Coriolus versicolor (CV), known in traditional Chinese medicine for over 2000 years, is currently used in China and Japan to reduce chemotherapy or radiotherapy side effects in cancer patients. Despite extensive research, its effects still need improvement. This study aimed to determine if combining CV extract with LY294002, an inhibitor of the phosphatidylinositol-3-kinase (PI3K) signalling pathway, enhances cancer cell treatment, potentially leading to a novel therapeutic approach. Three human cancer cell lines (MCF-7, HeLa, and A549) were treated with CV extract alone or combined with LY294002. Cell viability was assessed using MTT assays. Then, HeLa and MCF-7 cells most sensitive to the co-treatment were used to evaluate colony formation, apoptosis, cell cycle, cell migration and invasion, and phospho-PI3K expression. The results demonstrated that LY294002 enhanced the CV extract's anti-tumour effects by reducing cell viability and colony formation. The combined treatment with CV extract and LY294002 more effectively induced G0/G1 cell cycle arrest, promoted apoptosis, reduced cell invasion and migration, and inhibited phospho-PI3K expression compared to each agent alone. This study highlights the potent cytotoxic enhancement between CV extract and LY294002 on cancer cells, primarily by inhibiting phospho-PI3K expression. These findings suggest promising avenues for developing novel combination therapies targeting cancer.

• Klíčová slova
• Coriolus versicolor, LY294002, cancer, phosphatidylinositol 3-kinase,
• MeSH
• antitumorózní látky farmakologie   MeSH
• apoptóza * účinky léků   MeSH
• buněčný cyklus účinky léků   MeSH
• buňky A549 MeSH
• chromony * farmakologie   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• HeLa buňky MeSH
• inhibitory fosfoinositid-3-kinasy * farmakologie   MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• morfoliny * farmakologie   MeSH
• nádorové buněčné linie MeSH
• pohyb buněk * účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• rostlinné extrakty farmakologie   chemie   MeSH
• signální transdukce účinky léků   MeSH
• synergismus léků MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one MeSH Prohlížeč
• antitumorózní látky MeSH
• chromony * MeSH
• fosfatidylinositol-3-kinasy MeSH
• inhibitory fosfoinositid-3-kinasy * MeSH
• morfoliny * MeSH
• rostlinné extrakty MeSH

Specific patterns of mitochondrial dynamics have been repeatedly reported to promote drug resistance in cancer. However, whether targeting mitochondrial fission- and fusion-related proteins could be leveraged to combat multidrug-resistant pediatric sarcomas is poorly understood. Here, we demonstrated that the expression and activation of the mitochondrial fission mediator DRP1 are affected by chemotherapy exposure in common pediatric sarcomas, namely, rhabdomyosarcoma and osteosarcoma. Unexpectedly, decreasing DRP1 activity through stable DRP1 knockdown neither attenuated sarcoma drug resistance nor affected growth rate or mitochondrial network morphology. The minimal impact on sarcoma cell physiology, along with the up-regulation of fission adaptor proteins (MFF and FIS1) detected in rhabdomyosarcoma cells, suggests an alternative DRP1-independent mitochondrial fission mechanism that may efficiently compensate for the lack of DRP1 activity. By exploring the upstream mitophagy and mitochondrial fission regulator, AMPKα1, we found that markedly reduced AMPKα1 levels are sufficient to maintain AMPK signaling capacity without affecting chemosensitivity. Collectively, our findings challenge the direct involvement of DRP1 in pediatric sarcoma drug resistance and highlight the complexity of yet-to-be-characterized noncanonical regulators of mitochondrial dynamics.

• MeSH
• antitumorózní látky farmakologie   MeSH
• chemorezistence * genetika   MeSH
• dynaminy * metabolismus   genetika   MeSH
• GTP-fosfohydrolasy metabolismus   genetika   MeSH
• lidé MeSH
• membránové proteiny metabolismus   genetika   MeSH
• mitochondriální dynamika * účinky léků   MeSH
• mitochondriální proteiny * metabolismus   genetika   MeSH
• mitochondrie * metabolismus   účinky léků   MeSH
• mitofagie účinky léků   genetika   MeSH
• nádorové buněčné linie MeSH
• osteosarkom metabolismus   patologie   farmakoterapie   genetika   MeSH
• proteiny asociované s mikrotubuly metabolismus   genetika   MeSH
• rhabdomyosarkom metabolismus   genetika   patologie   MeSH
• sarkom * metabolismus   genetika   farmakoterapie   patologie   MeSH
• signální transdukce účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antitumorózní látky MeSH
• DNM1L protein, human MeSH Prohlížeč
• dynaminy * MeSH
• FIS1 protein, human MeSH Prohlížeč
• GTP-fosfohydrolasy MeSH
• membránové proteiny MeSH
• Mff protein, human MeSH Prohlížeč
• mitochondriální proteiny * MeSH
• proteiny asociované s mikrotubuly MeSH

