immune modulation
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The prevalence of centenarians, people who lived 100 years and longer, is steadily growing in the last decades. This exceptional longevity is based on multifaceted processes influenced by a combination of intrinsic and extrinsic factors such as sex, (epi-)genetic factors, gut microbiota, cellular metabolism, exposure to oxidative stress, immune status, cardiovascular risk factors, environmental factors, and lifestyle behavior. Epidemiologically, the incidence rate of cardiovascular diseases is reduced in healthy centenarians along with late onset of age-related diseases compared with the general aged population. Understanding the mechanisms that affect vascular ageing in centenarians and the underlying factors could offer valuable insights for developing strategies to improve overall healthy life span in the elderly. This review discusses these key factors influencing vascular ageing and how their modulation could foster healthy longevity.
- MeSH
- dlouhověkost * fyziologie MeSH
- kardiovaskulární nemoci patofyziologie epidemiologie MeSH
- lidé MeSH
- oxidační stres fyziologie MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- stárnutí * fyziologie MeSH
- střevní mikroflóra fyziologie MeSH
- zdravé stárnutí fyziologie MeSH
- životní styl MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy 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.
- MeSH
- adaptorové proteiny signální transdukční 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
- protinádorové látky farmakologie 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
This article provides an up-to-date review of the management of chronic pancreatitis, highlighting advancements in medical therapy, nutritional support, endoscopic and surgical approaches, and emerging treatments. Nutritional management accentuates addressing malabsorption and nutrient deficiencies. Advances in endoscopy and parenchyma-sparing surgical techniques have opened new avenues for improved patient outcomes, with total pancreatectomy and islet autotransplantation offering the only definitive solution for selected patients. Additionally, emerging therapies, including anti-inflammatory and immune-modulating agents, show promise for future treatment options. Emphasizing a multidisciplinary approach, this review aims to equip health care professionals with a comprehensive overview of current management strategies and future directions.
- MeSH
- chronická pankreatitida * terapie MeSH
- lidé MeSH
- nutriční podpora * metody MeSH
- pankreatektomie * metody MeSH
- transplantace Langerhansových ostrůvků metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Psoriáza je systémové zánětlivé onemocnění s převahou projevů na kůži. Je charakterizována komplexní patofyziologií určenou genovou predispozicí s výrazným podílem faktorů vnitřního i vnějšího prostředí, které se uplatňují epigenetickými mechanismy. Podstatnou součástí je poškozující zánět, na který cílí různé léčebné modality. U většiny nemocných jimi lze dosáhnout zhojení kožních projevů, následované ale obvykle exacerbací onemocnění. Jednou z příčin exacerbace by mohla být tzv. zánětlivá jizva charakterizovaná abnormálním nastavením buněčných složek vrozené a specifické imunity i kůže. Na jejím vzniku a udržování se podílejí epigenetické procesy, které bude možné v blízké budoucnosti léčebně modulovat.
Psoriasis is a systemic inflammatory disease with clinical presentation on skin. Pathophysiology of psoriasis is complex with genetic predisposition and substantial contribution of variable factors of both internal and external origins which is mediated by epigenetic mechanisms. Immunopathological mechanisms are the target of the most effective therapeutical modalities with the ultimate goal „clean skin“. However, the therapeutical efficacy is lost in time in majority of patients. Exacerbation of skin presentation could be caused by so called „inflammatory scar“ characterized by abnormal setting of both innate and specific immunity cellular substrate together with participation of skin cells. Inflammatory scar initiation and duration is regulated largely by epigenetic mechanisms, which could be therapeuticaly modulated in near future.
- Klíčová slova
- zánětlivá jizva,
- MeSH
- jizva * diagnóza etiologie klasifikace patologie MeSH
- kožní nemoci diagnóza klasifikace patologie MeSH
- lidé MeSH
- progrese nemoci MeSH
- psoriáza * diagnóza komplikace patofyziologie patologie MeSH
- zánět diagnóza klasifikace patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Spinocelulární karcinom kůže (cutaneous squamous cell carcinoma, cSCC) je jedním z nejčastějších kožních nádorů. Hlavní léčbou cSCC je chirurgický zákrok. Nicméně neoperabilní nebo metastazující cSCC zůstává neléčitelný. S nástupem imunoterapie se dostaly do popředí při léčbě těchto forem onemocnění checkpoint inhibitory, jako je cemiplimab. Cemiplimab je lék modulující imunitu, který se zaměřuje na receptor PD-1. Dosavadní výsledky ukazují nejen dobrou léčebnou odpověď, ale také dlouhodobou účinnost. Následující kazuistika dokazuje účinnost cemiplimabu i u zdánlivě neřešitelných případů.
