Waldenströmova makroglobulinémie (WM) patří k low-grade B-lymfomům. Je definována přítomností lymfoplazmocytárního lymfomu v kostní dřeni a monoklonálního imunoglobulinu typu IgM (M-IgM) v séru. Příznaky nemoci, anémie a trombocytopenie, mohou souviset s masou patologických buněk, stejně jako systémové zánětlivé projevy (B-symptomy). Velké spektrum symptomů však způsobuje M-IgM. Koncentrace M-IgM u WM nekoreluje s masou patologických buněk. Spektrum poruch způsobených M-IgM je vzhledem k diverzitě patofyziologických mechanizmů a lokalizaci poškození značně široké. Poškození může vzniknout depozicí kompletní molekuly nebo její části ve formě agregátů, amorfních, krystalických, mikrotubulárních či fibrilárních struktur. M-IgM může také pacienta poškozovat autoprotilátkovou aktivitou namířenou proti antigenům vlastních tkání. Dále může M-IgM tvořit imunitní komplexy a aktivovat komplement. Výjimečně může B buněčný klon indukovat tvorbu cytokinů. Proto je velmi obtížené včas rozpoznat symptomatickou formu WM. V této publikaci popisujeme pacientku poškozenou depozity M-IgM a řetězců lambda. Diskuze je zaměřena na přehled všech forem poškození člověka depozity M-IgM, mezi něž patří i popsaný případ.
Waldenström’s macroglobulinaemia (WM) is a low-grade B-cell lymphoproliferative disorder characterised by an immunoglobulin IgM monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic lymphoma. Clinical features may be related to the overall disease burden, such as anaemia, thrombocytopenia, and constitutional inflammatory symptoms, or may be directly attributable to the IgM paraprotein. The concentration of monoclonal IgM can vary widely in WM. There is no direct relationship between the concentration of monoclonal immunoglobulin IgM and bone marrow infiltration. The spectrum of monoclonal immunoglobulin IgM-related disorders is large because of the diversity of involved organs and pathogenic mechanisms. Lesions commonly result from the deposition of all or part of the M-IgM as aggregates, amorphous, crystalline, microtubular, or fibrillar forms. Other mechanisms include autoantibody activity against a tissue antigen, formation of immune complexes, and complement activation. In addition, even a small B-cell clone may absorb biologically active molecules or induce cytokine secretion. In our case report, we describe a female patient with monoclonal IgM and lambda liver deposition and we discuss the frequency and variety of disorders caused by deposition of monoclonal IgM and free light chain.
- Klíčová slova
- imunokomplexy,
- MeSH
- amyloid imunologie klasifikace MeSH
- amyloidóza diagnóza imunologie klasifikace patologie MeSH
- hepatomegalie etiologie imunologie MeSH
- imunoglobulin M imunologie krev škodlivé účinky MeSH
- krevní nemoci diagnóza etiologie krev MeSH
- lidé středního věku MeSH
- lidé MeSH
- Waldenströmova makroglobulinemie * diagnostické zobrazování diagnóza imunologie patologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
- práce podpořená grantem MeSH
Epstein-Barr virus (EBV), defined as a group I carcinogen by the World Health Organization (WHO), is present in the tumour cells of patients with different forms of B-cell lymphoma, including Burkitt lymphoma, Hodgkin lymphoma, post-transplant lymphoproliferative disorders, and, most recently, diffuse large B-cell lymphoma (DLBCL). Understanding how EBV contributes to the development of these different types of B-cell lymphoma has not only provided fundamental insights into the underlying mechanisms of viral oncogenesis, but has also highlighted potential new therapeutic opportunities. In this review, we describe the effects of EBV infection in normal B-cells and we address the germinal centre model of infection and how this can lead to lymphoma in some instances. We then explore the recent reclassification of EBV+ DLBCL as an established entity in the WHO fifth edition and ICC 2022 classifications, emphasising the unique nature of this entity. To that end, we also explore the unique genetic background of this entity and briefly discuss the potential role of the tumour microenvironment in lymphomagenesis and disease progression. Despite the recent progress in elucidating the mechanisms of this malignancy, much work remains to be done to improve patient stratification, treatment strategies, and outcomes.