bims-aucach 2021-12-19 papers

bims-aucach

Biomed News

on Autophagy and cachexia

Issue of 2021‒12‒19
twenty papers selected by
Kleiton Silva
Rowan University

RANKL Blockade Reduces Cachexia and Bone Loss Induced by Non-Metastatic Ovarian Cancer in Mice.
Nutrition challenges of cancer cachexia.
Curcumin alleviates arsenic-induced injury in duck skeletal muscle via regulating the PINK1/Parkin pathway and protecting mitochondrial function.
IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.
Lower citrate synthase activity, mitochondrial complex expression, and fewer oxidative myofibers characterize skeletal muscle from growth restricted fetal sheep.
The Severity of Muscle Performance Deterioration in Sarcopenia Correlates With Circulating Muscle Tissue-Specific miRNAs.
Walking Exercise Therapy Effects on Lower Extremity Skeletal Muscle in Peripheral Artery Disease.
Current guidelines for nutrition therapy in cancer: The arrival of a long journey or the starting point?
Factors related to dysphagia-specific quality of life in aged patients with neurologic disorders: A cross-sectional study.
REVOLUTION (Routine EValuatiOn of people LivIng with caNcer)-Protocol for a prospective characterisation study of patients with incurable cancer.
A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.
Crosstalk between anticancer drugs and mitochondrial functions.
Association of FGF19, FGF21 and FGF23 with carbohydrate metabolism parameters and insulin resistance in patients with chronic kidney disease.
Anorexia disrupts glutamate-glutamine homeostasis associated with astrocytes in the prefrontal cortex of young female rats.
The Relationship between Nutritional Status and Body Composition with Clinical Parameters, Tumor Stage, CA19-9, CEA Levels in Patients with Pancreatic and Periampullary Tumors.
Impact of TNF-α Gene Polymorphisms on Pancreatic and Non-Small Cell Lung Cancer-Induced Cachexia in Adult Egyptian Patients: A Focus on Pathogenic Trajectories.
Toxicity of induction chemotherapy in head and neck cancer: The central role of skeletal muscle mass.
The use of menopausal hormone therapy after cancer.
MicroRNA is a potential target for therapies to improve the physiological function of skeletal muscle after trauma.
[A case report of colchicine-induced myopathy in a patient with chronic kidney disease].

J Bone Miner Res. 2021 Dec 13.

RANKL Blockade Reduces Cachexia and Bone Loss Induced by Non-Metastatic Ovarian Cancer in Mice.

Fabrizio Pin, Alexander J Jones, Joshua R Huot, Ashok Narasimhan, Teresa A Zimmers, Lynda F Bonewald, Andrea Bonetto.

  Tumor- and bone-derived soluble factors have been proposed to participate in the alterations of skeletal muscle size and function in cachexia. We previously showed that mice bearing ovarian cancer (OvCa) exhibit cachexia associated with marked bone loss, whereas bone-targeting agents, such as bisphosphonates, are able to preserve muscle mass in animals exposed to anticancer drugs. De-identified CT images and plasma samples from female patients affected with OvCa were used for body composition assessment and quantification of circulating cross-linked C-telopeptide type I (CTX-I) and receptor activator of NF-kB ligand (RANKL), respectively. Female mice bearing ES-2 tumors were used to characterize cancer- and RANKL-associated effects on muscle and bone. Murine C2C12 and human HSMM myotube cultures were used to determine the OvCa- and RANKL-dependent effects on myofiber size. To the extent of isolating new regulators of bone and muscle in cachexia, here we demonstrate that subjects affected with OvCa display evidence of cachexia and increased bone turnover. Similarly, mice carrying OvCa present high RANKL levels. By using in vitro and in vivo experimental models, we found that elevated circulating RANKL is sufficient to cause skeletal muscle atrophy and bone resorption, whereas bone preservation by means of antiresorptive and anti-RANKL treatments concurrently benefit muscle mass and function in cancer cachexia. Altogether, our data contribute to identifying RANKL as a novel therapeutic target for the treatment of musculoskeletal complications associated with RANKL-expressing non-metastatic cancers. © 2021 American Society for Bone and Mineral Research (ASBMR).

Keywords:  ANTIRESORPTIVE TREATMENTS; BONE; CACHEXIA; CANCER; MUSCLE; RANKL

DOI:  https://doi.org/10.1002/jbmr.4480
JPEN J Parenter Enteral Nutr. 2021 Nov;45(S2): 16-25

Nutrition challenges of cancer cachexia.

Omnia U Gaafer, Teresa A Zimmers.

