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Pilot clinical trial of macimorelin to assess safety and efficacy in patients with cancer cachexia.

BACKGROUND: Cancer cachexia is associated with reduced body weight, appetite and quality of life (QOL) with no approved treatments. Growth hormone secretagogues like macimorelin have potential to mitigate these effects. METHODS: This pilot study assessed the safety and efficacy of macimorelin for 1 week. Efficacy was defined a priori as 1-week change in body weight (≥0.8 kg), plasma insulin-like growth factor (IGF)-1 (≥50 ng/mL) or QOL (≥15%). Secondary outcomes included food intake, appetite, functional performance, energy expenditure and safety laboratory parameters. Patients with cancer ca

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… Cancer cachexia may promote ghrelin resistance, wherein elevated ghrelin is seen simultaneously with depressed appetite, which might be overcome by exogenous ghrelin/GHS administration. 35 , 36 Macimorelin did not impact appetite, food intake or energy expenditure in the current study, which could suggest … Active ghrelin levels and active to total ghrelin ratio in cancer‐induced cachexia. J Clin Endocrinol Metab 2005;90:2920–2926. 37. Hiura Y, Takiguchi S, Yamamoto K, Takahashi T, Kurokawa Y, Yamasaki M, et al. …

Multifunctional Actions of Ninjinyoeito, a Japanese Kampo Medicine: Accumulated Scientific Evidence Based on Experiments With Cells and Animal Models, and Clinical Studies.

Herbal medicines are currently employed for the treatment of several types of diseases, and also employed for the improvement of Quality of Life (QOL) of patients over the world, in particular, in Asian countries. In Japan, a Japanese herbal medicine namely kampo medicine has been prescribed for the improvement of QOL of patients. Ninjinyoeito (NYT), composed of 12 herbal plants, is one of kampo medicines and used for helping recovery of diseases and improving several symptoms that suffer patients such as anemia, anorexia and fatigue. Recent scientific research approaches to kampo medicines wi

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… On the other hand, Rikkunshito, a kampo medicine prescribed for gastrointestinal disorders, enhances orexigenic ghrelin-mediated signaling ( 10 , 12 ). Acyl ghrelin is the active hormone and it degrades inactive form of des-acyl ghrelin by ghrelin deacylating enzymes ( 32 ). … Pachymic acid in Poria sclerotium as well as glycycoumarin in Glycyrrhiza and 10-gingerol in Ginger inhibited this enzyme activity and kept circulating acyl ghrelin levels, thus maintaining the effect of ghrelin ( 32 ). …

Abstracts of the 5(th) Cachexia Conference, Barcelona, Spain, December 5-8, 2009.

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Postoperative ileus-An ongoing conundrum.

BACKGROUND: Postoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder. PURPOSE: This review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non-pharmacological) and their effica

Quantitative gastrointestinal and psychological traits associated with obesity and response to weight-loss therapy.

BACKGROUND & AIMS: Weight loss after pharmacotherapy varies greatly. We aimed to examine associations of quantitative gastrointestinal and psychological traits with obesity, and to validate the ability of these traits to predict responses of obese individuals to pharmacotherapy. METHODS: In a prospective study, we measured gastric emptying of solids and liquids, fasting and postprandial gastric volume, satiation by nutrient drink test (volume to fullness and maximal tolerated volume), satiety after an ad libitum buffet meal, gastrointestinal hormones, and psychological traits in 328 normal-we

Peripheral administration of TAT-obestatin can influence the expression of liporegulatory genes but fails to affect food intake in mice.

Obestatin is a 23-amino-acid peptide originally regarded as an anorexigenic factor. However, most of the subsequent studies failed to confirm the initially reported anorexigenic properties of obestatin. Obestatin is incapable of crossing the blood brain barrier (BBB), which may affect its biological function. Here, we report the physiological effects of obestatin in mice after intraperitoneal administration of obestatin conjugated to the cell-permeable peptide TAT, which is capable of delivering different types of proteins through the BBB. Acute peripheral administration of 1 μmol/kg of TAT-ob

The L6 domain tetraspanin Tm4sf4 regulates endocrine pancreas differentiation and directed cell migration.