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Albendazole (ABZ) is an anthelmintic frequently used to treat haemonchosis, a common parasitosis of ruminants caused by the gastrointestinal nematode Haemonchus contortus. This parasite is able to protect itself against ABZ via the formation of inactive ABZ-glycosides. The present study was designed to deepen the knowledge about the role of UDP-glycosyltransferases (UGTs) in ABZ glycosylation in H. contortus. The induction effect of phenobarbital, a classical inducer of UGTs, as well as ABZ and ABZ-sulphoxide (ABZSO, the main active metabolite of ABZ) on UGTs expression and UGT activity toward ABZ was studied ex vivo in isolated adult nematodes. The effect of three potential UGT inhibitors (5-nitrouracil, 4,6-dihydroxy-5-nitropyrimidine and sulfinpyrazone) on ABZ glycosylation was tested. Pre-incubation of nematodes with ABZ and ABZSO led to increased expression of several UGTs as well as ABZ-glycosides formation in subsequent treatment. Phenobarbital also induced UGTs expression, but did not affect ABZ biotransformation. In the nematode's subcellular fraction, sulfinpyrazone inhibited UGT activity toward ABZ, although no effect of other inhibitors was observed. The inhibitory potential of sulfinpyrazone on the formation of ABZ-glycosides was also proved ex vivo in living nematodes. The obtained results confirmed the role of UGTs in ABZ biotransformation in H. contortus adults and revealed sulfinpyrazone as a potent inhibitor of ABZ glycosylation in this parasite. The possible use of sulfinpyrazone with ABZ in combination therapy merits further research.
- MeSH
- albendazol MeSH
- anthelmintika * terapeutické užití MeSH
- fenobarbital metabolismus farmakologie terapeutické užití MeSH
- glykosidy metabolismus farmakologie terapeutické užití MeSH
- glykosyltransferasy MeSH
- Haemonchus * MeSH
- hlístice * MeSH
- nemoci ovcí * farmakoterapie MeSH
- ovce MeSH
- sulfinpyrazon metabolismus farmakologie terapeutické užití MeSH
- uridindifosfát MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Klíčová slova
- mikrovilózní inkluzní nemoc,
- MeSH
- acidóza farmakoterapie MeSH
- genetické nemoci vrozené * farmakoterapie komplikace MeSH
- kojenec MeSH
- lidé MeSH
- malabsorpční syndromy farmakoterapie MeSH
- mikroklky patologie MeSH
- novorozenec MeSH
- parenterální výživa škodlivé účinky MeSH
- průjem kojenců * diagnóza farmakoterapie genetika komplikace MeSH
- sekvenční analýza DNA MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Haemonchus contortus is a parasitic nematode of ruminants which causes significant losses to many farmers worldwide. Since the drugs currently in use for the treatment of haemonchosis are losing their effectiveness due to the drug-resistance of this nematode, a new or repurposed drug is highly needed. As the antipsychotic drug sertraline (SRT) has been shown to be effective against the parasitic nematodes Trichuris muris, Ancylostoma caninum and Schistosoma mansoni, the aim of the present study was to evaluate the possible effect of SRT on H. contortus. The potential hepatotoxicity of SRT was tested in sheep, a common H. contortus host. In addition, the main metabolic pathways of SRT in H. contortus and the ovine liver were identified. While no effect of SRT on H. contortus egg hatching was observed, SRT was found to significantly decrease the viability of H. contortus adults in drug-sensitive and resistant strains, with its effect comparable to the commonly used anthelmintics levamisole and monepantel. Moreover, SRT in anthelmintically active concentrations showed no toxicity to the ovine liver. Biotransformation of SRT in H. contortus was weak, with most of the drug remaining unmetabolized. Production of the main metabolite hydroxy-SRT did not differ significantly between strains. Other minor metabolites such as SRT-O-glucoside, dihydroxy-SRT, and SRT-ketone were also identified in H. contorts adults. Compared to H. contortus, the ovine liver metabolized SRT more extensively, mainly via desmethylation and glucuronidation. In conclusion, the potency of SRT against H. contortus was proven, and it should be tested further toward possible repurposing.
