The small-molecule alkaloid halofuginone (HF) is obtained from febrifugine. Recent studies on HF have aroused widespread attention owing to its universal range of noteworthy biological activities and therapeutic functions, which range from parasite infections and fibrosis to autoimmune diseases. In particular, HF is believed to play an excellent anticancer role by suppressing the proliferation, adhesion, metastasis, and invasion of cancers. This review supports the goal of demonstrating various anticancer effects and molecular mechanisms of HF. In the studies covered in this review, the anticancer molecular mechanisms of HF mainly included transforming growth factor-β (TGF-β)/Smad-3/nuclear factor erythroid 2-related factor 2 (Nrf2), serine/threonine kinase proteins (Akt)/mechanistic target of rapamycin complex 1(mTORC1)/wingless/integrated (Wnt)/β-catenin, the exosomal microRNA-31 (miR-31)/histone deacetylase 2 (HDAC2) signaling pathway, and the interaction of the extracellular matrix (ECM) and immune cells. Notably, HF, as a novel type of adenosine triphosphate (ATP)-dependent inhibitor that is often combined with prolyl transfer RNA synthetase (ProRS) and amino acid starvation therapy (AAS) to suppress the formation of ribosome, further exerts a significant effect on the tumor microenvironment (TME). Additionally, the combination of HF with other drugs or therapies obtained universal attention. Our results showed that HF has significant potential for clinical cancer treatment.

• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Plicní arteriální hypertenze (PAH) je vzácné, ale závažné onemocnění, které je nevyléčitelné a progredující. I přes pokrok ve farmakologické léčbě PAH je morbidita i mortalita nemocných s PAH nadále vysoká. Jedním z nových léků, který mění prognózu nemocných, je sotatercept. Tento lék inhibuje signální dráhu transformujícího růstového faktoru β (transforming growth factor β, TGF-β), což vede k ovlivnění regulace růstu a diferenciace buněk plicních arteriol. Tento lék může zásadním způsobem pozitivně ovlivnit nejen symptomy, ale i celkovou mortalitu nemocných. Výsledky studií STELLAR a ZENITH ukázaly, že sotatercept významně zlepšuje vzdálenost, kterou jedinec ujde při šestiminutovém testu chůzí (six-minute walk test, 6MWT), snižuje riziko klinického zhoršení PAH a má pozitivní vliv na hemodynamiku PAH. Na základě provedených studií došlo k změně v léčebném schématu nemocných s PAH, kde sotatercept hraje významnou roli v kombinační farmakologické terapii.

Pulmonary arterial hypertension (PAH) is a rare but serious disease that is incurable and progressive. Despite advances in the pharmacological treatment of PAH, morbidity and mortality in PAH remain high One new drug that is changing the prognosis of patients is sotatercept. This drug inhibits the transforming growth factor β (TGFβ) signaling pathway, leading to an effect on the regulation of growth and differentiation of pulmonary arteriolar cells. This drug can have a major positive impact not only on symptoms but also on overall mortality. The results of the STELLAR and ZENITH trials showed that sotatercept improves the distance an individual walks in a six-minute walk test (6MWT), reduces the risk of clinical worsening of PAH and has a positive effect on the hemodynamics of PAH. Based on the studies conducted, there has been a change in the treatment regimen of PAH patients, with sotatercept playing a significant role in combination therapy.