Cutaneous squamous cell carcinoma (cSCC) is one of the most common skin cancers. The primary treatment for cSCC is surgical intervention. However, inoperable or metastatic cSCC remains difficult to treat. With the advent of immunotherapy, checkpoint inhibitors, such as cemiplimab, have become prominent in the treatment of these forms of the disease. Cemiplimab is an immune-modulating drug that targets the PD-1 receptor. Current results indicate not only a good therapeutic response but also long-term efficacy. The following case study demonstrates the effectiveness of cemiplimab even in seemingly intractable cases.
BACKGROUND: Age-related neurodegenerative diseases (NDs) pose a formidable challenge to healthcare systems worldwide due to their complex pathogenesis, significant morbidity, and mortality. Scope and Approach: This comprehensive review aims to elucidate the central role of the microbiotagut- brain axis (MGBA) in ND pathogenesis. Specifically, it delves into the perturbations within the gut microbiota and its metabolomic landscape, as well as the structural and functional transformations of the gastrointestinal and blood-brain barrier interfaces in ND patients. Additionally, it provides a comprehensive overview of the recent advancements in medicinal and dietary interventions tailored to modulate the MGBA for ND therapy. CONCLUSION: Accumulating evidence underscores the pivotal role of the gut microbiota in ND pathogenesis through the MGBA. Dysbiosis of the gut microbiota and associated metabolites instigate structural modifications and augmented permeability of both the gastrointestinal barrier and the blood-brain barrier (BBB). These alterations facilitate the transit of microbial molecules from the gut to the brain via neural, endocrine, and immune pathways, potentially contributing to the etiology of NDs. Numerous investigational strategies, encompassing prebiotic and probiotic interventions, pharmaceutical trials, and dietary adaptations, are actively explored to harness the microbiota for ND treatment. This work endeavors to enhance our comprehension of the intricate mechanisms underpinning ND pathogenesis, offering valuable insights for the development of innovative therapeutic modalities targeting these debilitating disorders.
- MeSH
- dysbióza metabolismus MeSH
- hematoencefalická bariéra metabolismus MeSH
- lidé MeSH
- mozek * metabolismus MeSH
- neurodegenerativní nemoci * mikrobiologie metabolismus MeSH
- osa mozek-střevo * fyziologie MeSH
- probiotika MeSH
- stárnutí * MeSH
- střevní mikroflóra * fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease often associated with underlying inflammatory bowel disease (IBD). This study investigates how PSC predisposes individuals to altered inflammatory immune responses compared with IBD alone. A case-control study was conducted with a cohort of 75 patients, including 16 with PSC (14 with concomitant IBD), 39 with IBD alone, and 20 controls. Serum bile acid profile, proteomic analysis, and immune-related gene expression in the colon tissue were examined. Colonic tissue from PSC patients exhibited up-regulation of immune regulation and inflammatory signaling mRNA markers, including LGR5, IL-8, CCL2, COX2, TWIST1, and SNAIL. Additionally, PSC patients displayed a distinct proinflammatory serum proteomic signature and moderate elevation of some bile acids, such as glycochenodeoxycholic acid (GCDCA). Co-incubation of human-derived monocytes with GCDCA partially replicated the inflammatory profile observed in PSC. These findings suggest that circulating bile acids modulate the peripheral immune system proinflammatory response, contributing to the unique PSC phenotype.
- MeSH
- dospělí MeSH
- idiopatické střevní záněty * imunologie komplikace krev genetika MeSH
- kolon metabolismus imunologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- monocyty imunologie metabolismus MeSH
- proteomika metody MeSH
- sklerozující cholangitida * imunologie krev komplikace genetika MeSH
- studie případů a kontrol MeSH
- žlučové kyseliny a soli * krev imunologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
Immune checkpoints are critical in modulating immune responses and maintaining self-tolerance. Cancer cells can exploit these mechanisms to evade immune detection, making immune checkpoints attractive targets for cancer therapy. The introduction of immune checkpoint inhibitors (ICIs) has transformed cancer treatment, with monoclonal antibodies targeting CTLA-4, PD-1, and PD-L1 demonstrating clinical success. However, challenges such as immune-related adverse events, primary and acquired resistance, and high treatment costs persist. To address these challenges, it is essential to explore alternative strategies, including small-molecule and peptide-based inhibitors, aptamers, RNA-based therapies, gene-editing technologies, bispecific and multispecific agents, and cell-based therapies. Additionally, innovative approaches such as lysosome-targeting chimeras, proteolysis-targeting chimeras, and N-(2-hydroxypropyl) methacrylamide copolymers are emerging as promising options for enhancing treatment effectiveness. This review highlights significant advancements in the field, focusing on their clinical implications and successes.
