bims-aucach Biomed News
on Autophagy and cachexia
Issue of 2022‒01‒09
nineteen papers selected by
Kleiton Silva
Rowan University
  1. Nek4 regulates mitochondrial respiration and morphology.
  2. Skeletal muscle phenotyping of Hippo gene-mutated mice reveals that Lats1 deletion increases the percentage of type I muscle fibers.
  3. Assessing mitochondrial respiration in permeabilized fibres and biomarkers for mitochondrial content in human skeletal muscle.
  4. Factors Mediating Exercise-induced Organ Crosstalk.
  5. Filamin C regulates skeletal muscle atrophy by stabilizing dishevelled-2 to inhibit autophagy and mitophagy.
  6. Renal failure suppresses muscle irisin expression, and irisin blunts cortical bone loss in mice.
  7. Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19.
  8. Reducing sarcolipin expression improves muscle metabolism in mdx mice.
  9. Myostatin gene inactivation increases post-mortem calpain-dependent muscle proteolysis in mice.
  10. Obesity attenuates inflammation, protein catabolism, dyslipidaemia, and muscle weakness during sepsis, independent of leptin.
  11. Patient-centred approaches for the management of unpleasant symptoms in kidney disease.
  12. PINK1 deficiency in gastric cancer compromises mitophagy, promotes the Warburg effect, and facilitates M2 polarization of macrophages.
  13. Therapeutic potential of Beclin1 for transition from AKI to CKD: autophagy-dependent and autophagy-independent functions.
  14. Biological Functions and Therapeutic Potential of Autophagy in Spinal Cord Injury.
  15. Autophagy in cancer: The cornerstone during glutamine deprivation.
  16. An Internal Review of Rates of Palliative Medicine Referral for Patients With Advanced Pancreatic Cancer.
  17. Advances in the Progression and Prognosis Biomarkers of Chronic Kidney Disease.
  18. Caring experiences of family caregivers of patients with pancreatic cancer: an integrative literature review.
  19. Muscle-specific functional deficits and lifelong fibrosis in response to paediatric radiotherapy and tumour elimination.
  1. FEBS J. 2022 Jan 05.
    Nek4 regulates mitochondrial respiration and morphology.
    Fernanda Luisa Basei, Camila de Castro Ferezin, Ana Luisa Rodrigues de Oliveira, Juan Pablo Muñoz, Antonio Zorzano, Jörg Kobarg.
      Nek4 is a serine/threonine kinase which has been implicated in primary cilia stabilization, DNA damage response, autophagy and epithelial-to-mesenchymal transition. The role of Nek4 in cancer cell survival and chemotherapy resistance has also been shown. However, the precise mechanisms by which Nek4 operates remain to be elucidated. Here, we show that Nek4 overexpression activates mitochondrial respiration coupled to ATP production, which is paralleled by increased mitochondrial membrane potential, and resistance to mitochondrial DNA damage. Congruently, Nek4 depletion reduced mitochondrial respiration and mtDNA integrity. Nek4 deficiency caused mitochondrial elongation, probably via reduced activity of the fission protein DRP1. In Nek4 overexpressing cells the increase in mitochondrial fission was concomitant to enhanced phosphorylation of DRP1 and Erk1/2 proteins, and the effects on mitochondrial respiration were abolished in the presence of a DRP1 inhibitor. This study shows Nek4 as a novel regulator of mitochondrial function that may explain the joint appearance of high mitochondrial respiration and mitochondrial fragmentation.
    Keywords:  DRP1; Nek4; fission; mitochondrial function
    DOI:  https://doi.org/10.1111/febs.16343
  2. Transgenic Res. 2022 Jan 05.
    Skeletal muscle phenotyping of Hippo gene-mutated mice reveals that Lats1 deletion increases the percentage of type I muscle fibers.
    Fakhreddin Yaghoob Nezhad, Annett Riermeier, Martin Schönfelder, Lore Becker, Martin Hrabĕ de Angelis, Henning Wackerhage.
      The Hippo signal transduction network regulates transcription through Yap/Taz-Tead1-4 in many tissues including skeletal muscle. Whilst transgenic mice have been generated for many Hippo genes, the resultant skeletal muscle phenotypes were not always characterized. Here, we aimed to phenotype the hindlimb muscles of Hippo gene-mutated Lats1-/-, Mst2-/-, Vgll3-/-, and Vgll4+/- mice. This analysis revealed that Lats1-/- mice have 11% more slow type I fibers than age and sex-matched wild-type controls. Moreover, the mRNA expression of slow Myh7 increased by 50%, and the concentration of type I myosin heavy chain is 80% higher in Lats1-/- mice than in age and sex-matched wild-type controls. Second, to find out whether exercise-related stimuli affect Lats1, we stimulated C2C12 myotubes with the hypertrophy agent clenbuterol or the energy stress agent AICAR. We found that both stimulated Lats1 expression by 1.2 and 1.3 fold respectively. Third, we re-analyzed published datasets and found that Lats1 mRNA in muscle is 63% higher in muscular dystrophy, increases by 17-77% after cardiotoxin-induced muscle injury, by 41-71% in muscles during overload-induced hypertrophy, and by 19-21% after endurance exercise when compared to respective controls. To conclude, Lats1 contributes to the regulation of muscle fiber type proportions, and its expression is regulated by physiological and pathological situations in skeletal muscle.
