Published: Jan. 1, 2024
Language: Английский
Metabolism, Journal Year: 2024, Volume and Issue: 161, P. 156053 - 156053
Published: Oct. 28, 2024
Leptin has been established as the prototype adipose tissue secreted hormone and a major regulator of several human physiology functions. Here, we are primarily reviewing findings from studies in humans involving leptin administration. We describing metabolic, endocrine immunologic effects replacement conditions deficiency, such short-term fasting healthy individuals, relative energy deficiency sports (REDS), congenital (CLD), generalized (GL) partial lipodystrophy (PL), HIV-associated (HIV-L) treatment excess (common obesity, type 2 diabetes, steatotic liver disease). comparing results with preclinical models present main conclusions regarding role physiology, pathophysiology therapeutics. conclude that, substitution effectively reduces body weight fat mass through reduction appetite, it improves hypertriglyceridemia, insulin resistance hepatic steatosis (especially GL PL), restores neuroendocrine function gonadotropic axis), regulates adaptive immune system cell populations bone health. On contrary, excess, common obesity does not improve any metabolic abnormalities. Strategies to overcome tolerance/resistance diabetes have provided promising animal studies, which should though be tested randomized clinical trials.
Language: Английский
Citations
4
Pharmacology Research & Perspectives, Journal Year: 2025, Volume and Issue: 13(1)
Published: Jan. 1, 2025
Cachexia is a multifactorial metabolic syndrome characterized by weight and skeletal muscle loss caused underlying illnesses such as cancer, heart failure, renal failure. Inflammation, insulin resistance, increased protein degradation, decreased food intake, anorexia are the primary pathophysiological drivers of cachexia. causes physical deterioration functional impairment, quality life, lower response to active treatment, ultimately morbidity mortality, while difficulties in tackling cachexia its advanced phases heterogeneity among patients require an individualized multidisciplinary approach from early stage. Specifically, strategies combining nutritional exercise interventions well pharmacotherapy that directly affect pathogenesis cachexia, anti-inflammatory, metabolism-improving, appetite-stimulating agents, have been proposed, but none which demonstrated sufficient evidence date. Nevertheless, several agents recently emerged, including anamorelin, ghrelin receptor agonist, growth differentiation factor 15 neutralization therapy, melanocortin antagonist, candidates for ameliorating associated with cancer Therefore, this review, we outline cachexia-associated pharmacotherapy, corticosteroids, progesterone analogs, cannabinoids, anti-psychotics, thalidomide previously explored their efficacy, addition aforementioned novel along mechanisms.
Language: Английский
Citations
0
International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(5), P. 2344 - 2344
Published: March 6, 2025
Cell-mediated immunity and chronic inflammation are hallmarks of kidney disease (CKD). Growth differentiation factor 15 (GDF15) is a marker an integrative signal in stress conditions. Epidermal growth (EGF) tubule-specific protein that modulates the regeneration injured renal tubules. Neopterin product activated monocytes macrophages serves as cell-mediated immunity. Our aim was to assess role above-mentioned parameters progression CKD children using artificial intelligence tools. The study group consisted 151 with stages 1-5. EGF, GDF15, neopterin serum concentrations were assessed by ELISA. patients' anthropometric data, biochemical parameters, values implemented into neural network (ANN). most precise model contained input classified patients either 1-3 or 4-5 groups excellent accuracy 96.77%. presented AI model, may serve useful predictor progression. It suggests essential inflammatory processes function decline course children.