Dermatomyositis (DM) is a rare and debilitating, systemic, autoimmune disease. While heterogenous in presentation and severity, DM is primarily characterised by a spectrum of skin and muscle disease, which may include proximal muscle weakness and recalcitrant cutaneous eruptions. DM may also be associated with joint pain and stiffness, inflammatory arthritis, dysphagia, fatigue, and calcinosis. The current standard of care for DM includes glucocorticoids, immunosuppressants, and intravenous immunoglobulin (IVIg). Unfortunately, these medications are not uniformly effective and can lead to adverse events, particularly with chronic use, necessitating discontinuation of therapy. Therefore, a substantial unmet need exists for more tailored and efficacious therapies that target DM pathogenesis. Brepocitinib is an oral, once-daily, novel, and specific TYK2/JAK1 inhibitor. Brepocitinib's potent inhibition of TYK2 and JAK1 reduces the signalling of pro-inflammatory cytokines, including IFN-α/β, IL-12, IL-23, and IFNγ, that have been implicated in the pathogenesis of DM. Other JAK inhibitors have been used off-label in both case series and open-label clinical trials in patients with DM; and brepocitinib has demonstrated efficacy in phase 2 clinical trials of several other autoimmune diseases, including plaque psoriasis, psoriatic arthritis, Crohn's disease, hidradenitis suppurativa, and ulcerative colitis. Therefore, there is a strong scientific and clinical rationale for the utility and potential effectiveness of brepocitinib in the treatment of DM patients. Currently, the safety, tolerability, and efficacy of brepocitinib is being evaluated in the largest (n=225) double-blind placebo-controlled phase 3 trial in DM patients to date (VALOR - NCT0543726).

• MeSH
• dermatomyozitida * farmakoterapie   diagnóza   imunologie   MeSH
• inhibitory proteinkinas * terapeutické užití   škodlivé účinky   MeSH
• Janus kinasa 1 * antagonisté a inhibitory   MeSH
• kinasa TYK2 * antagonisté a inhibitory   MeSH
• lidé MeSH
• signální transdukce účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inhibitory proteinkinas * MeSH
• JAK1 protein, human MeSH Prohlížeč
• Janus kinasa 1 * MeSH
• kinasa TYK2 * MeSH
• TYK2 protein, human MeSH Prohlížeč

Induction of senescence by chemotherapeutic agents arrests cancer cells and activates immune surveillance responses to contribute to therapy outcomes. In this investigation, we searched for ways to enhance the NK-mediated elimination of senescent cells. We used a staggered screen approach, first identifying siRNAs potentiating the secretion of immunomodulatory cytokines to later test for their ability to enhance NK-mediated killing of senescent cells. We identified that genetic or pharmacological inhibition of SMARCA4 enhanced senescent cell elimination by NK cells. SMARCA4 expression is elevated during senescence and its inhibition derepresses repetitive elements, inducing the SASP via activation of cGAS/STING and MAVS/MDA5 pathways. Moreover, a PROTAC targeting SMARCA4 synergized with cisplatin to increase the infiltration of CD8 T cells and mature, activated NK cells in an immunocompetent model of ovarian cancer. Our results indicate that SMARCA4 inhibitors enhance NK-mediated surveillance of senescent cells and may represent senotherapeutic interventions for ovarian cancer.

• MeSH
• buňky NK * imunologie   metabolismus   účinky léků   MeSH
• DNA-helikasy * metabolismus   genetika   MeSH
• jaderné proteiny * metabolismus   genetika   MeSH
• lidé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků farmakoterapie   metabolismus   patologie   genetika   imunologie   MeSH
• signální transdukce účinky léků   MeSH
• stárnutí buněk * účinky léků   MeSH
• transkripční faktory * metabolismus   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• DNA-helikasy * MeSH
• jaderné proteiny * MeSH
• SMARCA4 protein, human MeSH Prohlížeč
• transkripční faktory * MeSH