The purpose of this study was to evaluate the feasibility of using the expression profile of transforming growth factor beta (TGF-β-1-3) to assess the progression of L/S spine degenerative disease. The study group consisted of 113 lumbosacral (L/S) intervertebral disc (IVD) degenerative disease patients from whom IVDs were collected during a microdiscectomy, whereas the control group consisted of 81 participants from whom IVDs were collected during a forensic autopsy or organ harvesting. Hematoxylin and eosin staining was performed to exclude degenerative changes in the IVDs collected from the control group. The molecular analysis consisted of reverse-transcription real-time quantitative polymerase chain reaction (RT-qPCR), an enzyme-linked immunosorbent assay (ELISA), Western blotting, and an immunohistochemical analysis (IHC). In degenerated IVDs, we noted an overexpression of all TGF-β-1-3 mRNA isoforms with the largest changes observed for TGF-β3 isoforms (fold change (FC) = 19.52 ± 2.87) and the smallest for TGF-β2 (FC = 2.26 ± 0.16). Changes in the transcriptional activity of TGF-β-1-3 were statistically significant (p < 0.05). Significantly higher concentrations of TGF-β1 (2797 ± 132 pg/mL vs. 276 ± 19 pg/mL; p < 0.05), TGF-β2 (1918 ± 176 pg/mL vs. 159 ± 17 pg/mL; p < 0.05), and TGF-β3 (2573 ± 102 pg/mL vs. 152 ± 11 pg/mL) were observed in degenerative IVDs compared with the control samples. Determining the concentration profiles of TGF-β1-3 appears to be a promising monitoring tool for the progression of degenerative disease as well as for evaluating its treatment or developing new treatment strategies with molecular targets.

• Publikační typ
• časopisecké články MeSH

Myelodysplastický syndrom je klonální onemocnění hemopoezy. U nemocných s nízkým rizikem progrese choroby či přechodu do akutní myeloidní leukemie je dominantním problémem cytopenie, a to především anemie. Ta se vyskytuje až u 90 % nemocných. Hlubší anemie zvláště u nemocných závislých na transfuzích významně snižuje kvalitu života, zvyšuje morbiditu i mortalitu. Dosud jsme byli odkázáni u většiny nemocných (s výjimkou nemocných s 5q-syndromem, kteří jsou výbornými respondenty na terapii lenalidomidem) na transfuze či podání erytropoetinů. Erytropoetiny ale nejsou příliš účinné právě u nemocných s již vyvinutou závislostí na transfuzích. Proto je velkým přínosem v léčbě těchto nemocných nový přípravek luspatercept, inhibitor dráhy transformujícího růstového faktoru β (transforming growth factor β, TGF – β), který vede až u 50 % nemocných k eliminaci transfuzní potřeby, výraznému zlepšení kvality života, a jak bylo recentně prokázáno, i k prodloužení přežívání. Prezentujeme zde kazuistiku nemocné, kde byl tento přípravek úspěšně použit v kombinaci s erytropoetinem a v dlouhodobé léčbě vysokou dávkou.

Myelodysplastic syndrome (MDS) is a clonal disease of the hemopoesis. In patients with a low risk of disease progression or transition to acute myeloid leukemia, cytopenia, especially anemia, is the dominant problem. It occurs in up to 90% of patients. Deeper anemia, especially in transfusion-dependent patients, significantly reduces quality of life, increases morbidity and mortality. So far, we could use as a treatment only transfusions or erythropoetins for most patients (except for patients with 5q-syndrome, who are excellent responders to lenalidomide therapy). However, erythropoetins are not very effective in patients with already developed transfusion dependence. Therefore, the new drug luspatercept,an inhibitor of the transforming growth factor p pathway, is of great benefit in the treatment of these patients, resulting in the elimination of the need for transfusions in up to 50% of patients, a significant improvement in quality of life and, as recently demonstrated, prolonged survival. We present a case report of a patient where this agent was successfully used in combination with erythropoietin and in long-term high-dose therapy.