The nematode Haemonchus contortus, a gastrointestinal parasite of ruminants, can severely burden livestock production. Although anthelmintics are the mainstay in the treatment of haemonchosis, their efficacy diminishes due to drug-resistance development in H. contortus. An increased anthelmintics inactivation via biotransformation belongs to a significant drug-resistance mechanism in H. contortus. UDP-glycosyltransferases (UGTs) participate in the metabolic inactivation of anthelmintics and other xenobiotic substrates through their conjugation with activated sugar, which drives the elimination of the xenobiotics due to enhanced solubility. The UGTs family, in terms of the biotransformation of commonly used anthelmintics, has been well described in adults as a target stage. In contrast, the free-living juvenile stages of H. contortus have attracted less attention. The expression of UGTs considerably varies throughout the life cycle of the juvenile nematodes, suggesting their different roles. Furthermore, the constitutive expression in a susceptible strain with two resistant strains shows several resistance-related changes in UGTs expression, and the exposure of juvenile stages of H. contortus to albendazole (ABZ) and ABZ-sulfoxide (ABZSO; in sublethal concentrations) leads to the increased expression of several UGTs. The anthelmintic drug ABZ and its primary metabolite ABZSO biotransformation, tested in the juvenile stages, shows significant differences between susceptible and resistant strain. Moreover, higher amounts of glycosidated metabolites of ABZ are formed in the resistant strain. Our results show similarly, as in adults, the UGTs and glycosidations significant for resistance-related differences in ABZ biotransformation and warrant further investigation in their individual functions.
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- mikrovilózní inkluzní nemoc,
- MeSH
- acidóza MeSH
- lidé MeSH
- novorozenec MeSH
- parenterální výživa MeSH
- průjem kojenců genetika terapie vrozené MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
Albendazole (ABZ), a widely used anthelmintic drug, enters the environment mainly via livestock excrements. To evaluate the environmental impact of ABZ, the knowledge of its uptake, effects and metabolism in all non-target organisms, including plants, is essential. The present study was designed to identify the metabolic pathway of ABZ and to test potential ABZ phytotoxicity in fodder plant alfalfa, with seeds and in vitro regenerants used for these purposes. Alfalfa was chosen, as it may meet manure from ABZ-treated animals in pastures and fields. Alfalfa is often used as a feed of livestock, which might already be infected with helminths. The obtained results showed that ABZ did not inhibit alfalfa seed germination and germ growth, but evoked stress and a toxic effect in alfalfa regenerants. Alfalfa regenerants were able to uptake ABZ and transform it into 21 metabolites. UHPLC-MS/MS analysis revealed three new ABZ metabolites that have not been described yet. The discovery of the parent compound ABZ together with the anthelmintically active and instable metabolites in alfalfa leaves shows that the contact of fodder plants with ABZ-containing manure might represent not only a danger for herbivorous invertebrates, but also may cause the development of ABZ resistance in helminths.
The efficacy of anthelmintic therapy of farm animals rapidly decreases due to drug resistance development in helminths. In resistant isolates, the increased expression and activity of drug-metabolizing enzymes (DMEs), e.g. cytochromes P450 (CYPs), UDP-glycosyltransferases (UGTs) and P-glycoprotein transporters (P-gps), in comparison to sensitive isolates have been described. However, the mechanisms and circumstances of DMEs induction are not well known. Therefore, the present study was designed to find the changes in expression of CYPs, UGTs and P-gps in adult parasitic nematodes Haemonchus contortus exposed to sub-lethal doses of the benzimidazole anthelmintic drug albendazole (ABZ) and its active metabolite ABZ-sulfoxide (ABZSO). In addition, the effect of ABZ at sub-lethal doses on the ability to deactivate ABZ during consequent treatment was studied. The results showed that contact of H. contortus adults with sub-lethal doses of ABZ and ABZSO led to a significant induction of several DMEs, particularly cyp-2, cyp-3, cyp-6, cyp-7, cyp-8, UGT10B1, UGT24C1, UGT26A2, UGT365A1, UGT366C1, UGT368B2, UGT367A1, UGT371A1, UGT372A1 and pgp-3, pgp-9.1, pgp-9.2, pgp-10. This induction led to increased formation of ABZ metabolites (especially glycosides) and their increased export from the helminths' body into the medium. The present study demonstrates for the first time that contact of H. contortus with sub-lethal doses of ABZ (e.g. during underdose treatment) improves the ability of H. contortus adults to deactivate ABZ in consequent therapy.
- Klíčová slova
- mikrovilózní inkluzní nemoc,
- MeSH
- acidóza MeSH
- lidé MeSH
- novorozenec MeSH
- parenterální výživa MeSH
- průjem kojenců * diagnostické zobrazování genetika klasifikace terapie vrozené MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