    Keywords:  Fiber type; Hippo pathway; Lats1; Skeletal muscle; Transgenic mice
    DOI:  https://doi.org/10.1007/s11248-021-00293-4
  3. Acta Physiol (Oxf). 2022 Jan 05. e13772
    Assessing mitochondrial respiration in permeabilized fibres and biomarkers for mitochondrial content in human skeletal muscle.
    Jujiao Kuang, Nicholas J Saner, Javier Botella, Matthew J-C Lee, Cesare Granata, Zhenhuan Wang, Xu Yan, Jia Li, Amanda J Genders, David J Bishop.
      AIM: Assessments of mitochondrial respiration and mitochondrial content are common in skeletal muscle research and exercise science. However, many sources of technical and biological variation render these analyses susceptible to error. This study aimed to better quantify the reliability of the experimental design and/or techniques employed, therefore assist researcher in obtaining more reliable data.METHODS: We examined the repeatability of maximal mitochondrial oxidative phosphorylation in permeabilized muscle fibres via high-resolution respirometry, and of citrate synthase activity (a biomarker for mitochondrial content) in a microplate with spectrophotometery.
    RESULTS: For mitochondrial respiration using permeabilised skeletal muscle fibres, the variability was reduced by using three chambers and removing outliers compared to two chambers (CV reduced from 12.7% to 11.0%), and the minimal change that can be detected with 10 participants reduced from 17% to 13% according to modelling. For citrate synthase activity, the within-plate CV (3.5%) increased when the assay was repeated after 4 hours (CV = 10.2%) and 4 weeks (CV = 30.5%). The readings were correlated, but significantly different after 4 hours and 4 weeks.
    CONCLUSION: This research provides evidence for important technical considerations when measuring mitochondrial respiration and content using citrate synthase activity as a biomarker. When assessing mitochondrial respiration in human skeletal muscle, the technical variability of high-resolution respirometry can be reduced by increasing technical repeats and excluding outliers, practices which are not currently common. When analysing citrate synthase activity, our results highlight the importance of analysing all samples from the same study at the same time.
    Keywords:  Exercise; Human skeletal muscle; Mitochondrial content; Mitochondrial respiration
    DOI:  https://doi.org/10.1111/apha.13772
  4. Acta Physiol (Oxf). 2022 Jan 04. e13766
    Factors Mediating Exercise-induced Organ Crosstalk.
    Rugivan Sabaratnam, Jørgen F P Wojtaszewski, Kurt Højlund.
      Exercise activates a plethora of metabolic and signalling pathways in skeletal muscle and other organs causing numerous systemic beneficial metabolic effects. Thus, regular exercise may ameliorate and prevent the development of several chronic metabolic diseases. Skeletal muscle is recognized as an important endocrine organ regulating systemic adaptations to exercise. Skeletal muscle may mediate crosstalk with other organs through the release of exercise-induced cytokines, peptides and proteins, termed myokines, into the circulation. Importantly, other tissues such as the liver and adipose tissue may also release cytokines and peptides in response to exercise. Hence, exercise-released molecules are collectively called exerkines. Moreover, extracellular vesicles (EVs), in the form of exosomes or microvesicles, may carry some of the signals involved in tissue crosstalk. This review focuses on the role of factors potentially mediating crosstalk between muscle and other tissues in response to exercise.
    Keywords:  Exercise; crosstalk; exerkines; exosomes; hepatokines; myokines; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.13766
  5. Mol Ther Nucleic Acids. 2022 Mar 08. 27 147-164
    Filamin C regulates skeletal muscle atrophy by stabilizing dishevelled-2 to inhibit autophagy and mitophagy.
    Shunshun Han, Can Cui, Xiyu Zhao, Yao Zhang, Yun Zhang, Jing Zhao, Xiaoxu Shen, Haorong He, Jianping Wang, Menggen Ma, Diyan Li, Qing Zhu, Huadong Yin.
