bims-aucach Biomed News
on Autophagy and cachexia
Issue of 2022–02–13
eight papers selected by
Kleiton Silva, Rowan University
  1. Curcumin Targeting NF-κB/Ubiquitin-Proteasome-System Axis Ameliorates Muscle Atrophy in Triple-Negative Breast Cancer Cachexia Mice.
  2. Serum IL-35 levels is a new candidate biomarker of cancer-related cachexia in stage IV non-small cell lung cancer.
  3. Nanotherapeutics in autophagy: a paradigm shift in cancer treatment.
  4. Beclin1-mediated interplay between autophagy and apoptosis: New understanding.
  5. At-Home Exercise Guide for People With Chronic Kidney Disease.
  6. Exercise protocols: The gap between preclinical and clinical exercise oncology studies.
  7. Dietary magnesium supplementation inhibits abdominal vascular calcification in an experimental animal model of chronic kidney disease.
  8. THE RELATIONSHIP BETWEEN MYOSTATIN, INFLAMMATORY MARKERS AND SARCOPENIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE.
  1. Mediators Inflamm. 2022 ;2022 2567150
    Curcumin Targeting NF-κB/Ubiquitin-Proteasome-System Axis Ameliorates Muscle Atrophy in Triple-Negative Breast Cancer Cachexia Mice.
    Jin Zhang, Jin Zheng, Haitao Chen, Xinrong Li, Chenxiao Ye, Fan Zhang, Zewei Zhang, Qinghua Yao, Yong Guo.
       Background: Curcumin is a polyphenol plant-derived compound with anti-inflammatory, antioxidant stress, and anticancer properties that make it have the potential to treat cancer cachexia. However, the role of it in breast cancer cachexia remains unclear.
    Methods: The 4T1 cells were subcutaneously injected into BALB/c mice to induce breast cancer cachexia. After tumor formation, the animals were divided into groups and given curcumin or saline interventions. The therapeutic effect of curcumin on breast cancer cachexia was characterized by tumor growth, changes in body mass and gastrocnemius mass, muscle function test, histopathology, and serum nutrition indexes. Mitochondrial function in muscle tissue was observed by transmission electron microscopy and ATP detection, muscle inflammatory factors were detected by ELISA, muscle differential metabolites were detected by 1HNMR metabolomics, and the muscle tissue ubiquitination levels and NF-KB expression were also analyzed by RT-qPCR and Western blot.
    Results: Dynamic in vivo bioluminescence imaging find that curcumin inhibited the growth of tumor in triple-negative breast cancer- (TNBC-) bearing mice, slowed down the loss of body weight and gastrocnemius weight, corrected the mitochondrial dysfunction and malnutrition status, and also significantly improved skeletal muscle function. ELISA analysis found that the level of inflammatory factors in muscle tissue was reduced. 1HNMR metabolomics analysis suggested that curcumin could regulate energy metabolism pathways. RT-qPCR and Western blot analysis found that the expression of myogenic factor myogenin was increased and the expression of myodegradation factor myostatin was decreased in the gastrocnemius; the level of ubiquitination and activation of the NF-κB pathway were also declined.
    Conclusions: Curcumin reduces ubiquitination, inflammation in skeletal muscle by regulating the NF-KB/UPS axis and improves muscle malignant metabolic phenotype and mitochondrial dysfunction, to alleviate muscle atrophy and loss of function in mice with breast cancer cachexia.
    DOI:  https://doi.org/10.1155/2022/2567150
  2. Thorac Cancer. 2022 Feb 09.
    Serum IL-35 levels is a new candidate biomarker of cancer-related cachexia in stage IV non-small cell lung cancer.
    Zengxun Li, Lei Zhu, Han Zheng, Wenna Jiang, Yifei Wang, Zhansheng Jiang, Jie Xu.
