| 1. |
- Ambite, Ines, et al.
(författare)
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Molecular determinants of disease severity in urinary tract infection
- 2021
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Ingår i: Nature Reviews Urology. - : Springer Science and Business Media LLC. - 1759-4812 .- 1759-4820. ; 18:8, s. 468-486
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Forskningsöversikt (refereegranskat)abstract
- The most common and lethal bacterial pathogens have co-evolved with the host. Pathogens are the aggressors, and the host immune system is responsible for the defence. However, immune responses can also become destructive, and excessive innate immune activation is a major cause of infection-associated morbidity, exemplified by symptomatic urinary tract infections (UTIs), which are caused, in part, by excessive innate immune activation. Severe kidney infections (acute pyelonephritis) are a major cause of morbidity and mortality, and painful infections of the urinary bladder (acute cystitis) can become debilitating in susceptible patients. Disease severity is controlled at specific innate immune checkpoints, and a detailed understanding of their functions is crucial for strategies to counter microbial aggression with novel treatment and prevention measures. One approach is the use of bacterial molecules that reprogramme the innate immune system, accelerating or inhibiting disease processes. A very different outcome is asymptomatic bacteriuria, defined by low host immune responsiveness to bacteria with attenuated virulence. This observation provides the rationale for immunomodulation as a new therapeutic tool to deliberately modify host susceptibility, control the host response and avoid severe disease. The power of innate immunity as an arbitrator of health and disease is also highly relevant for emerging pathogens, including the current COVID-19 pandemic.
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| 2. |
- Ambite, Ines, et al.
(författare)
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Therapeutic Effects of IL-1RA against Acute Bacterial Infections, including Antibiotic-Resistant Strains
- 2024
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Ingår i: Pathogens. - 2076-0817. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Innate immunity is essential for the anti-microbial defense, but excessive immune activation may cause severe disease. In this study, immunotherapy was shown to prevent excessive innate immune activation and restore the anti-bacterial defense. E. coli-infected Asc−/− mice develop severe acute cystitis, defined by IL-1 hyper-activation, high bacterial counts, and extensive tissue pathology. Here, the interleukin-1 receptor antagonist (IL-1RA), which inhibits IL-1 hyper-activation in acute cystitis, was identified as a more potent inhibitor of inflammation and NK1R- and substance P-dependent pain than cefotaxime. Furthermore, IL-1RA treatment inhibited the excessive innate immune activation in the kidneys of infected Irf3−/− mice and restored tissue integrity. Unexpectedly, IL-1RA also accelerated bacterial clearance from infected bladders and kidneys, including antibiotic-resistant E. coli, where cefotaxime treatment was inefficient. The results suggest that by targeting the IL-1 response, control of the innate immune response to infection may be regained, with highly favorable treatment outcomes, including infections caused by antibiotic-resistant strains.
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| 3. |
- Brisuda, Antonín, et al.
(författare)
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Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex
- 2021
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Partially unfolded alpha-lactalbumin forms the oleic acid complex HAMLET, with potent tumoricidal activity. Here we define a peptide-based molecular approach for targeting and killing tumor cells, and evidence of its clinical potential (ClinicalTrials.gov NCT03560479). A 39-residue alpha-helical peptide from alpha-lactalbumin is shown to gain lethality for tumor cells by forming oleic acid complexes (alpha1-oleate). Nuclear magnetic resonance measurements and computational simulations reveal a lipid core surrounded by conformationally fluid, alpha-helical peptide motifs. In a single center, placebo controlled, double blinded Phase I/II interventional clinical trial of non-muscle invasive bladder cancer, all primary end points of safety and efficacy of alpha1-oleate treatment are reached, as evaluated in an interim analysis. Intra-vesical instillations of alpha1-oleate triggers massive shedding of tumor cells and the tumor size is reduced but no drug-related side effects are detected (primary endpoints). Shed cells contain alpha1-oleate, treated tumors show evidence of apoptosis and the expression of cancer-related genes is inhibited (secondary endpoints). The results are especially encouraging for bladder cancer, where therapeutic failures and high recurrence rates create a great, unmet medical need.
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| 4. |
- Butler, Daniel, et al.
(författare)
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Immunomodulation therapy offers new molecular strategies to treat UTI
- 2022
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Ingår i: Nature Reviews Urology. - : Springer Science and Business Media LLC. - 1759-4812 .- 1759-4820. ; 19:7, s. 419-437
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Forskningsöversikt (refereegranskat)abstract
- Innovative solutions are needed for the treatment of bacterial infections, and a range of antibacterial molecules have been explored as alternatives to antibiotics. A different approach is to investigate the immune system of the host for new ways of making the antibacterial defence more efficient. However, the immune system has a dual role as protector and cause of disease: in addition to being protective, increasing evidence shows that innate immune responses can become excessive and cause acute symptoms and tissue pathology during infection. This role of innate immunity in disease suggests that the immune system should be targeted therapeutically, to inhibit over-reactivity. The ultimate goal is to develop therapies that selectively attenuate destructive immune response cascades, while augmenting the protective antimicrobial defence but such treatment options have remained underexplored, owing to the molecular proximity of the protective and destructive effects of the immune response. The concept of innate immunomodulation therapy has been developed successfully in urinary tract infections, based on detailed studies of innate immune activation and disease pathogenesis. Effective, disease-specific, immunomodulatory strategies have been developed by targeting specific immune response regulators including key transcription factors. In acute pyelonephritis, targeting interferon regulatory factor 7 using small interfering RNA or treatment with antimicrobial peptide cathelicidin was protective and, in acute cystitis, targeting overactive effector molecules such as IL-1β, MMP7, COX2, cAMP and the pain-sensing receptor NK1R has been successful in vivo. Furthermore, other UTI treatment strategies, such as inhibiting bacterial adhesion and vaccination, have also shown promise.