      FilaminC (Flnc) is a member of the actin binding protein family, which is preferentially expressed in the cardiac and skeletal muscle tissues. Although it is known to interact with proteins associated with myofibrillar myopathy, its unique role in skeletal muscle remains largely unknown. In this study, we identify the biological functions of Flnc in vitro and in vivo using chicken primary myoblast cells and animal models, respectively. From the results, we observe that the growth rate and mass of the skeletal muscle of fast-growing chickens (broilers) were significantly higher than those in slow-growing chickens (layers). Furthermore, we find that the expression of Flnc in the skeletal muscle of broilers was higher than that in the layers. Our results indicated that Flnc was highly expressed in the skeletal muscle, especially in the skeletal muscle of broilers than in layers. This suggests that Flnc plays a positive regulatory role in myoblast development. Flnc knockdown resulted in muscle atrophy, whereas the overexpression of Flnc promotes muscle hypertrophy in vivo in an animal model. We also found that Flnc interacted with dishevelled-2 (Dvl2), activated the wnt/β-catenin signaling pathway, and controlled skeletal muscle development. Flnc also antagonized the LC3-mediated autophagy system by decreasing Dvl2 ubiquitination. Moreover, Flnc knockdown activated and significantly increased mitophagy. In summary, these results indicate that the absence of Flnc induces autophagy or mitophagy and regulates muscle atrophy.
    Keywords:  atrophy; autophagy; dishevelled-2; filamin C; mitophagy; skeletal muscle
    DOI:  https://doi.org/10.1016/j.omtn.2021.11.022
  6. J Cachexia Sarcopenia Muscle. 2022 Jan 07.
    Renal failure suppresses muscle irisin expression, and irisin blunts cortical bone loss in mice.
    Naoyuki Kawao, Miku Kawaguchi, Takashi Ohira, Hiroki Ehara, Yuya Mizukami, Yoshimasa Takafuji, Hiroshi Kaji.
      BACKGROUND: Chronic renal failure induces bone mineral disorders and sarcopenia. Skeletal muscle affects other tissues, including bone, by releasing myokines. However, the effects of chronic renal failure on the interactions between muscle and bone remain unclear.METHODS: We investigated the effects of renal failure on bone, muscle, and myokines linking muscle to bone using a mouse 5/6 nephrectomy (Nx) model. Muscle mass and bone mineral density (BMD) were analysed by quantitative computed tomography 8 weeks after Nx.
    RESULTS: Nephrectomy significantly reduced muscle mass in the whole body (12.1% reduction, P < 0.05), grip strength (10.1% reduction, P < 0.05), and cortical BMD at the femurs of mice (9.5% reduction, P < 0.01) 8 weeks after surgery, but did not affect trabecular BMD at the femurs. Among the myokines linking muscle to bone, Nx reduced the expression of irisin, a proteolytic product of fibronectin type III domain-containing 5 (Fndc5), in the gastrocnemius muscles of mice (38% reduction, P < 0.01). Nx increased myostatin mRNA levels in the gastrocnemius muscles of mice (54% increase, P < 0.01). In simple regression analyses, cortical BMD, but not trabecular BMD, at the femurs was positively related to Fndc5 mRNA levels in the gastrocnemius muscles of mice (r = 0.651, P < 0.05). The weekly administration of recombinant irisin to mice ameliorated the decrease in cortical BMD, but not muscle mass or grip strength, induced by Nx (6.2% reduction in mice with Nx vs. 3.3% reduction in mice with Nx and irisin treatment, P < 0.05).
    CONCLUSIONS: The present results demonstrated that renal failure decreases the expression of irisin in the gastrocnemius muscles of mice. Irisin may contribute to cortical bone loss induced by renal failure in mice as a myokine linking muscle to bone.
    Keywords:  Irisin; Muscle wasting; Osteopenia; Renal failure
    DOI:  https://doi.org/10.1002/jcsm.12892
  7. J Cachexia Sarcopenia Muscle. 2022 Jan 07.
    Skeletal muscle alterations in patients with acute Covid-19 and post-acute sequelae of Covid-19.
    Madu N Soares, Moritz Eggelbusch, Elie Naddaf, Karin H L Gerrits, Marike van der Schaaf, Bram van den Borst, W Joost Wiersinga, Michele van Vugt, Peter J M Weijs, Andrew J Murray, Rob C I Wüst.