Language: Английский
Citations
0
Analytical Biochemistry, Journal Year: 2025, Volume and Issue: unknown, P. 115848 - 115848
Published: March 1, 2025
Language: Английский
Citations
0
Clinical and Translational Medicine, Journal Year: 2025, Volume and Issue: 15(4)
Published: March 30, 2025
Metastatic solid tumours remain a major challenge in clinical medicine, demanding innovation with novel treatment approaches and new synergistic combinations. Immunotherapy immune checkpoint inhibitors (ICIs) targeting PD-1 PD-L1 has improved the outcome for numerous tumour types groundbreaking way. However, resistance to immunotherapy is very frequent ultimately impacts vast majority of patients treated, often resulting fatal outcome. Similarly, advanced cancer cachexia event. This serious debilitating syndrome characterized by severe muscle wasting, weight loss systemic metabolic dysfunction which associates dismal prognosis. Cachexia further worsens can prevent ability continue on therapy. In this context, our recent study published Nature, titled "Neutralizing GDF-15 overcome anti-PD-1 anti-PD-L1 tumours," demonstrates multifaceted roles growth differentiation factor 15 (GDF-15) plays provides initial data promising therapeutic strategy counteract cachexia.1 Here, we discuss potential benefits blockade as an emerging approach both potentiate simultaneously mitigate cachexia, highlighting advancements their future implications (Figure 1). GDF-15, stress-induced cytokine belonging transforming factor-beta (TGF-β) superfamily, most overexpressed tumours2 recently been identified pivotal immunosuppressive within microenvironment (TME). study, integrative high-throughput pan-cancer immune-transcriptomics analyses revealed significant correlations between GDF15 mRNA signatures reflecting immunosupressed TME non-small cell lung (NSCLC), urothelial (UC), hepatocellular (HCC), among others. Recent studies have demonstrated that tumour-derived impair lymphocyte function-associated antigen-1 (LFA-1)-dependent T recruitment, thereby hindering effective surveillance facilitating escape.3 placental overexpression during early phase pregnancy appears suppress unwarranted reaction against semi-allogeneic foetus. Preclinical mouse models indicated neutralization improves T-cell infiltration enhances responses inhibitors, particularly anti-PD-1/PD-L1 Mechanistically, increases trafficking cytotoxic CD8+ cells into while reversing milieu regulatory (Tregs) dampened dendritic activity.4 These effects underscore sensitize resistant response providing avenues combination immunotherapy. light these findings, investigated first-in-human trial if visugromab could revert primary secondary anti-PD1/PD-L1 ICI relapsed/refractory patients.1 Only who had exhausted all available options directly progressed or after relapsed continuously ongoing were enrolled. As sequential biopsies substantially increased infiltration, proliferation, granzyme B expression interferon-γ-related signalling tumour. was maintained even enhanced when adding nivolumab upfront, single-cycle monotherapy phase. highly refractory patient population, achieved objective remissions 14%–19% NSCLC, UC HCC. Specifically noteworthy duration depth achieved. More than half responding obtained deeper per RECIST 1.1 categories (SD, PR, CR) approved inhibitor regimen, quite included chemotherapy. addition, more responders either confirmed complete (as PET-CT). suggests significantly anti-tumour may broaden, deepen prolong activity significantly, up level. Beyond its role, key driver complex associated mass, anorexia, chronic inflammation insulin resistance.5-7 affects 80% mortality poor quality life due disturbances inflammatory mass loss.8, 9 Patients exhibit higher levels serum correlates loss, body index reduction lipid metabolism dysregulation (reviewed Reference [10]). Unlike conventional nutritional support, fails catabolic pathogenesis inhibition target one underlying pathophysiologic causes. suggest blocking not only prevents but also recover physical cachectic subjects.11, 12 Various pharmacologic undertaken treat cachexia. September 2024, randomized 2 anti-GDF-15 antibody ponsegromab New England Journal Medicine demonstrating potent alleviate cancer-related cachexia.13 Ponsegromab at doses 400 mg Q4W safe led highest dose gain (averaging > 5% first weeks) undergoing standard-of-care anti-cancer therapy substantially. Long-term follow-up (up 1 year treatment) still pending expected be reported second 2025. other compounds now entered field cachexia-treatment following ponsegromab, strong interest field. It remains elucidated though, will improve overall survival. Initiation 3 announced Of important note, many chemotherapeutics (e.g. cis- carboplatin) targeted cytotoxics drug conjugates) currently first- second-line are known induce tissue- and/or tumoral secretion GDF-15.14, effect contribute top already existing induction nausea, anorexia should enhance immunosuppression illustrates vicious cycle creating: reducing tolerability therapy, inducing promoting decay via potently prevent/reverse mechanism it regimens nausea emesis. naturally represents tempting mult-directional concept deserves investigation. First- therapies benefit addition blockade. Apart from being impaired (specifically anti-PD1/-L1), therapeutics settings (including chemotherapeutics, ADCs ICIs) fuel overexpression/release Hence, become pillar anticancer lines where agents mostly employed. Ongoing planned trials evaluating safety efficacy neutralizing antibodies regard read out coming years. Randomized suffering UC, non-squamous NSCLC HCC start later Despite data, several challenges remain. Optimal dosing strategies well modalities require dedicated exploration. Furthermore, identification validation predictive biomarkers GDF-15-driven help stratify would approach. conclusion, publications such ours role immunosuppression, induction. Targeting immunotherapies cancer-associated research progresses, integrating practice offer substantial improvements. opinion, play critical CPI improvement patients. Further investigations molecular mechanisms combinations crucial translate findings tangible benefits. I. Melero, K. Klar E. Leo prepared jointly manuscript. The authors wish express gratitude relatives, investigators staff participated contributed trial. Melero principal investigator served consultant Catalym GmbH. employees GmbH, Martinsried, Germany, biotechnology company developing anti-GDF15 visugromab. declare human ethics approval does apply
Language: Английский
Citations
0
International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3218 - 3218
Published: March 30, 2025
The present study provides a detailed review of cardiovascular biomarkers critical for the diagnosis, prognosis, and pathophysiology diseases, leading cause global morbidity mortality. These aid in detecting disease onset, progression, therapeutic responses, providing insights into molecular mechanisms. Enzyme markers like AST, CK-MB, LDH, CA-III, HBDH are pivotal myocardial injury during acute events. Protein such as CRP, H-FABP, MPO shed light on inflammation oxidative stress. Cardiac Troponins, gold standard infarction exhibit high specificity sensitivity, while IMA GPBB indicate ischemia early damage. Peptide markers, including BNP NT-proBNP, crucial heart failure diagnosis management, reflecting ventricular stress remodeling. Novel peptides MR-proANP MR-proADM assessing severity. Lipid lipoprotein-associated phospholipase A2 oxylipins provide lipid metabolism atherosclerosis. Inflammatory stress-related biomarkers, TNFα, IL-6, GDF-15, Pentraxin 3, illuminate chronic CVDs. Hormonal copeptin endothelin-1 highlight neurohormonal activation, emerging ST2, galectin-3, PAPP-A, TMAO elucidate fibrosis, remodeling, metabolic dysregulation. inclusion microRNAs long non-coding RNAs represents breakthrough biomarker research, offering sensitive tools detection, risk stratification, targeting. This emphasizes diagnostic prognostic utility these advancing care through personalized medicine.