  Cancer cachexia, or progressive weight loss, often despite adequate nutrition contributes greatly to cancer morbidity and mortality. Cachexia is metabolically distinct from starvation or protein malnutrition, although many patients with cancer and cachexia exhibit lowered appetite and food consumption. Tumors affect neural mechanisms that regulate appetite and energy expenditure, while promoting wasting of peripheral tissues via catabolism of cardiac and skeletal muscle, adipose, and bone. These multimodal actions of tumors on the host suggest a need for multimodal interventions. However, multiple recent consensus guidelines for management of cancer cachexia differ in treatment recommendations, highlighting the lack of effective, available therapies. Challenges to defining appropriate nutrition or other interventions for cancer cachexia include lack of consensus on definitions, low strength of evidence from clinical trials, and a scarcity of robust, rigorous, and mechanistic studies. However, efforts to diagnose, stage, and monitor cachexia are increasing along with clinical trial activity. Furthermore, preclinical models for cancer cachexia are growing more sophisticated, encompassing a greater number of tumor types in organ-appropriate contexts and for metastatic disease to model the clinical condition more accurately. It is expected that continued growth, investment, and coordination of research in this topic will ultimately yield robust biomarkers, clinically useful classification and staging algorithms, targetable pathways, pivotal clinical trials, and ultimately, cures. Here, we provide an overview of the clinical and scientific knowledge and its limitations around cancer cachexia.

Keywords:  animal models; anorexia; appetite; cachexia; cancer; malnutrition; nutrition

DOI:  https://doi.org/10.1002/jpen.2287
Toxicol Appl Pharmacol. 2021 Dec 09. pii: S0041-008X(21)00424-5. [Epub ahead of print] 115820

Curcumin alleviates arsenic-induced injury in duck skeletal muscle via regulating the PINK1/Parkin pathway and protecting mitochondrial function.

Juan Lan, Lixuan Tang, Shaofeng Wu, Riming Huang, Gaolong Zhong, Xuanxuan Jiang, Zhaoxin Tang, Lianmei Hu.

  Arsenic is a well-known environmental pollutant due to its toxicity, which can do harm to animals and human. Curcumin is a polyphenolic compound derived from turmeric, commonly accepted to have antioxidant properties. However, whether curcumin can ameliorate the damage caused by arsenic trioxide (ATO) in duck skeletal muscle remains largely unknown. Therefore, the present study aims to investigate the potential molecular mechanism of curcumin against ATO-induced skeletal muscle injury. The results showed that treating with curcumin could attenuate body weight loss induced by ATO and reduced arsenic content accumulation in the skeletal muscle of duck. Curcumin was also able to alleviated the oxidative stress triggered by ATO, which was manifested by the increase of T-AOC and SOD, and MDA decrease. Moreover, we observed that curcumin could ease mitochondrial damage and vacuolate degeneration of nucleus. Our further investigation found that ATO disrupted normal mitochondrial fission/fusion (Drp1, OPA1, Mfn1/2) and restrained mitochondrial biogenesis (PGC-1α, Nrf1/2, TFAM), while curcumin could promote mitochondrial fusion and activated PGC-1α pathway. Furthermore, curcumin was found that it could not only reduce the mRNA and protein levels of mitophagy (PINK1, Parkin, LC3, p62) and pro-apoptotic genes (p53, Bax, Caspase-3, Cytc), but also increased the levels of anti-apoptotic genes (Bcl-2). In conclusion, curcumin was able to alleviate ATO-induced skeletal muscle damage by improving mitophagy and preserving mitochondrial function, which can serve as a novel strategy to take precautions against ATO toxicity.

Keywords:  Apoptosis; Arsenic trioxide; Curcumin; Mitochondrial biogenesis; Mitochondrial dynamics; Skeletal muscle

DOI:  https://doi.org/10.1016/j.taap.2021.115820
FASEB J. 2022 Jan;36(1): e22062

IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.

Whitney L Stuard, Rossella Titone, Danielle M Robertson.

  Mitochondrial dysfunction or loss of homeostasis is a central hallmark of many human diseases. Mitochondrial homeostasis is mediated by multiple quality control mechanisms including mitophagy, a form of selective autophagy that recycles terminally ill or dysfunctional mitochondria in order to preserve mitochondrial integrity. Our prior studies have shown that members of the insulin-like growth factor (IGF) family localize to the mitochondria and may play important roles in mediating mitochondrial health in the corneal epithelium, an integral tissue that is required for the maintenance of optical transparency and vision. Importantly, the IGF-binding protein-3, IGFBP-3, is secreted by corneal epithelial cells in response to stress and functions to mediate intracellular receptor trafficking in this cell type. In this study, we demonstrate a novel role for IGFBP-3 in mitochondrial homeostasis through regulation of the short isoform (s)BNIP3L/NIX mitophagy receptor in corneal epithelial cells and extend this finding to non-ocular epithelial cells. We further show that IGFBP-3-mediated control of mitochondrial homeostasis is associated with alterations in lamellar cristae morphology and mitochondrial dynamics. Interestingly, both loss and gain of function of IGFBP-3 drive an increase in mitochondrial respiration. This increase in respiration is associated with nuclear accumulation of IGFBP-3. Taken together, these findings support a novel role for IGFBP-3 as a key mediator of mitochondrial health in mucosal epithelia through the regulation of mitophagy and mitochondrial morphology.

