CA inhibitors: Human carbonic anhydrases (CAs) are diagnostic and therapeutic targets. Various carborane cages are shown to act as active-site-directed inhibitors, and substitution with a sulfamide group and other substituents leads to compounds with high selectivity towards the cancer-specific isozyme IX. Crystal structures of the carboranes in the active site provide information that can be applied to the structure-based design of specific inhibitors.

• Klíčová slova
• carbonic anhydrases, carboranes, drug discovery, inhibitors, structure elucidation,
• MeSH
• inhibitory karboanhydras farmakologie   MeSH
• lidé MeSH
• objevování léků MeSH
• racionální návrh léčiv MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitory karboanhydras MeSH

OBJECTIVE: An evaluation of the safety of poly-ADP-ribose-polymerase inhibitors (PARPi) in ovarian cancer treatment. METHODS: An analysis of the studies on PARP inhibitors, a summary of the most common and serious adverse events. RESULTS: According to the studies, the most common adverse events of PARPi include hematotoxicity, nausea and vomiting. Serious adverse events leading to dose reduction or treatment interruption or termination include anemia, thrombocytopenia, nausea, fatigue and hypertension. CONCLUSION: According to the results of the recent studies, the treatment of ovarian cancer with PARP inhibitors is generally safe.

• Klíčová slova
• BRCA, PARP inhibitors, adverse events, ovarian cancer, ovarian neoplasms, side effects,
• MeSH
• epiteliální ovariální karcinom MeSH
• lidé MeSH
• nádory vaječníků * farmakoterapie   MeSH
• nauzea MeSH
• PARP inhibitory * škodlivé účinky   MeSH
• zvracení MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• PARP inhibitory * MeSH

Two trypsin inhibitor types, PII and PI II, were isolated by affinity chromatography of a potato extract on a column of trypsin immobilized on Sepharose 4B. Fraction PI I afforded after ion exchange chromatography on SE-Sephadex two isoinhibitors, PI IA (Mr approximately 18 000; pI approximately 6.3) and PI IB (Mr approximately 19 500; pI approximately 7.2). The chromatography of fraction PI II on SE-Sephadex yielded three inhibitors of approximately equal molecular weight (Mr approximately 13 500), PI IIC (pI approximately 6.3), PI IID (pI approximately 7.7), and PI IIE (pI approximately 9.1). All the inhibitors isolated show a high activity toward trypsin, acrosin, and chymotrypsin. Unlike the two isoinhibitors of PI I, which practically do not inhibit kallikrein, inhibitors PI II show an effect on this enzyme. Neither the isoinhibitors of PI I nor inhibitors PI II are active toward cathepsin D.

• MeSH
• akrosin antagonisté a inhibitory   MeSH
• inhibitory proteas * izolace a purifikace   MeSH
• rostliny analýza   MeSH
• zelenina analýza   MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• akrosin MeSH
• inhibitory proteas * MeSH

Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

• Klíčová slova
• anti-angiogenic effect, apoptosis, autophagy, cancer, cell cycle arrest, drug combinations, histone deacetylase inhibitors, histone deacetylases,
• MeSH
• acetylace účinky léků   MeSH
• apoptóza účinky léků   MeSH
• autofagie účinky léků   MeSH
• epigeneze genetická účinky léků   MeSH
• imunomodulace účinky léků   MeSH
• inhibitory angiogeneze farmakologie   terapeutické užití   MeSH
• inhibitory histondeacetylas farmakologie   terapeutické užití   MeSH
• klinické zkoušky jako téma MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• lidé MeSH
• preklinické hodnocení léčiv MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inhibitory angiogeneze MeSH
• inhibitory histondeacetylas MeSH
• protinádorové látky MeSH

BACKGROUND: JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers. METHODS: In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk. RESULTS: We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA. CONCLUSION: The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.