The homeodomain transcription factor Nkx2.2 is essential for pancreatic development and islet cell type differentiation. We have identified Tm4sf4, an L6 domain tetraspanin family member, as a transcriptional target of Nkx2.2 that is greatly upregulated during pancreas development in Nkx2.2(-/-) mice. Tetraspanins and L6 domain proteins recruit other membrane receptors to form active signaling centers that coordinate processes such as cell adhesion, migration and differentiation. In this study, we determined that Tm4sf4 is localized to the ductal epithelial compartment and is prominent in the

Chronic gastric electrical stimulation leads to weight loss via modulating multiple tissue neuropeptide Y, orexin, α-melanocyte-stimulating hormone and oxytocin in obese rats.

OBJECTIVES: Gastric electrical stimulation (GES) has great potential for the treatment of obesity. We investigated the impact of chronic GES on the alteration of adipose tissue and the regulation of neuropeptide Y (NPY), orexin (OX), α-melanocyte-stimulating hormone (α-MSH) and oxytocin (OXT), and their receptors in several tissues. MATERIAL AND METHODS: Most of the experiments included three groups of diet-induced obesity rats: (1) sham-GES (SGES); (2) GL-6mA (GES with 6 mA, 4 ms, 40 Hz, 2 s on, 3 s off at lesser curvature); and (3) SGES-PF (SGES rats receiving pair feeding to match the cons

Acute uterine irritation provokes colonic motility via transient receptor potential A(1)-dependent spinal NR2B phosphorylation in rats.

BACKGROUND: Patients with inflammatory gynecological/obstetrical problems often complain of irritable bowel syndrome. The authors examined whether acute uterus irritation reflexively provokes colonic motility in rat preparations. METHODS: A modified colon manometry and striated abdominal muscle electromyogram activity in response to mustard oil (MO) instillation into the uterine horn were continuously recorded in anesthetized rats. The lumbosacral (L6-S1) dorsal horn was dissected to assess the level and the cellular location of phosphorylated NR2B subunit using Western blotting and immunoflu

Towards Drug Repurposing in Cancer Cachexia: Potential Targets and Candidates.

As a multifactorial and multiorgan syndrome, cancer cachexia is associated with decreased tolerance to antitumor treatments and increased morbidity and mortality rates. The current approaches for the treatment of this syndrome are not always effective and well established. Drug repurposing or repositioning consists of the investigation of pharmacological components that are already available or in clinical trials for certain diseases and explores if they can be used for new indications. Its advantages comparing to de novo drugs development are the reduced amount of time spent and costs. In thi

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… Ghrelin Agonists Ghrelin was identified as the endogenous ligand of the growth hormone secretagogue (GHS) receptor; it is able to increase muscle mass through the GH/insulin-like growth factor-1 (IGF-1) axis and promote adiposity, and it is also a potent stimulator of food intake. … For these reasons, ghrelin has been suggested as a treatment to prevent cachexia [ 124 ]. Pralmorelin (GHRP-2) An example of one ghrelin agonist is the drug pralmorelin (GHRP-2), which is already approved in Japan and increases growth hormone release from the pituitary [ 123 ]. …

Obesity: pathophysiology and therapeutic interventions.

Over the past few decades, obesity has transitioned from a localized health concern to a pressing global public health crisis affecting over 650 million adults globally, as documented by WHO epidemiological surveys. As a chronic metabolic disorder characterized by pathological adipose tissue expansion, chronic inflammation, and neuroendocrine dysregulation that disrupts systemic homeostasis and impairs physiological functions, obesity is rarely an isolated condition; rather, it is frequently complicated by severe comorbidities that collectively elevate mortality risks. Despite advances in nutr

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… In both mice and humans, ghrelin-dependent hyperphagia and obesity are promoted by chronic AMPK activation [ 54 ]. … Additionally, obese mice have lower levels of GHSR expression and ghrelin transport across the BBB, which results in decreased ghrelin sensitivity and may encourage hypothalamic ghrelin resistance [ 55 , 56 ]. …

Cellular and Molecular Mechanisms Associating Obesity to Bone Loss.