Keywords:  autophagy; insulin-like growth factor type 1 receptor; mTOR; metabolism; mitochondria

DOI:  https://doi.org/10.1096/fj.202100710RR
Am J Physiol Regul Integr Comp Physiol. 2021 Dec 15.

Lower citrate synthase activity, mitochondrial complex expression, and fewer oxidative myofibers characterize skeletal muscle from growth restricted fetal sheep.

Jane Stremming, Eileen Chang, Leslie A Knaub, Michael L Armstrong, Peter R Baker, Stephanie R Wesolowski, Nichole Reisdorph, Jane E B Reusch, Laura D Brown.

  Skeletal muscle from the late gestation sheep fetus with intrauterine growth restriction (IUGR) has evidence of reduced oxidative metabolism. Using a sheep model of placental insufficiency and IUGR, we tested the hypothesis that by late gestation, IUGR fetal skeletal muscle has reduced capacity for oxidative phosphorylation due to intrinsic deficits in mitochondrial respiration. We measured mitochondrial respiration in permeabilized muscle fibers from biceps femoris (BF) and soleus (SOL) from control and IUGR fetal sheep. Using muscles including BF, SOL, tibialis anterior (TA), and flexor digitorum superficialis (FDS), we measured citrate synthase (CS) activity, mitochondrial complex subunit abundance, fiber type distribution, and gene expression of regulators of mitochondrial biosynthesis. Ex vivo mitochondrial respiration was similar in control and IUGR muscle. However, CS activity was lower in IUGR BF and TA, indicating lower mitochondrial content, and protein expression of individual mitochondrial complex subunits was lower in IUGR TA and BF in a muscle specific pattern. IUGR TA, BF, and FDS also had lower expression of type I oxidative fibers. Fiber type shifts that support glycolytic instead of oxidative metabolism may be advantageous for the IUGR fetus in a hypoxic and nutrient deficient environment, whereas these adaptions may be maladaptive in postnatal life.

Keywords:  fetal growth restriction; fetal programming; fiber type; mitochondria; nucleotides

DOI:  https://doi.org/10.1152/ajpregu.00222.2021
Physiol Res. 2021 Nov 30. 70(Suppl 1): S91-S98

The Severity of Muscle Performance Deterioration in Sarcopenia Correlates With Circulating Muscle Tissue-Specific miRNAs.

S Valášková, A Gažová, P Vrbová, T Koller, B Šalingova, A Adamičková, N Chomaničová, N Hulajová, J Payer, J Kyselovič.

Sarcopenia is defined as an age-associated loss of skeletal muscle function and muscle mass and is common in older adults. Sarcopenia as a disease is currently of interest not only to orthopedists and surgeons but also to internists, endocrinologists, rheumatologists, cardiologists, diabetologists, gynaecologists, geriatricians and paediatricians. In cooperation with the 5th Internal Medicine Clinic, we, as a unit of clinical research, aimed to describe a sarcopenic specific miRNA expression profile for disease diagnostics and classification of the severity of muscle performance deterioration. This study included a total of 80 patients (age 55-86 years) hospitalized at the V. Internal medicine clinic of LFUK and UNB with different severity of muscle performance deterioration. The study participants were evaluated and classified according to short physical performance battery score (SPPB). In this study, we investigated the role of circulating miRNAs in sarcopenia in the elderly. We hypothesized that sarcopenia effects the expression of muscle tissue-specific miRNAs (MyomiRNAs), which could be potentially reflected in the blood plasma miRNA expression profile. The expression of specific circulating miRNAs in patients with different muscle performances was analyzed. Patients' blood plasma was evaluated for the expression of myomiRNAs: miRNA-29a, miRNA-29b, miRNA-1, miRNA-133a, miRNA-133b, miRNA-206, miRNA-208b and miRNA-499, and the data were correlated with diagnostic indicators of the disease. We showed a specific sarcopenia miRNA profile that could be considered a possible biomarker for the disease. Patients with low muscle performance showed increased miRNA-1, miRNA-29a and miRNA-29b expression and decreased for the miRNA-206, miRNA-133a, miRNA-133b, miRNA-208b and miRNA-499 expression. We show that the severity of muscle performance deterioration in sarcopenia correlates with specific miRNA expression. We also propose the profile of miRNAs expression in blood plasma as a specific biomarker for sarcopenia diagnostics. Future clinical studies will be necessary to eventually naturally have to elucidate the underlined molecular mechanism responsible for specific miRNAs expression in sarcopenia pathology and progression of the disease.
Circ Res. 2021 Jun 11. 128(12): 1851-1867

Walking Exercise Therapy Effects on Lower Extremity Skeletal Muscle in Peripheral Artery Disease.

Mary M McDermott, Sudarshan Dayanidhi, Kate Kosmac, Sunil Saini, Joshua Slysz, Christiaan Leeuwenburgh, Lisa Hartnell, Robert Sufit, Luigi Ferrucci.