BACKGROUND: Luspatercept, an inhibitor of the transforming growth factor beta (TGF-β) pathway, is a novel treatment for anemic patients with lower-risk myelodysplastic syndromes (MDS) with transfusion dependence (TD) who do not respond to erythropoiesis-stimulating agents (ESA) therapy or are not suitable candidates for this treatment. We present real-world experience with luspatercept therapy from two hematology centers in the Czech Republic. METHODS: By January 2024, 54 MDS patients (33 men, 21 women) with a median age of 74 years (range, 55-95) were treated with luspatercept ± ESA at two Charles University hematology centers in Prague and Hradec Králové. According to the WHO 2016 classification, the cohort included 32 MDS-RS-MLD, seven MDS-MLD, two patients with 5q- + ring sideroblasts (RS), 12 RARS-T, and 1 patient with CMML-0 + RS. SF3B1 mutation data were available for 45 patients. All patients were in the IPSS-R and IPSS-M lower-risk groups (except four IPSS-M high). The median follow-up was 17 months (range, 1-54). All patients were transfusion-dependent. Thirty-five (64.8%) patients had a high transfusion burden (HTB) with ≥ 4 transfusion units (TU)/8 weeks, and 19 (35.2%) had a low transfusion burden (LTB) (< 4 TU/8 weeks). The median time between diagnosis and initiation of luspatercept was 27 months (range, 4-156). ESA were used prior to luspatercept in 45 patients, and luspatercept was used as first-line treatment in nine patients. Thirty-one (61%) patients were treated simultaneously with ESA. RESULTS: Only patients who received luspatercept for ≥ 8 weeks (51 patients) were assessed. We evaluated the achievement of transfusion independence (TI) lasting 8, 12, 16, and 24 weeks. Thirty-two (62.7%) patients achieved TI for ≥ 8 weeks, 31 (60.7%) for ≥ 12 weeks, 29 (56.8%) for ≥ 16 weeks, and 25 (49%) for ≥ 24 weeks. Hematologic improvement (HI) without TI was achieved in six patients (11.7%). Overall, HI + TI was achieved in 38 patients (74.5%). Epoetin alfa was used simultaneously in 31 patients (60.7%). In 21 (55.2%) of all responding patients, concomitant therapy with epoetin alfa led to an improved response, with 16 reaching TI. Thirteen (25.5%) patients were nonresponders. Eight (21%) patients experienced therapy failure and became transfusion-dependent again. Optimal response required a gradual increase in the luspatercept dose to 1.75 mg/kg in up to 35 patients, with 23 responders (TI + HI). Response rates varied by transfusion burden: 79% in LTB and 50% in HTB reached TI. Of RS+ patients, 70% reached TI, while only one out of five RS- patients achieved TI. Among 39 SF3B1-positive patients, 61.6% achieved TI. In the low and very low IPSS-M groups, 86% of patients responded (TI + HI), compared to 62% in the moderate-low group. Luspatercept was well-tolerated, with no adverse events higher than grade II toxicity. CONCLUSION: We have demonstrated in real-world clinical practice that luspatercept is a very effective agent, even in an unselected, pretreated, significantly TD MDS population. The effect was particularly high in the IPSS-M low and very low groups. We believe that the relatively high response rate in our patients was influenced by the frequent use of a higher dose (1.75 mg/kg) and especially by adding ESA to luspatercept in poorly responding patients.

• Publikační typ
• časopisecké články MeSH

Folistatín je nedávno objavený hepatokín vychytávajúci a inaktivujúci členov rodiny transformujúcich rastových faktorov β (TGFβ). Má význam v regulácii reprodukčných procesov, intrauterínnom vývoji, budovaní a zachovávaní svalovej hmoty počas regenerácie a hladovania, ale predovšetkým v regulácii metabolických pochodov. Jeho asociácia s diabetom 2. typu (DM2T) potvrdili, okrem iných, dve kohortové štúdie: švédska štúdia trvajúca 19 rokov (n = 4 060) a fínska štúdia trvajúca 4 roky (n = 883). Tie poukázali na jeho potenciál byť novým včasným prediktívnym biomarkerom pre DM2T. U pacientov s diabetickou kardiomyopatiou sa prejavil jeho protektívny účinok so schopnosťou regresie kardiálnej dysfunkcie a redukcie fibrózy myokardu. Najnovšie výskumy otvárajú aj otázku terapeutického využitia folistatínu pri diabete, a to zmenou jeho expresie na zlepšenie vychytávania glukózy a zvýšenie inzulínovej senzitivity tkanív.