Obesity is an alarming disease that favors the upset of other illnesses and enhances mortality. It is spreading fast worldwide may affect more than 1 billion people by 2030. The imbalance between excessive food ingestion and less energy expenditure leads to pathological adipose tissue expansion, characterized by increased production of proinflammatory mediators with harmful interferences in the whole organism. Bone tissue is one of those target tissues in obesity. Bone is a mineralized connective tissue that is constantly renewed to maintain its mechanical properties. Osteoblasts are responsib

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… Ghrelin is produced by the stomach, acting on appetite regulation and energy metabolism, improves the cardiovascular function, and can act in bone formation [ 123 ]. Erener et al. (2021) showed that ghrelin administration in mice enhanced the healing process of bone fractures [ 123 ]. … Notably, in patients with osteopenia, the systemic ghrelin concentration are inversely related to BMI values, and the osteoblasts isolated from those patients were resistant to ghrelin-mediated signaling [ 124 ]. …

Cancer cachexia: mechanisms and clinical implications.

Cachexia is a multifactorial process of skeletal muscle and adipose tissue atrophy resulting in progressive weight loss. It is associated with poor quality of life, poor physical function, and poor prognosis in cancer patients. It involves multiple pathways: procachectic and proinflammatory signals from tumour cells, systemic inflammation in the host, and widespread metabolic changes (increased resting energy expenditure and alterations in metabolism of protein, fat, and carbohydrate). Whether it is primarily driven by the tumour or as a result of the host response to the tumour has yet to be

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… These “appetite neurons” also express receptors for circulating leptin [ 83 ] and interleukin-1 β (IL-1 β ) [ 84 ], both of which downregulate appetite and receptors for ghrelin (the orexigenic protein, which increases AgRP) [ 85 ]. 3. … Ghrelin induces the release of growth hormone, regulates appetite, and has anti-inflammatory properties [ 129 , 130 ]. Initial human studies in Phase I open trials have confirmed safety and show some increase in appetite and body weight [ 131 ]. …

Expanded haemodialysis: news from the field.

Expanded haemodialysis (HDx) has emerged as a promising solution to improve haemodialysis effectiveness. A medium cut-off membrane allows the removal of a wider range of uraemic toxins. However, little is known about the potential interesting applications of HDx therapy. Feedback from the first routine use of HDx therapy under real-life conditions in European facilities was excellent for priming and rinse back. There was no adverse event after 5191 HDx treatments. Patients suffering from itching, restless legs syndrome, persistent asthenia or malnourishment could benefit from HDx therapy. More

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… For instance, leptin, pro-inflammatory cytokines such as IL-6, or more recently obestatin and acyl-ghrelin, have been associated with diminished appetite among patients with HD [ 8 , 9 ], and a wide range of accumulated middle molecules inhibited the ingestive behaviour in rats [ 10 ]. … Unacylated ghrelin and obestatin: promising biomarkers of protein energy wasting in children with chronic kidney disease. Pediatric Nephrology 2018; 33: 661–672 10. Anderstam B, Mamoun AH, Södersten P. et al. …

Molecular and cellular mechanisms of skeletal muscle atrophy: an update.

Skeletal muscle atrophy is defined as a decrease in muscle mass and it occurs when protein degradation exceeds protein synthesis. Potential triggers of muscle wasting are long-term immobilization, malnutrition, severe burns, aging as well as various serious and often chronic diseases, such as chronic heart failure, obstructive lung disease, renal failure, AIDS, sepsis, immune disorders, cancer, and dystrophies. Interestingly, a cooperation between several pathophysiological factors, including inappropriately adapted anabolic (e.g., growth hormone, insulin-like growth factor 1) and catabolic pr

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… The orexigenic hormone ghrelin as a potential means to target cachexia has recently received considerable attention [ 208 ]. The effects of synthetic human ghrelin, as well as ghrelin receptor agonists, are being evaluated in several trials. … Ghrelin, which is predominantly produced by the stomach, increases food intake through its actions on the hypothalamus [ 209 ]. In addition, serving as a growth hormone secretagogue and mainly mediating its effects via IGF-1, ghrelin also has anabolic effects. …

Herbal Medicine Ninjin'yoeito in the Treatment of Sarcopenia and Frailty.