  Walking exercise is the most effective noninvasive therapy that improves walking ability in peripheral artery disease (PAD). Biologic mechanisms by which exercise improves walking in PAD are unclear. This review summarizes evidence regarding effects of walking exercise on lower extremity skeletal muscle in PAD. In older people without PAD, aerobic exercise improves mitochondrial activity, muscle mass, capillary density, and insulin sensitivity in skeletal muscle. However, walking exercise increases lower extremity ischemia in people with PAD, and therefore, mechanisms by which this exercise improves walking may differ between people with and without PAD. Compared with people without PAD, gastrocnemius muscle in people with PAD has greater mitochondrial impairment, increased reactive oxygen species, and increased fibrosis. In multiple small trials, walking exercise therapy did not consistently improve mitochondrial activity in people with PAD. In one 12-week randomized trial of people with PAD randomized to supervised exercise or control, supervised treadmill exercise increased treadmill walking time from 9.3 to 15.1 minutes, but simultaneously increased the proportion of angular muscle fibers, consistent with muscle denervation (from 7.6% to 15.6%), while angular myofibers did not change in the control group (from 9.1% to 9.1%). These findings suggest an adaptive response to exercise in PAD that includes denervation and reinnervation, an adaptive process observed in skeletal muscle of people without PAD during aging. Small studies have not shown significant effects of exercise on increased capillary density in lower extremity skeletal muscle of participants with PAD, and there are no data showing that exercise improves microcirculatory delivery of oxygen and nutrients in patients with PAD. However, the effects of supervised exercise on increased plasma nitrite abundance after a treadmill walking test in people with PAD may be associated with improved lower extremity skeletal muscle perfusion and may contribute to improved walking performance in response to exercise in people with PAD. Randomized trials with serial, comprehensive measures of muscle biology, and physiology are needed to clarify mechanisms by which walking exercise interventions improve mobility in PAD.

Keywords:  exercise; ischemia; mitochondria; perfusion; peripheral artery disease; plasma; skeletal muscle

DOI:  https://doi.org/10.1161/CIRCRESAHA.121.318242
JPEN J Parenter Enteral Nutr. 2021 Nov;45(S2): 12-15

Current guidelines for nutrition therapy in cancer: The arrival of a long journey or the starting point?

Alessandro Laviano.

  Large epidemiological data reveal that cancer is progressively becoming a chronic and disabling disease. Implementation in daily practice of early therapies aiming at addressing patients' needs is imperative. Nutrition is a major determinant of patients' quality of life, yet it is frequently neglected. Hopefully, reverting this skeptical clinical approach to nutrition, clinical practice guidelines of nutrition care in patients with cancer have been developed and published by international oncology and nutrition societies. By analyzing the more recent guidelines, it appears that a number of issues may contribute to their insufficient implementation in daily practice. Among them are heterogeneity of recommendations across different guidelines and insufficient robustness of evidence, as well as questionable generalization of recommendations. Future guidelines should aim at providing tumor-specific recommendations for the whole clinical journey of patients with cancer. Also, new, interesting areas should be covered, including fasting metabolism and circadian rhythmicity.

Keywords:  cancer; guidelines; limitations; nutrition care; perspective

DOI:  https://doi.org/10.1002/jpen.2288
Geriatr Nurs. 2021 Dec 09. pii: S0197-4572(21)00366-9. [Epub ahead of print]43 159-166

Factors related to dysphagia-specific quality of life in aged patients with neurologic disorders: A cross-sectional study.

Sujin Jung, Ji-Su Kim, Insil Jang, Hyejin Kim.

  This cross-sectional study aimed to analyze dysphagia-specific quality of life and its influencing factors in aged patients with neurologic disorders, and is reported according to the STROBE checklist for observational research. The study included 120 outpatients, aged ≥65 years, diagnosed with neurologic diseases at a general hospital Neurology Department in Seoul, Korea. Data collected during a one-month (March and April 2021) questionnaire survey were statistically analyzed using SPSS. Factors related to dysphagia-specific quality of life were gender, education level, neurological diagnosis, type of diet, subjective swallowing disturbance, and affectionate support-a subscale of social support. The combined explanatory power of these factors was 42.1%. It is essential to note that the factors related to the emotional, functional, and physical domains-the subscales of dysphagia-specific quality of life-are different. Therefore, each factor should be considered when planning nursing interventions to improve dysphagia-specific quality of life.

Keywords:  Dysphagia; Nervous system disease; Nursing; Nutritional status; Quality of life; Social support; Subjective swallowing disturbance

DOI:  https://doi.org/10.1016/j.gerinurse.2021.11.016
PLoS One. 2021 ;16(12): e0261175

REVOLUTION (Routine EValuatiOn of people LivIng with caNcer)-Protocol for a prospective characterisation study of patients with incurable cancer.

Rebekah Patton, Jane Cook, Erna Haraldsdottir, Duncan Brown, Ross D Dolan, Donald C McMillan, Richard J E Skipworth, Marie Fallon, Barry J A Laird.

