to 0.26; P = .236), lean body weight (SMD, -0.17; 95% CI, -0.36 to 0.03, P = .095), or proinflammatory factors (interleukin-6: SMD, 0.31; 95% CI, -0.14 to 0.75; P = .18; tumor necrosis factor-α: SMD, -0.85; 95% CI, -2.39 to 0.69; P = .28) was observed. The use of n-3 PUFAs was associated with a significant improvement in quality of life (SMD, 0.70; 95% CI, 0.01-1.40; P = .048) and median duration of survival (median survival ratio, 1.10; 95% CI, 1.02-1.19; P = .014). For patients with cancer cachexia, our meta-analysis indicated that n-3 PUFAs improved quality of life and survival, but not body weight.

Atractylenolide I ameliorates cancer cachexia through inhibiting biogenesis of IL-6 and tumour-derived extracellular vesicles.

BACKGROUND: Atractylenolide I (AI) is a natural sesquiterpene lactone isolated from Atractylodes macrocephala Koidz, known as Baizhu in traditional Chinese medicine. AI has been found to ameliorate cancer cachexia in clinic cancer patients and in tumour-bearing mice. Here, we checked the influence of AI on biogenesis of IL-6 and extracellular vesicles (EVs) in cancer cachexia mice and then focused on studying mechanisms of AI in inhibiting the production of tumour-derived EVs, which contribute to the ameliorating effects of AI on cancer cachexia. METHODS: C26 tumour-bearing BALB/c mice were applied as animal model to examine the effects of AI (25 mg/kg) in attenuating cachexia symptoms, serum IL-6 and EVs levels. IL-6 and EVs secretion of C26 tumour cells treated with AI (0.31-5 µM) was further observed in vitro. The in vitro cultured C2C12 myotubes and 3T3-L1 mature adipocytes were used to check the potency of conditioned medium of C26 cells treated with AI (0.625-5 µM) in inducing muscle atrophy and lipolysis. The glycolysis potency of C26 cells under AI (0.31-5 µM) treatment was evaluated by measuring the extracellular acidification rate using Seahorse XFe96 Analyser. Levels of related signal proteins in both in vitro and in vivo experiments were examined using western blotting to study the possible mechanisms. STAT3 overexpression or knockout C26 cells were also used to confirm the effects of AI (5 µM). RESULTS: AI ameliorated cancer cachexia symptoms (P < 0.05), improved grip strength (P < 0.05) and decreased serum EVs (P < 0.05) and IL-6 (P < 0.05) levels of C26 tumour-bearing mice. AI directly inhibited EVs biogenesis (P < 0.001) and IL-6 secretion (P < 0.01) of cultured C26 cells. The potency of C26 medium in inducing C2C12 myotube atrophy (+59.54%, P < 0.001) and 3T3-L1 adipocyte lipolysis (+20.73%, P < 0.05) was significantly attenuated when C26 cells were treated with AI. AI treatment inhibited aerobic glycolysis and the pathway of STAT3/PKM2/SNAP23 in C26 cells. Furthermore, overexpression of STAT3 partly antagonized the effects of AI in suppressing STAT3/PKM2/SNAP23 pathway, EVs secretion, glycolysis and the potency of C26 medium in inducing muscle atrophy and lipolysis, whereas knockout of STAT3 enhanced the inhibitory effect of AI on these values. The inhibition of AI on STAT3/PKM2/SNAP23 pathway was also observed in C26 tumour tissues. CONCLUSIONS: AI ameliorates cancer cachexia by decreasing the production of IL-6 and EVs of tumour cells. The decreasing effects of AI on EVs biogenesis are based on its inhibition on STAT3/PKM2/SNAP23 pathway.

Nutritional Interventions to Improve Cachexia Outcomes in Cancer-A Systematic Review.

Background and Objectives: The prevalence of cachexia has increased across all of the cancer types and accounts for up to 20% of cancer-related deaths. This paper is a systematic review of nutritional interventions aiming to improve cachexia outcomes in cancer, focusing on weight gain. Materials and Methods: A search in Medline and Elsevier databases for articles up until the 23 January 2022, was conducted. Results: Out of 5732 screened records, 26 publications were included in the final analysis. Four randomized clinical trials showed a significant body weight (BW) increase in patients treated with eicosapentaenoic acid (EPA), ß-hydroxy-beta-methyl butyrate (ß-HMB), arginine, and glutamine or marine phospholipids (MPL). An upward BW trend was observed in patients treated with L-carnitine, an Ethanwell/Ethanzyme (EE) regimen enriched with ω-3 fatty acids, micronutrients, probiotics, fish oil, a leucine-rich supplement, or total parental nutrition (TPN) with a high dose of a branched-chain amino acid (BCAA). Conclusions: Although clinical trials relating to large numbers of nutritional supplements present promising data, many trials provided negative results. Further studies investigating the underlying mechanisms of action of these nutritional supplements in cancer cachexia are needed. Early screening for cancer cachexia risk and nutritional intervention in cancer patients before aggravating weight loss may stabilize their weight, preventing cachexia syndrome. According to the GRADE methodology, no positive recommendation for these nutritional supplements may be expressed.