      Skeletal muscle-related symptoms are common in both acute coronavirus disease (Covid)-19 and post-acute sequelae of Covid-19 (PASC). In this narrative review, we discuss cellular and molecular pathways that are affected and consider these in regard to skeletal muscle involvement in other conditions, such as acute respiratory distress syndrome, critical illness myopathy, and post-viral fatigue syndrome. Patients with severe Covid-19 and PASC suffer from skeletal muscle weakness and exercise intolerance. Histological sections present muscle fibre atrophy, metabolic alterations, and immune cell infiltration. Contributing factors to weakness and fatigue in patients with severe Covid-19 include systemic inflammation, disuse, hypoxaemia, and malnutrition. These factors also contribute to post-intensive care unit (ICU) syndrome and ICU-acquired weakness and likely explain a substantial part of Covid-19-acquired weakness. The skeletal muscle weakness and exercise intolerance associated with PASC are more obscure. Direct severe acute respiratory syndrome coronavirus (SARS-CoV)-2 viral infiltration into skeletal muscle or an aberrant immune system likely contribute. Similarities between skeletal muscle alterations in PASC and chronic fatigue syndrome deserve further study. Both SARS-CoV-2-specific factors and generic consequences of acute disease likely underlie the observed skeletal muscle alterations in both acute Covid-19 and PASC.
    Keywords:  Covid-19; Inflammation; Metabolism; Muscle wasting; Skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.12896
  8. Am J Physiol Cell Physiol. 2022 Jan 05.
    Reducing sarcolipin expression improves muscle metabolism in mdx mice.
    Rekha Balakrishnan, Satvik Mareedu, Gopal J Babu.
      Duchenne muscular dystrophy (DMD) is an inherited muscle wasting disease. Metabolic impairments and oxidative stress are major secondary mechanisms that severely worsen muscle function in DMD. Here, we sought to determine whether germline reduction or ablation of sarcolipin (SLN), an inhibitor of sarco/endoplasmic reticulum (SR) Ca2+ ATPase (SERCA) improves muscle metabolism and ameliorates muscle pathology in the mdx mouse model of DMD. Glucose and insulin tolerance tests show that glucose clearance rate and insulin sensitivity were improved in the SLN haploinsufficient mdx (mdx:sln+/-) and SLN deficient mdx (mdx:sln-/-) mice. The histopathological analysis shows that fibrosis and necrosis were significantly reduced in muscles of mdx:sln+/- and mdx:sln-/-mice. SR Ca2+ uptake, mitochondrial complex protein levels, complex activities, mitochondrial Ca2+ uptake and release, and mitochondrial metabolism were significantly improved and, lipid peroxidation and protein carbonylation were reduced in the muscles of mdx:sln+/- and mdx:sln-/-mice. These data demonstrate that reduction or ablation of SLN expression can improve muscle metabolism, reduce oxidative stress, decrease muscle pathology, and protects the mdx mice from glucose intolerance.
    Keywords:  Duchenne muscular dystrophy; SERCA; mdx; metabolism; sarcolipin
    DOI:  https://doi.org/10.1152/ajpcell.00125.2021
  9. Meat Sci. 2021 Dec 24. pii: S0309-1740(21)00312-0. [Epub ahead of print]185 108726
    Myostatin gene inactivation increases post-mortem calpain-dependent muscle proteolysis in mice.
    Rim Nassar, Barbara Vernus, Gilles Carnac, Gilles Fouret, Bénédicte Goustard, François Casas, Lionel Tintignac, Isabelle Cassar-Malek, Brigitte Picard, Iban Seiliez, Thomas Brioche, Christelle Koechlin-Ramonatxo, Christelle Bertrand-Gaday, Aline Hamade, Fadia Najjar, Béatrice Chabi, Anne Bonnieu.
      Myostatin deficiency leads to extensive skeletal muscle hypertrophy, but its consequence on post-mortem muscle proteolysis is unknown. Here, we compared muscle myofibrillar protein degradation, and autophagy, ubiquitin-proteasome and Ca2+-dependent proteolysis relative to the energetic and redox status in wild-type (WT) and myostatin knock-out mice (KO) during early post-mortem storage. KO muscles showed higher degradation of myofibrillar proteins in the first 24 h after death, associated with preserved antioxidant status, compared with WT muscles. Analysis of key autophagy and ubiquitin-proteasome system markers indicated that these two pathways were not upregulated in post-mortem muscle (both genotypes), but basal autophagic flux and ATP content were lower in KO muscles. Proteasome and caspase activities were not different between WT and KO mice. Conversely, calpain activity was higher in KO muscles, concomitantly with higher troponin T and desmin degradation. Altogether, these results suggest that calpains but not the autophagy, proteasome and caspase systems, explain the difference in post-mortem muscle protein proteolysis between both genotypes.
    Keywords:  Myofibrillar protein; Oxidative stress; Post-mortem; Proteolysis; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.meatsci.2021.108726
  10. J Cachexia Sarcopenia Muscle. 2022 Jan 07.
    Obesity attenuates inflammation, protein catabolism, dyslipidaemia, and muscle weakness during sepsis, independent of leptin.
    Wouter Vankrunkelsven, Sarah Derde, Jan Gunst, Sarah Vander Perre, Emiel Declerck, Lies Pauwels, Inge Derese, Greet Van den Berghe, Lies Langouche.