Transcription factors of the bHLH-PAS family play vital roles in animal development, physiology, and disease. Two members of the family require binding of low-molecular weight ligands for their activity: the vertebrate aryl hydrocarbon receptor (AHR) and the insect juvenile hormone receptor (JHR). In the fly Drosophila melanogaster, the paralogous proteins GCE and MET constitute the ligand-binding component of JHR complexes. Whilst GCE/MET and AHR are phylogenetically heterologous, their mode of action is similar. JHR is targeted by several synthetic agonists that serve as insecticides disrupting the insect endocrine system. AHR is an important regulator of human endocrine homeostasis, and it responds to environmental pollutants and endocrine disruptors. Whether AHR signaling is affected by compounds that can activate JHR has not been reported. To address this question, we screened a chemical library of 50,000 compounds to identify 93 novel JHR agonists in a reporter system based on Drosophila cells. Of these compounds, 26% modulated AHR signaling in an analogous reporter assay in a human cell line, indicating a significant overlap in the agonist repertoires of the two receptors. To explore the structural features of agonist-dependent activation of JHR and AHR, we compared the ligand-binding cavities and their interactions with selective and common ligands of AHR and GCE. Molecular dynamics modeling revealed ligand-specific as well as conserved side chains within the respective cavities. Significance of predicted interactions was supported through site-directed mutagenesis. The results have indicated that synthetic insect juvenile hormone agonists might interfere with AHR signaling in human cells.

• Klíčová slova
• aryl hydrocarbon receptor, endocrine disruptors, high-throughput screening, juvenile hormone receptor, ligand binding domain,
• MeSH
• buněčné linie MeSH
• Drosophila melanogaster * metabolismus   genetika   účinky léků   MeSH
• juvenilní hormony metabolismus   farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• proteiny Drosophily * metabolismus   genetika   chemie   MeSH
• receptory aromatických uhlovodíků * agonisté   metabolismus   genetika   MeSH
• signální transdukce účinky léků   MeSH
• transkripční faktory bHLH * metabolismus   genetika   agonisté   MeSH
• transkripční faktory metabolismus   genetika   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• AHR protein, human MeSH Prohlížeč
• gce protein, Drosophila MeSH Prohlížeč
• juvenilní hormony MeSH
• ligandy MeSH
• MET protein, Drosophila MeSH Prohlížeč
• proteiny Drosophily * MeSH
• receptory aromatických uhlovodíků * MeSH
• transkripční faktory bHLH * MeSH
• transkripční faktory MeSH

Nitric oxide (NO)-stimulated cyclic guanosine monophosphate (cGMP) is a key regulator of cardiovascular health, as NO-cGMP signalling is impaired in diseases like pulmonary hypertension, heart failure and chronic kidney disease. The development of NO-independent sGC stimulators and activators provide a novel therapeutic option to restore altered NO signalling. sGC stimulators have been already approved for the treatment of pulmonary arterial hypertension (PAH), chronic thromboembolic pulmonary hypertension (CTEPH), and chronic heart failure (HFrEF), while sGC activators are currently in phase-2 clinical trials for CKD. The best characterized effect of increased cGMP via the NO-sGC-cGMP pathway is vasodilation. However, to date, none of the sGC agonists are in development for hypertension (HTN). According to WHO, the global prevalence of uncontrolled HTN continues to rise, contributing significantly to cardiovascular mortality. While there are effective antihypertensive treatments, many patients require multiple drugs, and some remain resistant to all therapies. Thus, in addition to improved diagnosis and lifestyle changes, new pharmacological strategies remain in high demand. In this review we explore the potential of sGC stimulators and activators as novel antihypertensive agents, starting with the overview of NO-sGC-cGMP signalling, followed by potential mechanisms by which the increase in cGMP may regulate vascular tone and BP. These effects may encompass not only acute vasodilation, but also mid-term and chronic effects, such as the regulation of salt and water balance, as well as mitigation of vascular ageing and remodelling. The main section summarizes the preclinical and clinical evidence supporting the BP-lowering efficacy of sGC agonists.