• Klíčová slova
• Arthritis, Rheumatoid, Biological Therapy, Epidemiology, Therapeutics, Tumor Necrosis Factor Inhibitors,
• MeSH
• abatacept terapeutické užití   MeSH
• antirevmatika * terapeutické užití   MeSH
• inhibitory Janus kinas * terapeutické užití   MeSH
• inhibitory TNF MeSH
• interleukin-6 MeSH
• lidé MeSH
• revmatoidní artritida * chemicky indukované   farmakoterapie   MeSH
• TNF-alfa MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• abatacept MeSH
• antirevmatika * MeSH
• inhibitory Janus kinas * MeSH
• inhibitory TNF MeSH
• interleukin-6 MeSH
• TNF-alfa MeSH

Peptidases can be inhibited by natural or synthetic small-molecule compounds, or by gene-encoded, proteinaceous inhibitors. Small-molecule peptidase inhibitors have been in the spotlight of researchers and pharmaceutical companies for many years. The studies concerning gene-encoded inhibitors are less frequent. The last decade has seen a boom of fungal genomics followed by extensive bioinformatic analyses focused particularly on those species that can cause infections in humans, animals or crops. Many sequences of putative inhibitors have been identified on the basis of homology with gene-encoded peptidase inhibitors of Saccharomyces cerevisiae, mammals or other organisms. However, characterization of the respective proteins is often missing. Gene-encoding peptidase inhibitors are rather diverse in size, mode of action, type of the target peptidase and localization. While some of the inhibitors are secreted to extracellular space and participate in host-pathogen interactions, others act intracellularly and their precise role in fungal physiology is not fully understood. However, most of the gene-encoded peptidase inhibitors are rather selective and efficient, and may be an inspiration for future directions of antimycotic research.

• MeSH
• cystatiny antagonisté a inhibitory   metabolismus   MeSH
• databáze faktografické MeSH
• fungální proteiny antagonisté a inhibitory   genetika   metabolismus   MeSH
• houby genetika   metabolismus   MeSH
• inhibitory proteas chemie   metabolismus   MeSH
• karboxypeptidasy antagonisté a inhibitory   metabolismus   MeSH
• serinové endopeptidasy chemie   metabolismus   MeSH
• serpiny chemie   metabolismus   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• cystatiny MeSH
• fungální proteiny MeSH
• inhibitory proteas MeSH
• karboxypeptidasy MeSH
• serinové endopeptidasy MeSH
• serpiny MeSH

BACKGROUND: The use of immune checkpoint inhibitors has dramatically improved the prognosis of many cancer patients. However, their increasing use has also revealed several unexpected side effects - including cardiovascular complications. Increased attention was paid to them in recent years only, especially due to their potentially fatal character. Checkpoint inhibitors cardiotoxicity includes myocarditis, rhythm disorders (atrioventricular blocks, atrial and ventricular arrhythmias), pericarditis, myocardial infarction, left ventricular dysfunction/heart failure, dilated cardiomyopathy, cardiogenic shock and sudden cardiac death. The risk of ICI-associated cardiotoxicity is increased in patients treated with dual immune therapy, in combination with other cardiotoxic drugs, with preexisting cardiac damage, diabetes mellitus, underlying autoimmune disease and some other factors. Currently, there are no guidelines for prediction and management of ICI-associated cardiotoxicity. PURPOSE: Herein, we briefly summarize the findings regarding checkpoint inhibitor-induced cardiotoxicity and provide a new definition of anti-tumor-induced myocarditis together with a suitable design for immune- induced myocarditis management prepared by experts from the field of cardiooncology.

• Klíčová slova
• adverse events, cardiotoxicity, immune checkpoint inhibitors, immunotherapy, myocarditis,
• MeSH
• imunoterapie škodlivé účinky   MeSH
• inhibitory kontrolních bodů škodlivé účinky   MeSH
• kardiotoxicita etiologie   terapie   MeSH
• lidé MeSH
• myokarditida chemicky indukované   terapie   MeSH
• nádory farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory kontrolních bodů MeSH

PURPOSE OF REVIEW: Recent advancements in the understanding of the genetic background of genitourinary cancers allowed for a successful introduction of targeted antitumor agents to prostate cancer (PCa) treatment. Inhibitors of the poly ADP-ribose polymerase enzyme (PARPi) transformed the treatment landscape of metastatic prostate cancer, and being increasingly studied in earlier disease stages. However, they are associated with nonnegligible toxicity, therefore, we aimed to summarize their side-effect profile in patients with PCa. RECENT FINDINGS: Hematologic toxicities, particularly anemia, thrombocytopenia, and neutropenia are among the most common and serious adverse events associated with PARPi, highlighting the need for regular blood count monitoring. Nonhematologic side effects, including fatigue, nausea, vomiting, diarrhea, and constipation, are common, and can be mitigated with supportive interventions like dietary modifications, antiemetics, or stool management techniques. Special attention should be given to patients with therapy-resistant or persistent cytopenia, in whom bone marrow biopsy should be considered, as it can indicate myelodysplastic syndrome and acute myeloid leukemia. SUMMARY: PARP inhibitors represent a major advancement in the management of metastatic prostate cancer, offering a significant survival benefit in applicable cases. However, patients need to be carefully selected and informed, to allow for optimal balancing between the benefits and nonneglectable risks of severe toxicities. Better understanding of PARPi toxicity profile can improve personalized decision-making and enhance treatment compliance, through raising patients' awareness about the possible side effects of PARPi.