       BACKGROUND: Cancer-related cachexia is a major cause of treatment resistance and poor prognosis, which is characterized by anorexia and skeletal muscle depletion. To date, there have been no reports on the relationship between IL-35 and cancer-related cachexia in patients with stage IV non-small cell lung cancer.
    METHODS: Serum IL-35 levels in 86 patients with stage IV NSCLC were measured and statistically analyzed based on patients' clinicopathological parameters. Serum albumin levels, C-reactive protein, and skeletal muscle index (SMI) of the patients were also determined. In vivo studies using a mouse model were also conducted by subcutaneously injecting immunodeficiency (SCID) mice with overexpressing IL-35 cell lines and determining their daily food intake, bodyweight and muscle atrophy. Cachexia indicators were measured again after administering the mice with an anti-IL35 neutralizing antibody.
    RESULTS: Patients with stage IV NSCLC had significantly higher serum IL-35 levels than the healthy controls. Similarly, circulating IL-35 levels were significantly higher in patients with cachexia than those without. The SMI values of patients with high serum IL-35 levels were significantly lower than those with low serum IL-35 levels. Mice subcutaneously injected with LLC PLV-IL-35 cell lines exhibited anorexia, weight loss, and muscle atrophy. Moreover, these symptoms were significantly reduced after administering the mice with an anti-IL35 neutralizing antibody.
    CONCLUSIONS: This study reveals that high serum IL-35 expression is associated with non-small cell lung cancer cachexia and skeletal muscle atrophy. These findings highlight its potential as a biomarker and therapeutic target for controlling cachexia of advanced lung cancer.
    Keywords:  IL-35; SMI; cachexia; skeletal muscle atrophy; stage IV NSCLC
    DOI:  https://doi.org/10.1111/1759-7714.14307
  3. Drug Deliv Transl Res. 2022 Feb 11.
    Nanotherapeutics in autophagy: a paradigm shift in cancer treatment.
    Shloka Negi, Aiswarya Chaudhuri, Dulla Naveen Kumar, Deepa Dehari, Sanjay Singh, Ashish Kumar Agrawal.
      Autophagy is a catabolic process in which an organism responds to its nutrient or metabolic emergencies. It involves the degradation of cytoplasmic proteins and organelles by forming double-membrane vesicles called "autophagosomes." They sequester cargoes, leading them to degradation in the lysosomes. Although autophagy acts as a protective mechanism for maintaining homeostasis through cellular recycling, it is ostensibly a cause of certain cancers, but a cure for others. In other words, insufficient autophagy, due to genetic or cellular dysfunctions, can lead to tumorigenesis. However, many autophagy modulators are developed for cancer therapy. Diverse nanoparticles have been documented to induce autophagy. Also, the highly stable nanoparticles show blockage to autophagic flux. In this review, we revealed a general mechanism by which autophagy can be induced or blocked via nanoparticles as well as several studies recently performed to prove the stated fact. In addition, we have also elucidated the paradoxical roles of autophagy in cancer and how their differential role at different stages of various cancers can affect its treatment outcomes. And finally, we summarize the breakthroughs in cancer disease treatments by using metallic, polymeric, and liposomal nanoparticles as potent autophagy modulators.
    Keywords:  Apoptosis; Autophagosomes; Autophagy; Cancer; Chemotherapeutic agents; Nanoparticles
    DOI:  https://doi.org/10.1007/s13346-022-01125-6
  4. Int J Biol Macromol. 2022 Feb 07. pii: S0141-8130(22)00236-7. [Epub ahead of print]
    Beclin1-mediated interplay between autophagy and apoptosis: New understanding.
    Kumari Prerna, Vikash Kumar Dubey.