Follistatin is a recently discovered hepatokine that binds and neutralizes members of transforming growth factor β family (TGFβ). It has significance in reproductive actions, intrauterine development, building and maintaining muscle mass during regeneration and fasting, nevertheless mainly in regulation of metabolic pathways. Its association with type 2 diabetes (T2D) was besides other studies confirmed by two cohort studies: Swedish during 19-year follow-up (n = 4 060) and Finnish during 4-year follow-up (n = 883). Both demonstrated its potential to be a new early predictive biomarker for T2D. In patients with diabetic cardiomyopathy showed up its protective effect with capability to regress cardial dysfunction and reduce myocardial fibrosis. Latest researches opens up the issue of therapeutical usage of follistatin in diabetes with its change of expression for improvement of glucose uptake and increased insulin sensivity in tissues.

• MeSH
• biologické markery MeSH
• diabetes mellitus 2. typu * komplikace   prevence a kontrola   MeSH
• diabetická kardiomyopatie farmakoterapie   MeSH
• folistatin * fyziologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

• MeSH
• celogenomová asociační studie * MeSH
• dospělí MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus MeSH
• kolorektální nádory * genetika   epidemiologie   MeSH
• lidé MeSH
• mendelovská randomizace * MeSH
• rizikové faktory MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• metaanalýza MeSH

Transforming growth factor-β (TGF-β) and bone morphogenetic protein (BMP) signaling has fundamental roles in the regulation of the stem cell niche for both embryonic and adult stem cells. In zebrafish, male germ stem cell niche is regulated by follicle-stimulating hormone (Fsh) through different members of the TGF-β superfamily. On the other hand, the specific roles of TGF-β and BMP signaling pathways are unknown in the zebrafish male germ stem cell niche. Considering this lack of information, the present study aimed to investigate the pharmacological inhibition of TGF-β (A83-01) and BMP (DMH1) signaling pathways in the presence of recombinant zebrafish Fsh using testicular explants. We also reanalyzed single cell-RNA sequencing (sc-RNA-seq) dataset from adult zebrafish testes to identify the testicular cellular sites of smad expression, and to understand the physiological significance of the changes in smad transcript levels after inhibition of TGF-β or BMP pathways. Our results showed that A83-01 potentiated the pro-stimulatory effects of Fsh on spermatogonial differentiation leading to an increase in the proportion area occupied by differentiated spermatogonia with concomitant reduction of type A undifferentiated (Aund) spermatogonia. In agreement, expression analysis showed lower mRNA levels for the pluripotency gene pou5f3, and increased expression of dazl (marker of type B spermatogonia and spermatocyte) and igf3 (pro-stimulatory growth factor) following the co-treatment with TGF-β inhibitor and Fsh. Contrariwise, the inhibition of BMP signaling nullified the pro-stimulatory effects of Fsh, resulting in a reduction of differentiated spermatogonia and increased proportion area occupied by type Aund spermatogonia. Supporting this evidence, BMP signaling inhibition increased the mRNA levels of pluripotency genes nanog and pou5f3, and decreased dazl levels when compared to control. The sc-RNA-seq data unveiled a distinctive pattern of smad expression among testicular cells, primarily observed in spermatogonia (smad 2, 3a, 3b, 8), spermatocytes (smad 2, 3a, 8), Sertoli cells (smad 1, 3a, 3b), and Leydig cells (smad 1, 2). This finding supports the notion that inhibition of TGF-β and BMP signaling pathways may predominantly impact cellular components within the spermatogonial niche, namely spermatogonia, Sertoli, and Leydig cells. In conclusion, our study demonstrated that TGF-β and BMP signaling pathways exert antagonistic roles in the zebrafish germ stem cell niche. The members of the TGF-β subfamily are mainly involved in maintaining the undifferentiated state of spermatogonia, while the BMP subfamily promotes spermatogonial differentiation. Therefore, in the complex regulation of the germ stem cell niche by Fsh, members of the BMP subfamily (pro-differentiation) should be more predominant in the niche than those belonging to the TGF-β (anti-differentiation). Overall, these findings are not only relevant for understanding the regulation of germ stem cell niche but may also be useful for expanding in vitro the number of undifferentiated spermatogonia more efficiently than using recombinant hormones or growth factors.