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| 5. |
- Butler, Daniel S.C., et al.
(författare)
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A bacterial protease depletes c-MYC and increases survival in mouse models of bladder and colon cancer
- 2021
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Ingår i: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 39:6, s. 754-764
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Tidskriftsartikel (refereegranskat)abstract
- Is the oncogene MYC upregulated or hyperactive? In the majority of human cancers, finding agents that target c-MYC has proved difficult. Here we report specific bacterial effector molecules that inhibit cellular MYC (c-MYC) in human cells. We show that uropathogenic Escherichia coli (UPEC) degrade the c-MYC protein and attenuate MYC expression in both human cells and animal tissues. c-MYC protein was rapidly degraded by both cell-free bacterial lysates and the purified bacterial protease Lon. In mice, intravesical or peroral delivery of Lon protease delayed tumor progression and increased survival in MYC-dependent bladder and colon cancer models, respectively. These results suggest that bacteria have evolved strategies to control c-MYC tissue levels in the host and that the Lon protease shows promise for therapeutic targeting of c-MYC in cancer.
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| 6. |
- Chavoshi, Hadi, et al.
(författare)
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Crocin-loaded liposomes sensitize MDA-MB 231 breast cancer cells to doxorubicin by inducing apoptosis
- 2023
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Ingår i: Process Biochemistry. - 1359-5113. ; 130, s. 272-280
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Tidskriftsartikel (refereegranskat)abstract
- Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer with high heterogeneity and poor therapeutic responses to standard treatments. The use of herbal medicine for treatment of TNBC is gaining in popularity worldwide due to their better anti-tumor efficacy and less side effects compared to chemotherapy agents. Previous studies have shown that crocin, a natural carotenoid from saffron, induced cell apoptosis in a concentration-dependent behavior in TNBC MDA-MB-231 breast cancer cells. To improve anti-cancer properties of crocin, liposome-based formulation was prepared by the thin layer hydration-sonication method. The formulation was characterized based on particle size, zeta potential, morphology, encapsulation efficiency (EE) and cellular uptake. The formulation showed monodisperse distribution with an average size of 80 nm, about 70% EE and 11% loading capacity. The effect of crocin, and crocin-loaded liposomes in combination with doxorubicin (DOX) were evaluated using the MDA-MB-231 cell line. The results showed that crocin significantly increased the cytotoxicity of DOX, and crocin loaded liposome enhanced the cytotoxicity further. Flow cytometric analysis revealed that crocin loaded liposome in combination with DOX increased the number of cells in Sub-G1 and G2/M phases. Real time qPCR analysis showed that survivin, cyclin-B1, Bcl-xl mRNA were significantly down-regulated, while Bax and Bid mRNA levels were up-regulated following treatment with crocin loaded liposome compared to control. This study suggested that formulation of crocin into liposomes can be considered as a promising approach against tumor cells, especially when combining with the chemotherapy agent, DOX.
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| 7. |
- Co, Vanessa Anna, et al.
(författare)
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Schisandrin B Suppresses Colon Cancer Growth by Inducing Cell Cycle Arrest and Apoptosis : Molecular Mechanism and Therapeutic Potential
- 2024
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Ingår i: ACS Pharmacology and Translational Science. ; 7:3, s. 863-877
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Tidskriftsartikel (refereegranskat)abstract
- Colon cancer is among the most lethal and prevalent malignant tumors in the world, and the lack of effective therapies highlights the need for novel therapeutic approaches. Schisandrin B (Sch B), a lignan extracted from the fruit ofSchisandra chinensis, has been reported for its anticancer properties. However, to date, no studies have been done to characterize the exact molecular mechanisms underlying the antitumorigenic effects of Sch B in colon cancer. This study aimed to explore the antitumorigenic effects of Sch B in colon cancer and to understand the underlying therapeutic mechanism. A comprehensive analysis of the molecular mechanism underlying the antitumorigenic effects of Sch B on human colon cancer cells was performed using a combination of Raman spectroscopy, RNA-seq, computational docking, and molecular biological experiments. The in vivo efficacy was evaluated by a mouse xenograft model. Sch B reduced cell proliferation and triggered apoptosis in human colon cancer cell lines. Raman spectroscopy, computational, RNA-seq, and molecular and cellular studies revealed that Sch B activated unfolded protein responses by interacting with CHOP and upregulating CHOP, which thereby induced apoptosis. CHOP knockdown alleviated the Sch B-induced reduction in cell viability and apoptosis. Sch B reduced colon tumor growth in vivo. Our findings demonstrated that Sch B induced apoptosis and inhibited cell proliferation and tumor growth in vitro and in vivo. These results provided an essential background for clinical trials examining the effects of Sch B in patients with colon cancer.