      The definition for autophagy holds a 'single' meaning as a conserved cellular process that constitutes a recycling pathway for damaged organelles and long-lived proteins to maintain nutrient homeostasis and mediate quality control within the cell. But this process of autophagy may behave ambiguously depending on the physiological stress as the stress progresses in the cellular microenvironment; the 'single' meaning of the autophagy changes from the 'cytoplasmic turnover process' to 'tumor suppressive' and a farther extent, 'tumor promoter' process. In a tumorigenic state, the chemotherapy-mediated resistance and intolerance due to upregulated autophagy in cancer cells have become a significant concern. This concern has provided insight to the scientific community to enter into the arena of cross-talk between autophagy and apoptosis. Recent findings and ongoing research have provided insights on some of the key regulators of this cross-talk; one of them is Beclin1 and their involvement in the physiological and the pathophysiological processes; however, reconciliation of these two forms of death remains an arena to be explored extensively. This review sheds light on the interplay between autophagy and apoptosis, emphasizing one of the key players, Beclin1, and its importance in health and diseases.
    Keywords:  Apoptosis; Autophagy; Bcl-2; Beclin1; Tumor promoter; Tumor suppressor
    DOI:  https://doi.org/10.1016/j.ijbiomac.2022.02.005
  5. Arch Phys Med Rehabil. 2022 Feb 04. pii: S0003-9993(21)01734-2. [Epub ahead of print]
    At-Home Exercise Guide for People With Chronic Kidney Disease.
      
    DOI:  https://doi.org/10.1016/j.apmr.2021.11.010
  6. Metabol Open. 2022 Mar;13 100165
    Exercise protocols: The gap between preclinical and clinical exercise oncology studies.
    Mahmoud Delphan, Neda Delfan, Daniel West, Maryam Delfan.
       Introduction: Preclinical studies provide foundational knowledge to develop new effective treatments for use in clinical practice. Similar to clinical exercise oncology studies, it is also important to monitor, identify and/or avoid cancer-induced complications in preclinical (e.g., murine) exercise oncology studies. This may help close the gap between preclinical and clinical exercise oncology studies. The aim of the present mini review is to provide insight into exercise protocol design in preclinical exercise oncology studies in order to close the preclinical-clinical gap. A secondary aim was to examine exercise-responsive outcomes in the preclinical versus clinical setting.
    Method: We reviewed animal studies in exercise oncology. A literature search was performed in PubMed/Medline and studies in English were screened.
    Results: We found that the majority of preclinical exercise protocols have not been at least tested clinically. We found some evidence that certain outcomes of preclinical studies (e.g., markers of cellular and molecular adaptation) that translate to clinical studies. However, this translation was dependent on the use, by investigators in their study design, of suitable and applicable preclinical exercise protocols.
    Conclusions: Cancer and its treatment-induced complications (e.g., fatigue, cardiac atrophy, cachexia, etc.) have largely been ignored in the exercise protocols of preclinical oncology studies. Preclinical exercise oncology studies should consider the limitations of human exercise oncology studies when conducting gap analysis for their study design to increase the probability that findings related to mechanistic adaptations in exercise oncology will be translatable to the clinical setting. By virtue of paying heed to patient compliance and adverse effects, clinical exercise oncology research teams must design relevant, feasible exercise protocols; researchers in preclinical exercise oncology should also take such factors into consideration in order to help bridge the gap between preclinical and clinical studies in exercise oncology.
    Keywords:  Cancer-induced complications; Clinical; Exercise Oncology; Exercise protocols; Gap analysis; Preclinical; Translational failure
    DOI:  https://doi.org/10.1016/j.metop.2022.100165
  7. Nephrol Dial Transplant. 2022 Feb 03. pii: gfac026. [Epub ahead of print]
    Dietary magnesium supplementation inhibits abdominal vascular calcification in an experimental animal model of chronic kidney disease.
    Nicoline H J Leenders, Caro Bos, Tiny Hoekstra, Leon J Schurgers, Marc G Vervloet, Joost G J Hoenderop.
       BACKGROUND: Vascular calcification is a key process involved in cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Magnesium supplementation may counteract vascular calcification. In this study, we aimed to determine whether an increased dietary magnesium intake inhibits vascular calcification in CKD in vivo and to explore the mechanisms underlying these effects.