      BACKGROUND: Muscle weakness is a frequently occurring complication of sepsis, associated with increased morbidity and mortality. Interestingly, obesity attenuates sepsis-induced muscle wasting and weakness. As the adipokine leptin is strongly elevated in obesity and has been shown to affect muscle homeostasis in non-septic conditions, we aimed to investigate whether leptin mediates the protective effect of obesity on sepsis-induced muscle weakness.METHODS: In a mouse model of sepsis, we investigated the effects of genetic leptin inactivation in obese mice (leptin-deficient obese mice vs. diet-induced obese mice) and of leptin supplementation in lean mice (n = 110). We assessed impact on survival, body weight and composition, markers of muscle wasting and weakness, inflammation, and lipid metabolism. In human lean and overweight/obese intensive care unit (ICU) patients, we assessed markers of protein catabolism (n = 1388) and serum leptin (n = 150).
    RESULTS: Sepsis mortality was highest in leptin-deficient obese mice (53% vs. 23% in diet-induced obese mice and 37% in lean mice, P = 0.03). Irrespective of leptin, after 5 days of sepsis, lean mice lost double the amount of lean body mass than obese mice (P < 0.0005). Also, irrespective of leptin, obese mice maintained specific muscle force up to healthy levels (P = 0.3) whereas lean mice suffered from reduced specific muscle force (72% of healthy controls, P < 0.0002). As compared with lean septic mice, both obese septic groups had less muscle atrophy, liver amino acid catabolism, and inflammation with a 50% lower plasma TNFα increase (P < 0.005). Conversely, again mainly irrespective of leptin, obese mice lost double amount of fat mass than lean mice after 5 days of sepsis (P < 0.0001), showed signs of increased lipolysis and ketogenesis, and had higher plasma HDL and LDL lipoprotein concentrations (P ≤ 0.01 for all). Muscle fibre type composition was not altered during sepsis, but a higher atrophy sensitivity of type IIb fibres compared with IIa and IIx fibres was observed, independent of obesity or leptin. After 5 days of critical illness, serum leptin was higher (P < 0.0001) and the net waste of nitrogen (P = 0.006) and plasma urea-to-creatinine ratio (P < 0.0001) was lower in overweight/obese compared with lean ICU human patients.
    CONCLUSIONS: Leptin did not mediate the protective effect of obesity against sepsis-induced muscle wasting and weakness in mice. Instead, obesity-independent of leptin-attenuated inflammation, protein catabolism, and dyslipidaemia, pathways that may play a role in the observed muscle protection.
    Keywords:  Atrophy; Critical illness; Intensive care unit acquired weakness; Leptin; Muscle weakness; Protein catabolism; Sepsis
    DOI:  https://doi.org/10.1002/jcsm.12904
  11. Nat Rev Nephrol. 2022 Jan 03.
    Patient-centred approaches for the management of unpleasant symptoms in kidney disease.
    Kamyar Kalantar-Zadeh, Mark B Lockwood, Connie M Rhee, Ekamol Tantisattamo, Sharon Andreoli, Alessandro Balducci, Paul Laffin, Tess Harris, Richard Knight, Latha Kumaraswami, Vassilios Liakopoulos, Siu-Fai Lui, Sajay Kumar, Maggie Ng, Gamal Saadi, Ifeoma Ulasi, Allison Tong, Philip Kam-Tao Li.
      Patients with chronic kidney disease (CKD) frequently experience unpleasant symptoms. These can be gastrointestinal (constipation, nausea, vomiting and diarrhoea), psychological (anxiety and sadness), neurological (lightheadedness, headache and numbness), cardiopulmonary (shortness of breath and oedema), dermatological (pruritus and dry skin), painful (muscle cramps, chest pain and abdominal pain) or involve sexual dysfunction, sleep disorders and fatigue. These symptoms often occur in clusters, with one of them as the lead symptom and others as secondary symptoms. Uraemic toxins (also called uremic toxins) are often considered to be the main cause of CKD-associated symptom burden, but treatment of uraemia by dialysis often fails to resolve them and can engender additional symptoms. Indeed, symptoms can be exacerbated by comorbid conditions, pharmacotherapies, lifestyle and dietary regimens, kidney replacement therapy and ageing. Patients with kidney disease, including those who depend on dialysis or transplantation, should feel actively supported in their symptom management through the identification and targeting of unpleasant symptoms via a tailored palliative care approach. Such an approach may help minimize the burden and consequences of kidney disease, and lead to improved patient outcomes including health-related quality of life and better life participation.
    DOI:  https://doi.org/10.1038/s41581-021-00518-z
  12. Cancer Lett. 2021 Dec 31. pii: S0304-3835(21)00655-8. [Epub ahead of print]529 19-36
    PINK1 deficiency in gastric cancer compromises mitophagy, promotes the Warburg effect, and facilitates M2 polarization of macrophages.