INTRODUCTION: There is a pressing need for a holistic characterisation of people with incurable cancer. In this group, where quality of life and improvement of symptoms are therapeutic priorities, the physical and biochemical manifestations of cancer are often studied separately, giving an incomplete picture. In order to improve care, spur therapeutic innovation, provide meaningful endpoints for trials and set priorities for future research, work must be done to explore how the tumour influences the clinical phenotype. Characterisation of the host-tumour interaction may also provide information regarding prognosis, allowing appropriate planning of investigations, treatment and referral to palliative medicine services.METHODS: Routine EValuatiOn of people LivIng with caNcer (REVOLUTION) is a prospective observational study that aims to characterise people with incurable cancer around five key areas, namely body composition, physical activity, systemic inflammatory response, symptoms, and quality of life by developing a bio-repository. Participants will initially be recruited from a single centre in the UK and will have assessments of body composition (bio-impedance analysis [BIA] and computed tomography [CT]), assessment of physical activity using a physical activity monitor, measurement of simple markers of inflammation and plasma cytokine proteins and three symptom and quality of life questionnaires.
DISCUSSION: This study aims to create a comprehensive biochemical and clinical characterisation of people with incurable cancer. Data in this study can be used to give a better understanding of the 'symptom phenotype' and quality of life determinants, development of a profile of the systemic inflammatory response and a detailed characterisation of body composition.

DOI: https://doi.org/10.1371/journal.pone.0261175
Hum Mol Genet. 2021 Dec 17. pii: ddab360. [Epub ahead of print]

A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic tau mouse model of Alzheimer disease.

Ramesh Kandimalla, Maria Manczak, Jangampalli Adi Pradeepkiran, Hallie Morton, P Hemachandra Reddy.

  The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy, and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer's disease (ad). Our lab reported increased levels of Aβ and P-Tau, and abnormal interactions between Aβ and Drp1, P-Tau, and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in ad. These abnormal interactions, result in the proliferation of dysfunctional mitochondria in ad neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in ad. To determine the impact of reduced Drp1 in ad, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/-) mice and generated double mutant (P301LDrp1+/-) mice. In the current study, we assessed cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology & mitochondrial function, dendritic spines in Tau mice relative to double mutant mice. When compared to Tau mice, double mutant mice did better on Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA and proteins levels autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared to Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number is reduced and length is increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.

Keywords:  Mitochondria Alzheimer’s disease Mitophagy Autophagy Dynamin-related protein 1 Oxidative stress Mitochondrial biogenesis

DOI:  https://doi.org/10.1093/hmg/ddab360
Curr Res Pharmacol Drug Discov. 2021 ;2 100047

Crosstalk between anticancer drugs and mitochondrial functions.

Kuleshwar Sahu, Urvashi Langeh, Charan Singh, Arti Singh.

  Chemotherapy is an important component of cancer treatment, which has side effects like vomiting, peripheral neuropathy, and numerous organ toxicity but the most significant outcomes of chemotherapy are cognitive impairment, which is mainly referred to as chemobrain or CICI (chemotherapy-induced cognitive impairment). It is characterized by difficulty with language, concentrating, processing speed, learning, and memory, as it affects the hippocampus areas of the brain. Mitochondrial dysfunction and oxidative stress are one of the major mechanisms causing chemobrain. The generation of reactive oxygen species (byproducts of oxidative phosphorylation) mainly occurs in mitochondria that play a prominent role in the induction of oxidative stress. The homeostasis of ROS in the mitochondria is maintained by mitochondrial antioxidant mechanism via enzymes like catalase, glutathione, and superoxide dismutase. Lungs and breast cancer are the two most common types of cancer, which are the most leading cancers in the world with about 4.18 million cases. In this review we exposed the current knowledge regarding chemotherapy-induced oxidative stress and mitochondrial dysfunction to cause cognitive impairment.We especially focused on the antineoplastic agent (ADRIAMYCIN, CYCLOPHOSPHAMIDE), platinum group agent CISPLATIN, antimetabolite agents (METHOTREXATE), and nitrogen mustard agent (CARMUSTINE) which increase oxidative stress and inflammatory markers in the PNS (peripheral nervous system) as well as the central nervous system. We also highlight the behavioural and functional changes in the brain.

Keywords:  Chemobrain; Chemotherapy; Cognitive impairment; Mitochondrial dysfunction; Oxidative stress; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.crphar.2021.100047
J Appl Biomed. 2020 Aug;18(2-3): 61-69

Association of FGF19, FGF21 and FGF23 with carbohydrate metabolism parameters and insulin resistance in patients with chronic kidney disease.

Malgorzata Marchelek-Mysliwiec, Violetta Dziedziejko, Katarzyna Dolegowka, Andrzej Pawlik, Krzysztof Safranow, Joanna Stepniewska, Magda Wisniewska, Jolanta Malyszko, Kazimierz Ciechanowski.