• MeSH
• buněčná diferenciace genetika   MeSH
• dánio pruhované * genetika   MeSH
• folikuly stimulující hormon farmakologie   metabolismus   MeSH
• messenger RNA genetika   MeSH
• pyrazoly * MeSH
• spermatogeneze genetika   MeSH
• spermatogonie * metabolismus   MeSH
• testis metabolismus   MeSH
• thiosemikarbazony * MeSH
• transformující růstový faktor beta metabolismus   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Tumor necrosis factor-alpha (TNF-α) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not respond to this therapy in the long term, which delays efficient control of the intestinal inflammation. METHODS: We analyzed the power of serum biomarkers to predict the failure of anti-TNF-α. We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF-α, CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor-β1 (TGF-β1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1). RESULTS: We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF-β1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF-β1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment. CONCLUSIONS: The TGF-β1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF-β) are not markedly influenced by the treatment and that anti-TNF-α therapy decreases MMP-9 without influencing the treatment outcome.

• MeSH
• inhibitory TNF MeSH
• insulinu podobný růstový faktor II * MeSH
• lidé MeSH
• matrixová metaloproteinasa 9 MeSH
• transformující růstový faktor beta1 * MeSH
• vaskulární endoteliální růstový faktor A MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Growth hormone (GH) the most abundant hormone secreted by the anterior pituitary gland could have a role with other growth factors in wound healing because they can help in the physiological wound healing process.Aims: To investigate the effects of GH on facial skin wound healing in rabbits and to evaluate its effect on "insulin-like growth factor (IGF-1)" and "transforming growth factor- β (TGF-β)" in serum. Material and Method: Thirty healthy male rabbits included in this study were classified into two groups according to the day of euthanization 7 and 14 days of study, each group was subdivided into three groups; negative control group, positive control group, and treatment group, full-thickness circle 1 cm wounds were excised in the skin of the forehead for each rabbit without any medication.3-(treated group) full-thickness circle 1 cm wounds will excise in the skin of the forehead for each rabbit, 0.1ml [contain 1.2mg /3.6 IU] of growth hormone injected subcutaneously around the incision, the injection process is every other day.Result: showed a highly significant difference among all study groups in serum TGF-β (ng/L) and IGF (ng/ml) during the first and second weeks. the serum TGF-β at the end of the first and second weeks showed a significant elevation in the treatment group when compared to the other study groups. There is no significant difference between the two control groups. The serum IGF at the end of the first and second weeks showed a significant difference in IGF levels among all study groups.Conclusions: Topical GH has a role in skin wound healing since it can increase the serum level of TGF-β. GH also causes a decrease in serum IGF. Topical GH may have a positive impact on skin wound healing.

• MeSH
• aplikace lokální MeSH
• experimenty na zvířatech MeSH
• hojení ran * fyziologie   účinky léků   MeSH
• injekce subkutánní MeSH
• insulinu podobný růstový faktor I analýza   fyziologie   metabolismus   MeSH
• králíci MeSH
• kůže zranění   MeSH
• obličej MeSH
• růstový hormon aplikace a dávkování   terapeutické užití   MeSH
• studie případů a kontrol MeSH
• transformující růstový faktor beta analýza   fyziologie   metabolismus   MeSH
• Check Tag
• králíci MeSH