• Klíčová slova
• BRCA, adverse event, anemia, fatigue, genetic test, niraparib, olaparib, poly ADP-ribose polymerase inhibitors, prostate cancer, side effects, talazoparib, toxicity,
• MeSH
• lidé MeSH
• nádory prostaty * farmakoterapie   patologie   MeSH
• PARP inhibitory * škodlivé účinky   MeSH
• urogenitální nádory * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• PARP inhibitory * MeSH

Alopecia areata is a disease of autoimmune origin which causes non scarring hair loss. The extent of alopecia varies from a small patch to complete scalp and body hair loss, which can have huge psychosocial impact for those affected. Treatment modalities which have been used so far included nonspecific immunosuppressive medications, such as corticosteroids, cyclosporine, and methotrexate, or topical immunomodulators, such as diphencyprone, dithranol, and squaric acid dibutylester. The recognition of the importance of Janus kinase pathway in alopecia areata pathogenesis enabled more specific approaches in treatment. Positive outcomes of Janus kinase inhibitors in several trials granted approval for baricitinib which became the first on-label treatment for alopecia areata. The aim of this review is to summarize the role, efficacy and safety of several Janus kinase inhibitors in alopecia areata.

• Klíčová slova
• Alopecia areata, Alopecia areata treatment, Baricitinib, JAK/STAT, Janus kinase inhibitors, Olumiant,
• MeSH
• adjuvancia imunologická terapeutické užití   MeSH
• alopecia areata * farmakoterapie   patologie   MeSH
• inhibitory Janus kinas * terapeutické užití   farmakologie   MeSH
• Janus kinasy terapeutické užití   MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• inhibitory Janus kinas * MeSH
• Janus kinasy MeSH

Protease inhibitors regulate various biological processes and prevent host tissue/organ damage. Specific inhibition/regulation of proteases is clinically valuable for treating several diseases. Psoriasis affects the skin in the limbs and scalp of the body, and the contribution of cysteine and serine proteases to the development of skin inflammation is well documented. Cysteine protease inhibitors from ticks have high specificity, selectivity, and affinity to their target proteases and are efficient immunomodulators. However, their potential therapeutic effect on psoriasis pathogenesis remains to be determined. Therefore, we tested four tick cystatins (Sialostatin L, Sialostatin L2, Iristatin, and Mialostatin) in the recently developed, innate immunity-dependent mannan-induced psoriasis model. We explored the effects of protease inhibitors on clinical symptoms and histological features. In addition, the number and percentage of immune cells (dendritic cells, neutrophils, macrophages, and γδT cells) by flow cytometry, immunofluorescence/immunohistochemistry and, the expression of pro-inflammatory cytokines (TNF-a, IL-6, IL-22, IL-23, and IL-17 family) by qPCR were analyzed using skin, spleen, and lymph node samples. Tick protease inhibitors have significantly decreased psoriasis symptoms and disease manifestations but had differential effects on inflammatory responses and immune cell populations, suggesting different modes of action of these inhibitors on psoriasis-like inflammation. Thus, our study demonstrates, for the first time, the usefulness of tick-derived protease inhibitors for treating skin inflammation in patients.

• Klíčová slova
• autoimmune disease, immune responses, protease inhibitors, psoriasis, tick,
• MeSH
• dermatitida * MeSH
• endopeptidasy MeSH
• inhibitory cysteinových proteinas MeSH
• inhibitory proteas MeSH
• lidé MeSH
• mannany MeSH
• přirozená imunita MeSH
• proteasy MeSH
• psoriáza * chemicky indukované   farmakoterapie   MeSH
• zánět farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• endopeptidasy MeSH
• inhibitory cysteinových proteinas MeSH
• inhibitory proteas MeSH
• mannany MeSH
• proteasy MeSH