Leucine Supplementation in Cancer Cachexia: Mechanisms and a Review of the Pre-Clinical Literature.

Cancer cachexia (CC) is a complex syndrome of bodily wasting and progressive functional decline. Unlike starvation, cachexia cannot be reversed by increased energy intake alone. Nonetheless, targeted nutritional support is a necessary component in multimodal syndrome management. Due to the highly catabolic nature of cancer cachexia, amino acid supplementation has been proposed. Interestingly, leucine has been found to increase protein synthesis and decrease protein degradation via mTORC1 pathway activation. Multiple pre-clinical studies have explored the impact of leucine supplementation in cachectic tumor-bearing hosts. Here, we provide an overview of leucine's proposed modes of action to preserve lean mass in cachexia and review the current pre-clinical literature related to leucine supplementation during CC. Current research indicates that a leucine-rich diet may attenuate CC symptomology; however, these works are difficult to compare due to methodological differences. There is need for further pre-clinical work exploring leucine's potential ability to modulate protein turnover and immune response during CC, as well as the impact of additive leucine on tumor growth.

Taurine Supplementation Inhibits the Expression of Atrogin-1 and MURF-1, Protein Degradation Marker Genes, in Skeletal Muscle of C26-Induced Cachexia Mouse Model.

This study was designed to investigate the therapeutic effects of taurine in attenuating muscle atrophy. C26 carcinoma cells were cultured and injected into the scapulae of Balb/c mice with 1 × 106 cells. Taurine (200 µl suspension) was orally administered at the concentration of 200 mg/kg of body weight for 2 weeks. Femur muscle tissue, spleen, and gonadal fat tissue were collected and weighed. Muscle tissue was stained by H&E for histopathological analysis. The transcriptional expression of atrogin-1 and MuRF-1 gene was checked by real-time PCR. C26 cells, which induced tumor growth, caused a loss in muscle mass and gonadal fat tissue mass. Simultaneously, there was an increase in spleen and tumor tissue mass. In contrast, taurine supplementation showed a downregulatory effect on the transcriptional expression profile of muscle degradative factors atrogin-1 and MuRF-1. Our findings suggest that taurine has the potential to inhibit muscle atrophy and can be developed as a safe treatment option against muscle loss in sarcopenia patients.

A Double-Blind, Placebo-Controlled Randomized Phase IIa Study: Evaluating the Effect of Curcumin for Treatment of Cancer Anorexia-Cachexia Syndrome in Solid Cancer Patients.

OBJECTIVE: We aim to investigate the effect of curcumin on preventing cancer anorexia-cachexia syndrome (CACS) via through mechanism of inhibition on NF-kB signal pathway. Outcome measurement for primary end point was improvement of body tissue composition, and the secondary end points were body weight and body mass index, hand grip muscle strengthening, and safety. METHODS: This is randomized, double-blind, placebo-controlled phase ll a study, 33 patients with CACS in solid malignancy were enrolled and randomized in 1:1 to receive oral curcumin (at a dose of 800 mg twice daily) or placebo for 8 weeks. RESULTS: All parameters of body compositions were not statistically significant different between two groups, which were consist body fat mass [-1.25(SEM 0.87) vs. +0.63(SEM 0.55); p=0.119], skeletal muscle mass [-0.35(SEM 0.60) vs.+0.33(SEM 0.42); p=0.408] and percent body fat [-0.47(SEM 0.95) vs. -0.29(SEM 0.82); p=0.893] including with basal metabolic rate [-13.47(SEM 21.94) vs. +15.30(13.76); p=0.336]. The average of weight loss was also not statistically significant different between two groups. [-1.4 kg(SEM 0.89) in curcumin vs-1.12 kg(SEM 0.73), p=0.810]. Notably, patient with curcumin had less reduction of hand-grip muscle strength on both hands [Rt. handed: -2.47 in curcumin vs. -5.36 in placebo; p=0.318] [Lt. handed: -1.98 vs. -5.43; p=0.317], and basal metabolic rate than placebo group. Most adverse events were grade 1 on both groups similarly. CONCLUSION: Curcumin was not shown to be superior to placebo with regard to increasing the body composition in cancer patients with CACS. However, curcumin might show some clinical benefits, including slow progression of hand-grip muscle strength loss, and basal metabolic rate. Further investigations should be explored.