    METHODS: Sprague Dawley rats were partially nephrectomized and fed a diet with high phosphate and either high or normal magnesium content for 16 weeks. Primary outcome was tissue calcium content of the aorta in the high versus normal dietary magnesium group. In addition, we analyzed plasma mineral concentrations, aortic vascular calcification identified with Von Kossa staining, calcium apposition time, and aortic expression of genes related to vascular calcification.
    RESULTS: The number of animals in the highest tissue calcium content tertile, was significantly lower in the abdominal aorta (1 [10%] vs. 6 [55%], p = 0.03) in the high versus normal dietary magnesium group, but did not differ in the aortic arch and thoracic aorta. Von Kossa staining and calcium apposition time corresponded to these results. Median tissue calcium content was not significantly different between the groups. Serum phosphate concentrations and expression of osteogenic markers in the aorta did not differ between the groups.
    CONCLUSIONS: This study demonstrates that increased dietary magnesium inhibits abdominal vascular calcification in an experimental animal model of CKD in vivo. These are promising results for CKD patients and further study is needed to identify the mechanisms involved and to determine clinical relevance in patients.
    Keywords:  chronic kidney disease (CKD); magnesium; vascular calcification
    DOI:  https://doi.org/10.1093/ndt/gfac026
  8. J Ren Nutr. 2022 Feb 02. pii: S1051-2276(22)00011-5. [Epub ahead of print]
    THE RELATIONSHIP BETWEEN MYOSTATIN, INFLAMMATORY MARKERS AND SARCOPENIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE.
    Emre Yasar, Nilüfer Acar Tek, Merve Yasemin Tekbudak, Gamze Yurtdaş, Özlem Gülbahar, Gizem Özata Uyar, Zeynep Ural, Özge Mengi Çelik, Yasemin Erten.
       OBJECTIVE: To determine the prevalence of sarcopenia in patients with chronic kidney disease (CKD), investigate the relationship of the serum myostatin level with sarcopenia and inflammatory markers.
    METHODS: The study was conducted with four patient groups: renal transplantation (TX), stage 3-5 non-dialysis-dependent CKD (NDD-CKD), hemodialysis (HD), and peritoneal dialysis (PD). Laboratory parameters, serum myostatin, C-reactive protein, and interleukin-6 ​​(IL-6) levels were studied. Body composition was estimated using a multifrequency bioimpedance analysis. Handgrip strength (HGS) was evaluated with a handgrip dynamometer. The HGS and appendicular skeletal muscle index (ASMI) measurements were used to determine sarcopenia presence.
    RESULTS: The study included 130 patients [72(55%) males]. The patient distribution in groups was as follows: 37 in HD, 28 in PD, 37 in renal TX, and 28 in NDD-CKD. The highest level of myostatin was measured in the HD group and the lowest in the TX group (p<0.001). The HGS measurement was significantly lower only in the PD group compared to the TX group (p=0.025). The myostatin was negatively correlated with HGS, albumin, estimated glomerular filtration rate, and Kt/Vurea. However, myostatin had no correlation with inflammatory markers or ASMI. Sarcopenia was present in 37 (29%) of all patients: 15 (40%) in the HD group, nine (32%) in NDD-CKD, seven (25%) in PD, and six (16%) in TX. When the patients with and without sarcopenia were compared, only myostatin was higher in the former (p=0.045). As a result of multivariate analysis, myostatin was the only independent factor which predict sarcopenia (OR: 1.002, 95% CI:1.001-1.005, p=0.048).
    CONCLUSION: To prevent devastating events associated with sarcopenia in patients with CKD, renal transplantation seems to be the best treatment solution. For the early recognition of sarcopenia, the measurement of the serum myostatin level may be a promising diagnostic approach.
    Keywords:  dialysis; inflammatory markers; myostatin; sarcopenia; transplantation
    DOI:  https://doi.org/10.1053/j.jrn.2022.01.011
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