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| 8. |
- Hien, Tran Thi, et al.
(författare)
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Bladder cancer therapy without toxicity—A dose-escalation study of alpha1-oleate
- 2020
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 147:9, s. 2479-2492
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Tidskriftsartikel (refereegranskat)abstract
- Potent chemotherapeutic agents are required to counteract the aggressive behavior of cancer cells and patients often experience severe side effects, due to tissue toxicity. Our study addresses if a better balance between efficacy and toxicity can be attained using the tumoricidal complex alpha1-oleate, formed by a synthetic, alpha-helical peptide comprising the N-terminal 39 amino acids of alpha-lactalbumin and the fatty acid oleic acid. Bladder cancer was established, by intravesical instillation of MB49 cells on day 0 and the treatment group received five instillations of alpha1-oleate (1.7-17 mM) on days 3 to 11. A dose-dependent reduction in tumor size, bladder size and bladder weight was recorded in the alpha1-oleate treated group, compared to sham-treated mice. Tumor markers Ki-67, Cyclin D1 and VEGF were inhibited in a dose-dependent manner, as was the expression of cancer-related genes. Remarkably, toxicity for healthy tissue was not detected in alpha1-oleate-treated, tumor-bearing mice or healthy mice or rabbits, challenged with increasing doses of the active complex. The results define a dose-dependent therapeutic effect of alpha1-oleate in a murine bladder cancer model.
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| 9. |
- Hien, Tran Thi, et al.
(författare)
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Long-term prevention of bladder cancer progression by alpha1-oleate alone or in combination with chemotherapy
- 2023
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 153:3, s. 584-599
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Tidskriftsartikel (refereegranskat)abstract
- Bladder cancer is common and one of the most costly cancer forms, due to a lack of curative therapies. Recently, clinical safety and efficacy of the alpha1-oleate complex was demonstrated in a placebo-controlled study of nonmuscle invasive bladder cancer. Our study investigated if long-term therapeutic efficacy is improved by repeated treatment cycles and by combining alpha1-oleate with low-dose chemotherapy. Rapidly growing bladder tumors were treated by intravesical instillation of alpha1-oleate, Epirubicin or Mitomycin C alone or in combination. One treatment cycle arrested tumor growth, with a protective effect lasting at least 4 weeks in mice receiving 8.5 mM of alpha1-oleate alone or 1.7 mM of alpha-oleate combined with Epirubicin or Mitomycin C. Repeated treatment cycles extended protection, defined by a lack of bladder pathology and a virtual absence of bladder cancer-specific gene expression. Synergy with Epirubicin was detected at the lower alpha1-oleate concentration and in vitro, alpha1-oleate was shown to enhance the uptake and nuclear translocation of Epirubicin, by tumor cells. Effects at the chromatin level affecting cell proliferation were further suggested by reduced BrdU incorporation. In addition, alpha1-oleate triggered DNA fragmentation, defined by the TUNEL assay. The results suggest that bladder cancer development may be prevented long-term in the murine model, by alpha1-oleate alone or in combination with low-dose Epirubicin. In addition, the combination of alpha1-oleate and Epirubicin reduced the size of established tumors. Exploring these potent preventive and therapeutic effects will be of immediate interest in patients with bladder cancer.
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| 10. |
- Tran, Hien Thi, et al.
(författare)
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BAMLET administration via drinking water inhibits intestinal tumor development and promotes long-term health
- 2024
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Ingår i: Scientific Reports. - 2045-2322. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Though new targeted therapies for colorectal cancer, which progresses from local intestinal tumors to metastatic disease, are being developed, tumor specificity remains an important problem, and side effects a major concern. Here, we show that the protein-fatty acid complex BAMLET (bovine alpha-lactalbumin made lethal to tumor cells) can act as a peroral treatment for colorectal cancer. ApcMin/+ mice, which carry mutations relevant to hereditary and sporadic human colorectal cancer, that received BAMLET in the drinking water showed long-term protection against tumor development and decreased expression of tumor growth-, migration-, metastasis- and angiogenesis-related genes. BAMLET treatment via drinking water inhibited the Wnt/β-catenin and PD-1 signaling pathways and prolonged survival without evidence of toxicity. Systemic disease in the lungs, livers, spleens, and kidneys, which accompanied tumor progression, was inhibited by BAMLET treatment. The metabolic response to BAMLET included carbohydrate and lipid metabolism, which were inhibited in tumor prone ApcMin/+ mice and weakly regulated in C57BL/6 mice, suggesting potential health benefits of peroral BAMLET administration in addition to the potent antitumor effects. Together, these findings suggest that BAMLET administration in the drinking water maintains antitumor pressure by removing emergent cancer cells and reprogramming gene expression in intestinal and extra-intestinal tissues.
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