    Ying Xu, Jiawei Lu, Yinbing Tang, Wenjie Xie, Heteng Zhang, Beibei Wang, Shouliang Zhang, Wenji Hou, Chen Zou, Pengcheng Jiang, Wenbo Zhang.
      Cancer cells are typically characterized by abnormal quality control of mitochondria, production of reactive oxygen species (ROS), dysregulation of the cell redox state, and the Warburg effect. Mutation or depletion of PTEN-induced kinase 1 (PINK1) or Parkin leads to mitophagy defects and accumulation of malfunctioning mitochondria, and is often detected in a variety of tumors. However, PINK1's role in the progression of gastric cancer (GC) remains unclear, with its main effect being on mitochondrial turnover, metabolic reprogramming, and tumor microenvironment (TME) alteration. To address these issues, we first assessed the expression levels of PINK1, mitophagy-associated molecules, ROS, HIF-1α, glycolysis-associated genes, and macrophage signatures in GC tissues and matched tumor-adjacent normal samples. In addition, GC cell lines (AGS and MKN-45) and xenograft mouse models were used to determine the mechanism by which PINK1 regulates mitophagy, metabolic reprogramming, tumor-associated macrophage (TAM) polarization, and GC progression. We found that PINK1 loss correlated with advanced stage GC and poorer overall survival. GC tissues with lower PINK1 levels showed compromised mitophagy signaling and enhanced glycolytic enzyme expression. In vitro experiments demonstrated that PINK1 deficiency promoted GC cell proliferation and migration through the inhibition of mitophagy, production of mitochondrial ROS, stabilization of HIF-1α, and facilitation of the Warburg effect under both normoxic and hypoxic conditions. Moreover, PINK1 deficiency in GC cells promoted TAM polarization toward the M2-like phenotype. Reintroduction of PINK1 or inhibition of HIF-1α effectively repressed PINK1 deficiency-mediated effects on GC cell growth, metabolic shift, and TAM polarization. Thus, mitophagy defects caused by PINK1 loss conferred a metabolic switch through accumulation of mtROS and stabilization of HIF-1α, thereby facilitating the M2 polarization of TAM to remodel an immunosuppressive microenvironment in GC. Our results clarify the mechanism between PINK1 and GC progression and may provide a novel strategy for the treatment of GC.
    Keywords:  Metabolic reprogramming; Mitochondria; ROS,HIF-1α; Tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.canlet.2021.12.032
  13. Kidney Int. 2022 Jan;pii: S0085-2538(21)01048-6. [Epub ahead of print]101(1): 13-15
    Therapeutic potential of Beclin1 for transition from AKI to CKD: autophagy-dependent and autophagy-independent functions.
    Satoshi Minami, Shuhei Nakamura.
      Acute kidney injury (AKI) increases the risk of chronic kidney disease (CKD), but the mechanisms of CKD development after AKI remain unclear. Recent studies have elucidated that autophagy protects against AKI, but the role of autophagy during the AKI-to-CKD transition is controversial. Beclin1 is a key molecule for autophagy as well as endocytosis and phagocytosis. Shi et al. demonstrate that Beclin1 activates autophagy and is a promising therapeutic target for AKI-to-CKD transition.
    DOI:  https://doi.org/10.1016/j.kint.2021.10.021
  14. Front Cell Dev Biol. 2021 ;9 761273
    Biological Functions and Therapeutic Potential of Autophagy in Spinal Cord Injury.
    Hai-Yang Liao, Zhi-Qiang Wang, Rui Ran, Kai-Sheng Zhou, Chun-Wei Ma, Hai-Hong Zhang.
      Autophagy is an evolutionarily conserved lysosomal degradation pathway that maintains metabolism and homeostasis by eliminating protein aggregates and damaged organelles. Many studies have reported that autophagy plays an important role in spinal cord injury (SCI). However, the spatiotemporal patterns of autophagy activation after traumatic SCI are contradictory. Most studies show that the activation of autophagy and inhibition of apoptosis have neuroprotective effects on traumatic SCI. However, reports demonstrate that autophagy is strongly associated with distal neuronal death and the impaired functional recovery following traumatic SCI. This article introduces SCI pathophysiology, the physiology and mechanism of autophagy, and our current review on its role in traumatic SCI. We also discuss the interaction between autophagy and apoptosis and the therapeutic effect of activating or inhibiting autophagy in promoting functional recovery. Thus, we aim to provide a theoretical basis for the biological therapy of SCI.