  Insulin resistance (IR) is characterised by increased gluconeogenesis in the liver and the resistance of peripheral receptors to insulin. Several factors, including IR, type 2 diabetes, new-onset diabetes after transplant (NODAT) and secondary parathyroidism, are related to chronic kidney disease (CKD). These factors are associated with higher mortality due to the increased risk of cardiovascular complications. Many factors have been identified as potential markers of IR in CKD. These factors include fibroblast growth factors (FGFs), a subfamily of endocrine polypeptides. In this study, we examined the association of FGF19, FGF21 and FGF23 with selected parameters related to carbohydrate metabolism and insulin resistance in non diabetic patients with predialysis CKD and in non diabetic patients after renal transplantation. The study included 108 non diabetic subjects: 40 patients with predialysis CKD, 45 patients with CKD who had undergone renal transplantation, and 23 healthy subjects (control group). In patients who had undergone renal transplantation, concentrations of FGF23 were increased compared to the control group and patients with predialysis CKD. The highest and lowest FGF19 concentrations were observed in CKD patients and in patients who had undergone kidney transplantation, respectively. This difference was statistically significant. Leptin concentrations were higher in CKD patients compared to the control group and patients who had undergone kidney transplantation. There were no statistically significant differences in adiponectin concentrations, lean body mass or fat tissue mass between the studied groups. HOMA-IR and insulin levels were significantly increased in CKD patients and in patients who had undergone renal transplantation in comparison to the control group. The results of the study suggest the involvement of FGF in carbohydrate metabolism and insulin resistance in patients with predialysis CKD, as well as a correlation with kidney function.

Keywords:  Body composition; Chronic kidney disease; FGF19; FGF21; FGF23; Insulin

DOI:  https://doi.org/10.32725/jab.2020.005
Behav Brain Res. 2021 Dec 11. pii: S0166-4328(21)00603-3. [Epub ahead of print] 113715

Anorexia disrupts glutamate-glutamine homeostasis associated with astrocytes in the prefrontal cortex of young female rats.

Pamela Reyes-Ortega, María Berenice Soria-Ortiz, Verónica M Rodríguez, Eva Olivia Vázquez-Martínez, Mauricio Díaz-Muñoz, Daniel Reyes-Haro.

  Anorexia nervosa is an eating disorder characterized by self-starvation and excessive weight loss with a notorious prevalence in young women. The neurobiology of AN is unknown but murine models, like dehydration induced anorexia, reproduce weight loss and avoidance of food despite its availability. Astrocytes are known to provide homeostatic support to neurons, but it is little explored if anorexia affects this function. In this study, we tested if DIA disrupts glutamate-glutamine homeostasis associated with astrocytes in the prefrontal cortex of young female rats. Our results showed that anorexia reduced the lactate/pyruvate ratio, as well as endogenous glutamate and glutamine. These effects correlated with a reduced expression of the glutamate transporters (GLT-1 and GLAST) and glutamine synthetase, all of them are preferentially expressed by astrocytes. Accordingly, the expression of GFAP was reduced. Anorexia reduced the astrocyte density, promoted a de-ramified morphology, and augmented the de-ramified/ramified astrocyte ratio in the medial prefrontal cortex and orbitofrontal cortex, but not in the motor cortex (M2). The increase of a de-ramified phenotype correlated with increased expression of vimentin and nestin. Based on these results, we conclude that anorexia disrupts glutamate-glutamine homeostasis and the redox state associated with astrocyte dysfunction.

Keywords:  Anorexia; GFAP; food avoidance; food restriction; glutamate transporters; glutamine synthetase

DOI:  https://doi.org/10.1016/j.bbr.2021.113715
Curr Oncol. 2021 Nov 17. 28(6): 4805-4820

The Relationship between Nutritional Status and Body Composition with Clinical Parameters, Tumor Stage, CA19-9, CEA Levels in Patients with Pancreatic and Periampullary Tumors.

Aneta Jachnis, Maciej Tomasz Słodkowski.

  Recent studies have obtained inadequate data on the association between nutritional status, body composition, clinical parameters and tumor stage in patients withpancreatic and periampullary tumors. The purpose of this study was to assess the relationship between nutritional status (NS), body composition (BC) and selected clinical parameters in patients with pancreatic and periampullary cancer, as well as describe the differences between resection and non-resection groups. This is a prospective study of 76 patients with pancreatic and periampullary tumors. We evaluated NS, BMI, body mass loss (BML) and albumin, total protein, CRP, CEA, CA19-9, lipase, amylase, tumor stage, and BC using bioelectrical impedance (BIA). All subjects were divided into resection (n = 59) and non-resection (n = 17) groups. The non-resection group had a worse NS, as well as increased amylase and WBC, compared to the resection. The selected parameters of BC corresponded to BML albumin, TP, NS, age, BMI, Karnofsky, RBC, HCT and HGB. No associations were found between BC with tumor size, CRP, CA19-9, and CEA. We recorded the relationship between metastasis and NRS, as well as tumor size with SGA. The percentage of BML was positively correlated with age and CRP but negatively correlated with RBC, HGB, HCT and anthropometric measurements. We found many statistical correlations with NS and selected parameters, as well as differences between the resection and non-resection group. The detection of early prognostic factors of nutritional impairments would improve the quality of life and reduce the rate of postoperative complications.