Endometriosis, a complex inflammatory disease, affects a significant proportion of women of reproductive age, approximately 10-15%. The disease involves the growth of endometrial glands and stroma outside the uterine cavity, leading to tissue remodeling and fibrosis. Hormonal imbalances, accompanied by local and general inflammation and pain, are key features of endometriosis. Endometriotic lesions are associated with the overproduction of cytokines, metalloproteinases, prostaglandins, reactive oxygen radicals, and extracellular vesicles. Genetic predisposition and cytokine gene polymorphisms have been documented. Macrophages, dendritic cells, mast cells, Th1 in the early phase, Th2 in the late phase, and T regulatory cells play a crucial role in endometriosis. Reduced NK cell function and impaired immune vigilance contribute to endometrial growth. The strong inflammatory condition of the endometrium poses a barrier to the proper implantation of the zygote, contributing to the infertility of these patients. Cytokines from various cell types vary with the severity of the disease. The role of microbiota in endometriosis is still under study. Endometriosis is associated with autoimmunity and ovarian cancer. Hormonal treatments and surgery are commonly used; however, recent interest focuses on anti-inflammatory and immunomodulatory therapies, including cytokine and anti-cytokine antibodies. Modulating the immune response has proven critical; however, more research is needed to optimize treatment for these patients.
- MeSH
- cytokiny metabolismus imunologie MeSH
- endometrióza * imunologie terapie patologie etiologie MeSH
- endometrium imunologie patologie MeSH
- lidé MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
INTRODUCTION: The immunosuppressive roles of galectin-3 (Gal-3) in carcinogenesis make this lectin an attractive target for pharmacological inhibition in immunotherapy. Although current clinical immunotherapies appear promising in the treatment of solid tumors, their efficacy is significantly weakened by the hostile immunosuppressive tumor microenvironment (TME). Gal-3, a prominent TME modulator, efficiently subverts the elimination of cancer, either directly by inducing apoptosis of immune cells or indirectly by binding essential effector molecules, such as interferon-gamma (IFNγ). METHODS: N-(2-Hydroxypropyl)methacrylamide (HPMA)-based glycopolymers bearing poly-N-acetyllactosamine-derived tetrasaccharide ligands of Gal-3 were designed, synthesized, and characterized using high-performance liquid chromatography, dynamic light scattering, UV-Vis spectrophotometry, gel permeation chromatography, nuclear magnetic resonance, high-resolution mass spectrometry and CCK-8 assay for evaluation of glycopolymer non-toxicity. Pro-immunogenic effects of purified glycopolymers were tested by apoptotic assay using flow cytometry, competitive ELISA, and in vitro cell-free INFγ-based assay. RESULTS: All tested glycopolymers completely inhibited Gal-3-induced apoptosis of monocytes/macrophages, of which the M1 subtype is responsible for eliminating cancer cells during immunotherapy. Moreover, the glycopolymers suppressed Gal-3-induced capture of glycosylated IFNγ by competitive inhibition to Gal-3 carbohydrate recognition domain (CRD), which enables further inherent biological activities of this effector, such as differentiation of monocytes into M1 macrophages and repolarization of M2-macrophages to the M1 state. CONCLUSION: The prepared glycopolymers are promising inhibitors of Gal-3 and may serve as important supportive anti-cancer nanosystems enabling the infiltration of proinflammatory macrophages and the reprogramming of unwanted M2 macrophages into the M1 subtype.
- MeSH
- akrylamidy chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- galektin 3 * antagonisté a inhibitory MeSH
- galektiny MeSH
- interferon gama * metabolismus MeSH
- krevní proteiny MeSH
- lidé MeSH
- makrofágy účinky léků MeSH
- monocyty * účinky léků MeSH
- nádorové mikroprostředí účinky léků MeSH
- polymery * chemie farmakologie MeSH
- protinádorové látky * farmakologie chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