    Keywords:  autophagy; autophagy-regulated; biological functions; spinal cord injury; therapeutic target
    DOI:  https://doi.org/10.3389/fcell.2021.761273
  15. Eur J Pharmacol. 2021 Dec 30. pii: S0014-2999(21)00879-7. [Epub ahead of print] 174723
    Autophagy in cancer: The cornerstone during glutamine deprivation.
    Hamza M Fares, Xiaodan Lyu, Xiaoting Xu, Renchao Dong, Muyao Ding, Shichao Mi, Yifan Wang, Xue Li, Shengtao Yuan, Li Sun.
      Over the past two decades, researchers have revealed the crucial functions of glutamine in supporting the hyperproliferation state of cancer cells. Glutamine acts on maintaining high energy production, supporting redox status and amino acid homeostasis. Therefore, cancer cells exhibit excessive uptake of the extracellular glutamine, synthesize it in some cases, and recycle intracellular and extracellular proteins to provide an additional source of glutamine to satisfy the increasing glutamine demand. On the other hand, autophagy's role is still debated regarding tumor initiation and progression. However, most cancer cells urgently need autophagy to overcome the existential threats during glutamine restriction stress. Downstream to various stress pathways induced during such a condition, autophagy is considered an indispensable cytoprotective tool to maintain cell integrity and survival. However, the overactivation of the autophagy process is related to lethal consequences. This review summarized glutamine pathways to control autophagy and highlighted autophagy's primary activation pathways, and discussed the roles during glutamine deprivation.
    Keywords:  Autophagy; Cancer cell metabolism; Glutamine deprivation
    DOI:  https://doi.org/10.1016/j.ejphar.2021.174723
  16. Cureus. 2021 Nov;13(11): e19670
    An Internal Review of Rates of Palliative Medicine Referral for Patients With Advanced Pancreatic Cancer.
    Deanna L Huffman, Urwat T Vusqa, Karthik Shankar, Lynna Alnimer, Yazan Samhouri, Srividya Srinivasamaharaj, Srikrishna V Malayala, Dulabh Monga.
      Background The American Society of Clinical Oncology recommends that patients with advanced cancer receive palliative care services in concurrence with active treatment. While the benefits of palliative care are clear, integration of palliative care can be challenging. We aim to review rates of palliative care consultation in patients with advanced pancreatic cancer at our institution, intending to improve these rates. Methods We retrospectively reviewed the electronic records of all patients with pancreatic cancer treated at Allegheny General Hospital diagnosed between 2009-2020. Summary statistics are presented as percentages for categorical data and median with interquartile range for quantitative data. Results Of the 171 patients reviewed, 121 completed all treatment and evaluation within our health network (Pittsburgh, United States). The median age was 63 years (IQR 40-91 years); 55 patients (45%) were male; the majority were white (107 patients, 88%). At the time of diagnosis, 28% of our patients had stage IV disease (34 patients), and 19.8% of patients who developed stage IV disease had palliative care referrals. Conclusions Palliative care is an integral part of usual care for advanced pancreatic cancer. Our analysis showed that palliative care is underutilized in our hospital. We aim to improve palliative care integration in our patients' care by adding a hard stop to electronic medical records to remind physicians to offer palliative care to our patients with pancreatic cancer and to arrange lecture series to emphasize the importance of palliative care in this setting.
    Keywords:  electronic health record; pain management; palliative care; pancreatic cancer; quality review
    DOI:  https://doi.org/10.7759/cureus.19670
  17. Front Pharmacol. 2021 ;12 785375
    Advances in the Progression and Prognosis Biomarkers of Chronic Kidney Disease.
    Zhonghong Yan, Guanran Wang, Xingyang Shi.
      Chronic kidney disease (CKD) is one of the increasingly serious public health concerns worldwide; the global burden of CKD is increasingly due to high morbidity and mortality. At present, there are three key problems in the clinical treatment and management of CKD. First, the current diagnostic indicators, such as proteinuria and serum creatinine, are greatly interfered by the physiological conditions of patients, and the changes in the indicator level are not synchronized with renal damage. Second, the established diagnosis of suspected CKD still depends on biopsy, which is not suitable for contraindication patients, is also traumatic, and is not sensitive to early progression. Finally, the prognosis of CKD is affected by many factors; hence, it is ineviatble to develop effective biomarkers to predict CKD prognosis and improve the prognosis through early intervention. Accurate progression monitoring and prognosis improvement of CKD are extremely significant for improving the clinical treatment and management of CKD and reducing the social burden. Therefore, biomarkers reported in recent years, which could play important roles in accurate progression monitoring and prognosis improvement of CKD, were concluded and highlighted in this review article that aims to provide a reference for both the construction of CKD precision therapy system and the pharmaceutical research and development.