Language: Английский
Citations
0
New England Journal of Medicine, Journal Year: 2024, Volume and Issue: 391(24), P. 2373 - 2376
Published: Dec. 18, 2024
The author describes the science behind a study of ponsegromab to treat cancer cachexia. Ponsegromab suppresses pathway in neurons located specific regions brain stem.
Language: Английский
Citations
2
Physiological Reports, Journal Year: 2024, Volume and Issue: 12(23)
Published: Dec. 1, 2024
Growth differentiation factor (GDF15) has been considered a biomarker and recently hormonal driver for diseases in different populations. However, the role of GDF15 as health outcomes obese men from racial/ethnic background not evaluated. The objective this study was to investigate differences on relationship between markers glucometabolic status, profile, body composition bone mineral density (BMD) men. One hundred ninety-three diverse backgrounds were enrolled. BMD measured by dual energy X-ray absorptiometry. Serum GDF15, osteocalcin, C-terminal telopeptide, sclerostin, adiponectin, leptin, estradiol, testosterone, follicle-stimulating hormone, luteinizing 25-hydroxyvitamin D, lipid hemoglobin A1C (A1C) measured. Non-African Americans (NAA) had significantly higher level than African (AA). Level also patients with type 2 diabetes (T2DM). In both groups correlated lean mass. However. fat, LDL total cholesterol femoral neck only NAA appendicular mass AA. Ethnicity, T2DM found be independent predictors GDF15. We conclude that may influence parameters which affect cardiovascular risk osteoporosis races.
Language: Английский
Citations
1
medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown
Published: Nov. 15, 2024
Abstract Biological age reflects actual aging and overall health, but current clocks are often complex difficult to interpret, limiting their clinical application. In this study, we introduced a Gompertz law-based biological (GOLD BioAge) model that simplified assessment. We estimated GOLD BioAge using biomarkers found significant associations of the difference from chronological (BioAgeDiff) with risks morbidity mortality in NHANES. Moreover, developed ProtAge MetAge proteomics metabolomics data, which outperformed clinical-only predicting chronic disease UK Biobank. Benchmark analysis illustrated our models exceeded common across diverse groups both NHANES The results demonstrated algorithm effectively applied omics showing excellent performance age-related outcomes. Additionally, created version called Light BioAge, used three for reliably captured validation cohorts (CHARLS, RuLAS, CLHLS). It significantly predicted onset frailty, stratified frail individuals, collectively identified individuals at high risk mortality. summary, could provide valuable framework assessment public health practice. Highlights law based was proposed construct convenient interpretable calculations, had better risks. Our approach applicable metabolomics, yielding great prospect improve accuracy prevent diseases. version, biomarkers, it independently cohorts. BioAgeDiff
Language: Английский
Citations
0
Published: Nov. 27, 2024
Biological age reflects actual aging and overall health, but current clocks are often complex difficult to interpret, limiting their clinical application. In this study, we introduced a Gompertz law-based biological (GOLD BioAge) model that simplified assessment. We estimated GOLD BioAge using biomarkers found significant associations of the difference from chronological (BioAgeDiff) with risks morbidity mortality in NHANES. Moreover, developed ProtAge MetAge proteomics metabolomics data, which outperformed clinical-only predicting chronic disease UK Biobank. Benchmark analysis illustrated our models exceeded common across diverse groups both NHANES The results demonstrated algorithm effectively applied omics showing excellent performance age-related outcomes. Additionally, created version called Light BioAge, used three for reliably captured validation cohorts (CHARLS, RuLAS, CLHLS). It significantly predicted onset frailty, stratified frail individuals, collectively identified individuals at high risk mortality. summary, could provide valuable framework assessment public health practice.
Language: Английский
Citations
0