• MeSH
• agonisté guanylátcyklázy terapeutické užití   farmakologie   MeSH
• aktivátory enzymů terapeutické užití   farmakologie   MeSH
• antihypertenziva * terapeutické užití   farmakologie   MeSH
• guanosinmonofosfát cyklický * metabolismus   MeSH
• hypertenze * farmakoterapie   patofyziologie   MeSH
• lidé MeSH
• oxid dusnatý metabolismus   MeSH
• rozpustná guanylátcyklasa * metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• agonisté guanylátcyklázy MeSH
• aktivátory enzymů MeSH
• antihypertenziva * MeSH
• guanosinmonofosfát cyklický * MeSH
• oxid dusnatý MeSH
• rozpustná guanylátcyklasa * MeSH

Acute myeloid leukemia (AML), a heterogeneous hematologic malignancy, has generally a poor prognosis despite the recent advancements in diagnostics and treatment. Genetic instability, particularly mutations in the FMS-like tyrosine kinase 3 (FLT3) gene, is associated with severe outcomes. Approximately 30 % of AML patients harbor FLT3 mutations, which have been linked to higher relapse and reduced survival rates. Traditional AML treatments employ cytarabine and anthracyclines drugs. Furthermore, the development of FLT3 inhibitors has significantly improved therapy for FLT3-mutated AML patients. For example, the introduction of midostaurin, the first FLT3 inhibitor, improved patient outcomes. However, resistant AML cell clones continue to pose a challenge to the success of AML treatment. This review discusses FLT3 kinase, mutations, and role in AML pathogenesis. It explores the molecular mechanisms of FLT3 activation, signaling pathways, and the structure and function of the FLT3 receptor. Current and emerging therapeutic approaches are presented, while highlighting the latest FLT3 inhibitors in clinical use, and strategies to overcome drug resistance. Future directions, including personalized therapies and novel drug designs, are examined to provide updated insights into FLT3-targeted treatments. This comprehensive review aims to guide clinicians and researchers in the development of innovative therapies to improve AML patient outcomes.

• Klíčová slova
• Acute myeloid leukemia, Drug resistance, FLT3 inhibitors, FLT3 mutations, FMS-like tyrosine kinase 3, Personalized medicine,
• MeSH
• akutní myeloidní leukemie * farmakoterapie   genetika   MeSH
• antitumorózní látky terapeutické užití   farmakologie   MeSH
• chemorezistence účinky léků   MeSH
• cílená molekulární terapie * MeSH
• inhibitory proteinkinas * terapeutické užití   farmakologie   MeSH
• lidé MeSH
• mutace MeSH
• signální transdukce účinky léků   MeSH
• tyrosinkinasa 3 podobná fms * antagonisté a inhibitory   genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• FLT3 protein, human MeSH Prohlížeč
• inhibitory proteinkinas * MeSH
• tyrosinkinasa 3 podobná fms * MeSH

INTRODUCTION: The E3 ubiquitin ligase Cbl-b is a novel target in immune-oncology, with critical roles in regulating T-cell activation and signaling pathways. By facilitating the ubiquitination and degradation of key signaling proteins, Cbl-b modulates immune responses, maintaining immune homeostasis and preventing unwarranted T-cell proliferation. The therapeutic potential of Cbl-b as a cancer immunotherapy target is underscored by its contribution to an immunosuppressive tumor microenvironment, with efforts currently underway to develop small-molecule inhibitors. AREAS COVERED: We reviewed the small molecules, and antibody-drug conjugates targeting Cbl-b from 2018 to 2024. The patents were gathered through publicly available databases and analyzed with in-house developed cheminformatic workflow, described within the manuscript. EXPERT OPINION: Targeting Cbl-b presents a promising approach in immuno-oncology, offering a novel pathway to potentiate the immune system's ability to combat cancer beyond PDL1/PD1 inhibition. The development and clinical advancement of Cbl-b inhibitors, as evidenced by the ongoing trials, mark a significant step toward harnessing this target for therapeutic benefits. Overall, the strategic inhibition of Cbl-b holds substantial promise for improving cancer immunotherapy outcomes, heralding a new era in the fight against cancer.

• Klíčová slova
• CBL-B, antibody drug conjugate, automated patent analysis, immune oncology, small molecule,
• MeSH
• adaptorové proteiny signální transdukční MeSH
• antitumorózní látky farmakologie   MeSH
• cílená molekulární terapie * MeSH
• imunokonjugáty farmakologie   MeSH
• imunoterapie * metody   MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   MeSH
• nádory * imunologie   farmakoterapie   MeSH
• patenty jako téma * MeSH
• protoonkogenní proteiny c-cbl * imunologie   antagonisté a inhibitory   MeSH
• signální transdukce účinky léků   MeSH
• T-lymfocyty imunologie   účinky léků   MeSH
• vyvíjení léků * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• antitumorózní látky MeSH
• CBLB protein, human MeSH Prohlížeč
• imunokonjugáty MeSH
• protoonkogenní proteiny c-cbl * MeSH