    Keywords:  advances; biomarkers for early diagnosis; chronic kidney disease; prognostic biomarkers; progression biomarkers
    DOI:  https://doi.org/10.3389/fphar.2021.785375
  18. Support Care Cancer. 2022 Jan 07.
    Caring experiences of family caregivers of patients with pancreatic cancer: an integrative literature review.
    Yoonjoo Kim, Wonhee Baek.
      PURPOSE: This review summarizes and synthesizes the available empirical literature on the experiences concerned with the problems and challenges faced by caregivers of patients with pancreatic cancer.METHODS: An integrative review method was used, and a literature search was conducted using five databases. We searched the terms "pancreatic cancer," "caregiver," and "experience," and used the Boolean operators OR and AND to combine them. The Joanna Briggs Institute critical appraisal tools were used to assess the quality of the included studies.
    RESULTS: Four qualitative studies, one mixed method, and three quantitative studies met the selection criteria and were included in the review. Informal family caregivers of patients with pancreatic cancer experienced multifaceted roles, lack of information, difficulties in maintaining emotional well-being, and positive coping. The factors associated with their caring experience included the caregivers' demographics, patients' psychological status, and clinical characteristics.
    CONCLUSION: Caregivers of patients with pancreatic cancer have various experiences while providing care. Health care providers should offer opportunities for caregivers to recognize their feelings, provide sufficient information and psychological support, and foster coping strategies to maintain the physical and psychosocial well-being of caregivers.
    Keywords:  Caregiver; Caring experience; Family; Pancreatic cancer
    DOI:  https://doi.org/10.1007/s00520-021-06793-7
  19. J Cachexia Sarcopenia Muscle. 2022 Jan 08.
    Muscle-specific functional deficits and lifelong fibrosis in response to paediatric radiotherapy and tumour elimination.
    Jacob G Kallenbach, John F Bachman, Nicole D Paris, Roméo S Blanc, Thomas O'Connor, Esraa Furati, Jacqueline P Williams, Joe V Chakkalakal.
      BACKGROUND: As paediatric cancer survivors are living into adulthood, they suffer from the age-related, accelerated decline of functional skeletal muscle tissue, termed sarcopenia. With ionizing radiation (radiotherapy) at the core of paediatric cancer therapies, its direct and indirect effects can have lifelong negative impacts on paediatric growth and maintenance of skeletal muscle. Utilizing our recently developed preclinical rhabdomyosarcoma mouse model, we investigated the late effects of paediatric radiation treatment on skeletal muscles from late adolescent (8 weeks old) and middle-aged (16 months old) mice.METHODS: Paediatric C57BL/6J male mice (3 weeks old) were injected with rhabdomyosarcoma cells into their right hindlimbs, and then fractionated irradiation (3 × 8.2 Gy) was administered to those limbs at 4 weeks old to eliminate the tumours. Radiation-alone and tumour-irradiated mice were assessed at either 8 weeks (3 weeks post-irradiation) or 16 months (14 months post-irradiation) of age for muscle physiology, myofibre characteristics, cell loss, histopathology, fibrosis, inflammatory gene expression, and fibrotic gene expression.
    RESULTS: Mice that received only paediatric radiation demonstrated reduced muscle mass (-17%, P < 0.001), muscle physiological function (-25%, P < 0.01), muscle contractile kinetics (-25%, P < 0.05), satellite cell number (-45%, P < 0.05), myofibre cross-sectional area (-30%, P < 0.0001), and myonuclear number (-17%, P < 0.001). Paediatric radiation increased inflammatory gene expression, increased fibrotic gene expression, and induced extracellular matrix protein deposition (fibrosis) with tumour elimination exacerbating some phenotypes. Paediatric tumour-eliminated mice demonstrated exacerbated deficits to function (-20%, P < 0.05) and myofibre size (-17%, P < 0.001) in some muscles as well as further increases to inflammatory and fibrotic gene expression. Examining the age-related effects of paediatric radiotherapy in middle-aged mice, we found persistent myofibre atrophy (-20%, P < 0.01), myonuclear loss (-18%, P < 0.001), up-regulated inflammatory and fibrotic signalling, and lifelong fibrosis.
    CONCLUSIONS: The results from this paediatric radiotherapy model are consistent and recapitulate the clinical and molecular features of accelerated sarcopenia, musculoskeletal frailty, and radiation-induced fibrosis experienced by paediatric cancer survivors. We believe that this preclinical mouse model is well poised for future mechanistic insights and therapeutic interventions that improve the quality of life for paediatric cancer survivors.
    Keywords:  Ageing; Cancer survivorship; DNA damage; Development; Frailty; Musculoskeletal; Physiology; Radiation; Regeneration; Rhabdomyosarcoma; Sarcopenia; Stem cell
    DOI:  https://doi.org/10.1002/jcsm.12902
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