Keywords:  body composition; malnutrition; nutritional status; pancreatic cancer

DOI:  https://doi.org/10.3390/curroncol28060406
Front Oncol. 2021 ;11 783231

Impact of TNF-α Gene Polymorphisms on Pancreatic and Non-Small Cell Lung Cancer-Induced Cachexia in Adult Egyptian Patients: A Focus on Pathogenic Trajectories.

Rana Yehia, Mona Schaalan, Dalaal M Abdallah, Amr S Saad, Neven Sarhan, Samira Saleh.

  Background: Cachexia is a frequent syndrome in pancreatic and non-small cell lung (NSCL) cancer patients. The storm of cancer-induced inflammatory cytokines, in particular TNF-α, is a crucial pathogenic mechanism. Among the molecular alterations accused of cancer-induced cachexia, TNF-α 308 G/A (rs1800629) and -1031T/C (rs1799964) are single-nucleotide polymorphisms (SNPs) within the gene encoding this pro-inflammatory cytokine. Recent studies have demonstrated the crucial role of non-coding microRNAs (miRNAs) in pathogenesis of different diseases including cachexia. Moreover, the mechanistic cytokine signaling pathway of miR-155, as a TNF-α regulator, supports the involvement of SOCS1, TAB2, and Foxp3, which are direct targets of TNF-α gene.Aim: A case-control study (NCT04131478) was conducted primarily to determine the incidence of TNF-α 308 G/A (rs1800629) and -1031T/C (rs1799964) gene polymorphisms in adult Egyptian patients with local/advanced or metastatic pancreatic or NSCL cancer and investigate both as cachexia risk factors. The association of gene polymorphism with cachexia severity and the expression of miR-155 in cachectic patients were analyzed. A mechanistic investigation of the cytokine signaling pathway, involving SOCS1, TAB2, and Foxp3, was also performed.
Results: In both pancreatic and NSCL cancer cohorts, the mutant TNF-α variant of 308 G/A was positively associated with cachexia; on the contrary, that of 1031T/C was negatively associated with cachexia in the NSCL cancer patients. MiR-155 was higher in cachexia and in alignment with its severity in the cachectic group as compared with the non-cachectic group in both the pancreatic and NSCL cancer patients. Though TAB2 did not change to any significant extent in cachectic patients, the levels of SOCS1 and Foxp3 were significantly lower in the cachectic group as compared with the non-cachectic group.
Conclusion: Carriers of the A allele 308 G/A gene and high miR-155 are at greater risk of cachexia in both the pancreatic and NSCL cancer patients; however, the mutant variant of 1031T/C gene is protective against cachexia in the NSCL cancer patients. Finally, high levels of miR-155 in the cachectic group lead to negative feedback inhibition of both SOCS1 and Foxp3 in both the pancreatic and NSCL cancer patients.

Keywords:  Foxp3; SOCS1; TAB2; TNF-α gene; cachexia; miR-155; pancreatic and NSCL cancer; single-nucleotide polymorphism

DOI:  https://doi.org/10.3389/fonc.2021.783231
Head Neck. 2021 Dec 16.

Toxicity of induction chemotherapy in head and neck cancer: The central role of skeletal muscle mass.

Alexane Lere-Chevaleyre, Maureen Bernadach, Céline Lambert, Lucie Cassagne, Mathilde Puechmaille, Thierry Mom, Laurent Gilain, Michel Lapeyre, Yves Boirie, Julian Biau, Nicolas Saroul.

  BACKGROUND: To assess the impact of nutritional status on tolerance to induction chemotherapy by docetaxel, cisplatin and 5-fluorouracil (ICT) in head and neck cancer (HNC).METHODS: Ninety-two HNC patients were included. Toxicity was assessed according to common terminology criteria for adverse events. Nutritional status was assessed by body mass index (BMI), serum albumin, nutritional risk index (NRI), and CT scan (skeletal muscle mass index [SMI] at the first lumbar vertebral level).
RESULTS: Before treatment, average BMI was 22.7 ± 4.6 kg/m2 , serum albumin 38.7 ± 5.8 g/L, NRI 97.6 ± 10.6, and SMI 36.4 ± 7.9 cm2 /m2 . After treatment, BMI was 23 ± 4.5, serum albumin 30.2 ± 7.1, and NRI 88.1 ± 9.2. During ICT, 52 (62%) patients developed at least one toxicity ≥ Grade 3. Pre-treatment SMI was the only predictive factor of toxicity irrespective of BMI (p = 0.04).
CONCLUSION: Low skeletal muscle mass is a predictive factor of toxicity to ICT in HNC.

Keywords:  body composition; chemo-toxicity; head and neck cancer; muscular mass; nutritional status; taxotere-platine-fluorouracil

DOI:  https://doi.org/10.1002/hed.26954
Best Pract Res Clin Obstet Gynaecol. 2021 Nov 15. pii: S1521-6934(21)00168-1. [Epub ahead of print]

The use of menopausal hormone therapy after cancer.