BACKGROUND: Leishmaniasis is a group of neglected vector-borne diseases transmitted by phlebotomine sand flies. Leishmania parasites must overcome various defenses in the sand fly midgut, including the insects's immune response. Insect immunity is regulated by the ecdysone hormone, which binds to its nuclear receptor (EcR) and activates the transcription of genes involved in insect immunity. However, the role of ecdysone in sand fly immunity has never been studied. Phlebotomus perniciosus is a natural vector of Leishmania infantum; here, we manipulated its neuroendocrine system using azadirachtin (Aza), a natural compound known to affect ecdysone synthesis. METHODS: Phlebotomus perniciosus larvae and adult females were fed on food containing either Aza alone or Aza plus ecdysone, and the effects on mortality and ecdysis were evaluated. Genes related to ecdysone signaling and immunity were identified in P. perniciosus, and the expression of antimicrobial peptides (AMPs), EcR, the ecdysone-induced genes Eip74EF and Eip75B, and the transcription factor serpent were analyzed using quantitative polymerase chain reaction (PCR). RESULTS: Aza treatment inhibited molting of first-instar (L1) larvae to L2, with only 10% of larvae molting compared to 95% in the control group. Serpent and Eip74EF, attacin, defensin 1, and defensin 2 genes were downregulated by Aza treatment in larvae. Similarly, Aza-treated adult females also presented suppression of ecdysone signaling-related genes and the AMPs attacin and defensin 2. Notably, all gene repression caused by Aza was reversed by adding ecdysone concomitantly with Aza to the larval or female food, indicating that these genes are effective markers for ecdysone repression. CONCLUSIONS: These results highlight the critical role of ecdysone in regulating the development and immunity of P. perniciosus, which potentially could interfere with Leishmania infection.

• Klíčová slova
• Phlebotomus perniciosus, Antimicrobial peptides, Azadirachtin, Ecdysone,
• MeSH
• antimikrobiální peptidy genetika   farmakologie   MeSH
• ekdyson * MeSH
• hmyz - vektory účinky léků   genetika   parazitologie   imunologie   MeSH
• hmyzí proteiny genetika   metabolismus   MeSH
• larva * účinky léků   imunologie   genetika   MeSH
• limoniny * farmakologie   MeSH
• Phlebotomus * účinky léků   genetika   parazitologie   imunologie   MeSH
• shazování tělního pokryvu účinky léků   MeSH
• signální transdukce * účinky léků   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antimikrobiální peptidy MeSH
• azadirachtin MeSH Prohlížeč
• ekdyson * MeSH
• hmyzí proteiny MeSH
• limoniny * MeSH

Docosahexaenoic acid (DHA) is an omega-3 polyunsaturated fatty acid with promising anticancer potential. Anaemia is a frequent adverse effect of anticancer treatment caused in part by eryptosis and haemolysis. Thus, it is important to investigate the role of DHA in red blood cell (RBC) death. RBCs were treated with anticancer concentrations (10-100 μM) of DHA under different physiological conditions, and fluorescence-assisted cell sorting was employed to measure eryptotic markers. Cell membrane scrambling was detected by annexin-V-FITC labelling, cytoplasmic Ca2+ by Fluo4/AM, cell size by forward scatter (FSC), and oxidative stress by H2DCFDA. Haemolytic markers were also assayed by photometric methods. DHA caused significant phospholipid scrambling with Ca2+ accumulation, loss of cellular volume, and oxidative stress. These changes were associated with dacrocyte formation, as revealed by electron microscopy. Moreover, DHA exhibited a dual effect on membrane integrity: it was haemolytic under isotonic conditions and anti-haemolytic in hypotonic environments. Importantly, inhibition of Rac1 GTPase activity with NSC23766 significantly reduced DHA-mediated haemolysis, as did co-administration of either sucrose or polyethylene glycol 8,000. Conversely, the presence of 125 mM KCl and urea without extracellular Ca2+ significantly exacerbated DHA toxicity. In conclusion, this is the first report that identifies key biochemical mechanisms underlying the cytotoxic effects of DHA in RBCs, promoting further development and validation of DHA in anticancer therapy.

• Klíčová slova
• DHA, Rac GTPase, anticancer, calcium, eryptosis, haemolysis,
• MeSH
• eryptóza * účinky léků   MeSH
• erytrocyty účinky léků   metabolismus   MeSH
• hemolýza * účinky léků   MeSH
• kyseliny dokosahexaenové * farmakologie   MeSH
• lidé MeSH
• oxidační stres * účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• vápník * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyseliny dokosahexaenové * MeSH
• vápník * MeSH