Frailty and sarcopenia have recently gained considerable attention in terms of preventive care in Japan, which has an ever-increasing aging population. Sarcopenia is defined as atrophy of skeletal muscles caused by the age-related decrease in growth hormone/insulin-like growth factor and sex hormones. The Japanese Ministry of Health, Labor and Welfare reports that frailty can lead to impairment of both mental and physical functioning. Chronic diseases such as diabetes and dementia may underlie frailty. It is important to prevent progression of frailty and extend the healthy lifespan. In herbal

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… C. unshiu peel, Poria, Glycyrrhiza root, and panaxadiol derived from ginseng root improve ghrelin signaling underlying the mechanism of action of Ninjin'yoeito, leading to appetite stimulation and improvement in sarcopenia. … Hesperidin treats appetite loss and sarcopenia via suppression of the serotonin pathway and recovery of ghrelin secretion in the stomach [Figure 2A ; ( 68 )]. The improvement of sarcopenia by ghrelin can be attributed to the activation of the GH/ IGF-1 system ( 69 ). …

Indications for Sleeve Gastrectomy-Is It Worth Waiting for Comorbidities to Develop?

(1) Background and Objectives: Morbid obesity significantly increases the prevalence of comorbidities, such as heart disease, restrictive lung disease, stroke, diabetes mellitus and more. (2) Methods: Patients undergoing gastric sleeve surgery were divided into three groups with BMI between 30-34.9 kg/m2 (Group I), 35-39.9 kg/m2 (Group II), and over 40 kg/m2 (Group III). Preoperative examinations included cardiac ultrasound, respiratory function and laboratory tests, and preoperative comorbidities were also recorded. Following a one-year follow-up, we compared the rate of weight loss in the th

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… In addition to its restrictive effect, the procedure is also referred to as an endocrine surgical procedure since the gastric fundus is removed, in which a majority of ghrelin-producing cells are located [ 23 ]. … Analysis of the results of sleeve gastrectomy for morbid obesity and the role of ghrelin Surg. Today 2008 38 481 483 10.1007/s00595-007-3648-8 18516524 24. Poher A.L. Tschöp M.H. Müller T.D. …

Emerging concepts in the medical and surgical treatment of obesity.

The relentless rise in the prevalence of obesity predicts an exponential increase in the incidence of obesity-related complications. Medical and surgical treatments are necessary to prevent and treat obese co-morbidities, thereby avoiding disability and premature death. Interventions for obesity should be evaluated not by weight loss alone but against the new incidence in obesity-related co-morbidities, their remission or improvement. In combination with lifestyle measures, currently available pharmacological therapies -- rimonabant, orlistat and sibutramine -- achieve 5-10% weight loss, altho

Роль кишечника микробиота-митохондрия в нейродегенерации: основополагающие механизмы и потенциальные методы лечения.

Появляющиеся данные свидетельствуют о том, что микробиота кишечника тесно связана с патологическими проявлениями множественных нейродегенеративных заболеваний через ось кишечника, которая относится к перекрестку между кишечником и центральной нервной системой. Еще важнее то, что митохондрия считается выдающимся посредником взаимодействия между кишечной микробиотой и мозгом. Кишечные микробы могут модифицировать функцию митохондриала в центральной нервной системе, чтобы повлиять на развитие нейродегенеративных заболеваний. Митохондрия необходима для удовлетворения значительных потребностей носи

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… Ghrelin was previously shown to ameliorate Aβ-induced mitochondrial membrane depolarization, increase neuronal survival, and exert neuroprotective effects in an animal model of AD (Martins et al., 2013). … Ghrelin may represent a potential new treatment option for neurodegenerative diseases due to its anti-inflammatory and antiapoptotic actions associated with mitochondrial regulation. …