Annabelle Brennan, Martha Hickey.

  The changing landscape of gynaecological and breast cancers has involved the development of more targeted and effective therapies, and improved survival. Ultimately, these changes result in an increasing number of women surviving their cancer diagnosis, with increasing emphasis on quality-of-life issues by following treatments. Many of these women experience severe menopausal symptoms associated with cancer treatments, but the hormonal nature of many gynaecological and breast cancers complicates the effective management of these symptoms. Generally, there is a paucity of high-quality data directly examining the safety of menopausal hormone therapy (MHT) following many female cancers, and more research is needed with long term follow-up to ensure the provision of comprehensive, patient-focussed care. This article aims to synthesise and evaluate the current evidence to provide comprehensive yet accessible information to clinicians to help guide treatment decisions about the use of MHT in women, who have experienced, or are at increased risk of, both gynaecological and breast cancers. These treatment decisions should often be made in a multi-disciplinary setting which encourages shared decision-making with patients.

Keywords:  BRCA, Breast cancer; Cervical cancer; Endometrial cancer; Hormone replacement therapy, HRT; Menopausal hormone therapy, MHT; Ovarian cancer

DOI:  https://doi.org/10.1016/j.bpobgyn.2021.11.005
Neural Regen Res. 2022 Jul;17(7): 1617-1622

MicroRNA is a potential target for therapies to improve the physiological function of skeletal muscle after trauma.

Xin-Yi Gu, Bo Jin, Zhi-Dan Qi, Xiao-Feng Yin.

  MicroRNAs can regulate the function of ion channels in many organs. Based on our previous study we propose that miR-142a-39, which is highly expressed in denervated skeletal muscle, might affect cell excitability through similar mechanisms. In this study, we overexpressed or knocked down miR-142a-3p in C2C12 cells using a lentivirus method. After 7 days of differentiation culture, whole-cell currents were recorded. The results showed that overexpression of miR-142a-3p reduced the cell membrane capacitance, increased potassium current density and decreased calcium current density. Knockdown of miR-142a-3p reduced sodium ion channel current density. The results showed that change in miR-142a-3p expression affected the ion channel currents in C2C12 cells, suggesting its possible roles in muscle cell electrophysiology. This study was approved by the Animal Ethics Committee of Peking University in July 2020 (approval No. LA2017128).

Keywords:  C2C12; denervation; ion channels; miR-142a-3p; microRNA; muscle; patch clamp; potassium; sodium; whole-cell currents

DOI:  https://doi.org/10.4103/1673-5374.330620
Beijing Da Xue Xue Bao Yi Xue Ban. 2021 Dec 18. 53(6): 1188-1190

[A case report of colchicine-induced myopathy in a patient with chronic kidney disease].

Y J DU, W C Liu, X Chen, Y J Cheng.

Colchicine plays an important role in the treatment of gout and some other diseases. Besides gastrointestinal symptoms, myopathy has been reported as a rare side effect of colchicine in some patients. We report a case of myopathy in a patient with chronic kidney disease caused by high-dose colchicine, and then review literature on colchicine-induced myopathy, so as to provide some experience for the clinical diagnosis, treatment and medication safety. A 51-year-old male patient with 10 years of gout and 5 years of chronic kidney disease history and irregular treatment was admitted to the hospital with complaint of recurrent left wrist arthralgia and emerging lower extremities myalgia after intake of 40-50 mg colchicine in total within 20 days. Laboratory examinations showed significantly increased creatine kinase (CK) and then colchicine-induced myopathy was diagnosed preliminarily. After withdrawl of colchicine and implementation of hydration, alkalization and intramuscular injection of compound betamethasone, the symptoms of arthralgia and myalgia were relieved within 3 days and CK decreased to normal range gradually. According to literature reports, colchicine related myopathy was mostly characterized by proximal myasthenia and myalgia, accompanied by elevated CK level, which usually occurred days to weeks after initial administration of colchicine at the usual dosage in patients with renal impairment or a change in the underlying disease state in those receiving long-term therapy, and the features might remit within three to four weeks after the drug was discontinued. Electromyography of proximal muscles showed myopathy marked by abnormal spontaneous activity and muscle pathology waa marked by accumulation of lysosomes and autophagic vacuoles. Chronic kidney disease, liver cirrhosis, higher colchicine dose and concomitant cytochrome P450 3A4 (CYP3A4) inhibitors were associated with increased risk of myo-pathy. Based on the similar efficacy and lower adverse reaction rate compared with larger dosage, small dose of colchicine was recommended by many important current guidelines and recommendations in the treatment of gout. In consideration of potential risks, colchicine should be used with caution in patients with kidney or liver impairment, and in those taking CYP3A4 or P-glycoprotein inhibitors. For those patients, the drug dose should be adjusted and the latent adverse reactions should be monitored carefully.

Keywords: Colchicine; Myopathy; Side effect