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This study demonstrates the concept of an angle-variable compact spectral module. As a key feature, the filter-based module enables highly efficient wavelength-selective light detection by applying the reflective beam path according to the origami example. It was accomplished through inclined mirrors, which allow for different incident angles on the wavelength separating interference filters used in a robust assembly with no moving parts. To experimentally verify the concept, a wavelength range between 550 and 700â nm was detected by 11 spectral channels. These initial results showed the potential to develop easily scalable and application-tailored sensors, which can overcome conventional filter-based sensor approaches that use upright or fixed-angle illumination.
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This study explores the design and optimization of cascaded double-hyperchromatic optical systems (i.e., 2×2 lenses), focusing on achieving an extremely linear axial spectral decomposition characterized by an exceptionally low equivalent Abbe number. The investigation involves two double hyperchromats, considering both purely refractive systems and hybrid configurations that combine refractive and diffractive elements. For purely refractive systems, alternating focal length signs of divergent and collective lenses are crucial to achieve significant axial chromatic dispersion. In hybrid systems, the position of the diffractive optical element (DOE) and the selection of focal lengths play key roles in obtaining extremely low equivalent Abbe numbers. The optimized systems demonstrate absolute equivalent Abbe numbers of 0.983 for purely refractive and 0.65 for hybrid systems-more than four times lower than the absolute Abbe number of a single diffractive element. Notably, even systems using standard materials exhibit significantly low equivalent Abbe numbers of 2.5 and 1.4 for pure refractive and hybrid configurations, respectively. These results offer promising opportunities for improving optical applications based on axial spectral decomposition, overcoming previous limitations of axial chromatic spreading.
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Primary amoebic meningoencephalitis is a rare but fatal central nervous system (CNS) disease caused by the "brain-eating amoeba" Naegleria fowleri. A major obstacle is the requirement for drugs with the ability to cross the blood-brain barrier, which are used in extremely high doses, cause severe side effects, and are usually ineffective. We discovered that the 4-aminomethylphenoxy-benzoxaborole AN3057 exhibits nanomolar potency against N. fowleri, and experimental treatment of infected mice significantly prolonged survival and demonstrated a 28% relapse-free cure rate.
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Amebiasis , Infecciones Protozoarias del Sistema Nervioso Central , Meningoencefalitis , Naegleria fowleri , Animales , Ratones , Amebiasis/tratamiento farmacológico , Infecciones Protozoarias del Sistema Nervioso Central/tratamiento farmacológico , Barrera HematoencefálicaRESUMEN
Many of the currently available anti-parasitic and anti-fungal frontline drugs have severe limitations, including adverse side effects, complex administration, and increasing occurrence of resistance. The discovery and development of new therapeutic agents is a costly and lengthy process. Therefore, repurposing drugs with already established clinical application offers an attractive, fast-track approach for novel treatment options. In this study, we show that the anti-cancer drug candidate MitoTam, a mitochondria-targeted analog of tamoxifen, efficiently eliminates a wide range of evolutionarily distinct pathogens in vitro, including pathogenic fungi, Plasmodium falciparum, and several species of trypanosomatid parasites, causative agents of debilitating neglected tropical diseases. MitoTam treatment was also effective in vivo and significantly reduced parasitemia of two medically important parasites, Leishmania mexicana and Trypanosoma brucei, in their respective animal infection models. Functional analysis in the bloodstream form of T. brucei showed that MitoTam rapidly altered mitochondrial functions, particularly affecting cellular respiration, lowering ATP levels, and dissipating mitochondrial membrane potential. Our data suggest that the mode of action of MitoTam involves disruption of the inner mitochondrial membrane, leading to rapid organelle depolarization and cell death. Altogether, MitoTam is an excellent candidate drug against several important pathogens, for which there are no efficient therapies and for which drug development is not a priority.
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Antineoplásicos , Trypanosoma brucei brucei , Animales , Antineoplásicos/metabolismo , Antineoplásicos/farmacología , Reposicionamiento de Medicamentos , Potencial de la Membrana Mitocondrial , Plasmodium falciparumRESUMEN
Hyperchromatic systems are characterized by strong longitudinal chromatic aberrations that are quantitatively described by very small equivalent Abbe numbers. In this contribution, doublet systems are systematically studied with the aim of obtaining extreme values for the equivalent Abbe numbers. Both purely refractive combinations and hybrid systems of diffractive and refractive components are considered. Chromatic axial splitting is determined as a function of the optical powers of the individual components as well as the dispersion properties of the materials involved. In order to determine actual implementable configurations for extremely small equivalent Abbe numbers, a systematic ray-trace analysis is performed in addition to paraxial studies, taking into account geometric constraints on lens curvatures and considering also complete, continuous dispersion curves. As extreme values for systems with appropriate imaging quality, an equivalent Abbe number of υ~=-2.5 is obtained for the purely refractive approach, and υ~=0.4 for the hybrid case, which is more than 8 times smaller than the absolute value of a single diffractive lens.
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This paper demonstrates a method to significantly enhance the detection efficiency of filter-based spectral sensors without the use of additional dichroic optics for spectral preselection. The fundamental principle is that light reflected from one interference filter or filter segment can be used consecutively, reducing the overall system losses. The proof-of-concept is presented using two compact optical modules. The first module uses 10 individual filters between 520 and 800 nm, and the second is capable of continuous spectrum acquisition between 450 and 825 nm using a linear variable filter (LVF) as a key element. An efficiency increase factor of up to approximately 100 compared to a common system, where the entire LVF is directly illuminated, was demonstrated.
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This paper presents concept, optical design, and the implementation of a novel, to the best of our knowledge, lithographic exposure tool for the fabrication of rotationally symmetric meso- and microscale optical structures using a variable ring-shaped light distribution. Compared to the conventional lithographic technique of direct writing in Cartesian coordinates, which is intrinsically suboptimal for the fabrication of rotationally symmetric optical structures, this approach allows for fast exposure and avoids disturbing stitching effects. The diameter of the exposure ring varies between 1.6 and 6.5 mm, and the ring width measures â¼75µm full width at half-maximum for all diameters. The basic capabilities of the exposure tool are demonstrated by the fabrication of exemplary meso- and microscale structures such as diffractive axicon elements, phase rings, Fresnel zone plates and zone plate arrays.
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Lignin is a promising resource for the sustainable production of platform chemicals and biofuels. The paper industry produces large quantities of lignin every year, mostly dissolved in a black liquor. With the help of hydrothermal liquefaction, black liquor can be used directly as a feedstock to depolymerize the lignin to desired products. However, because various cooking chemicals (e.g., NaHS, NaOH) used in the Kraft process, dominant in the paper industry, are also dissolved in the black liquor, it is necessary to study in detail their influence on the process as well as their fate. In this work, the focus was on the fate of sulfur and the influence of sulfide (HS-). For this purpose, hydrothermal liquefaction experiments (250-400 °C) were carried out with black liquor and self-prepared model black liquor with different sulfide concentrations (0-3 g·L-1 HS-) in batch reactors (V = 25 mL), and the products were analyzed to understand the chemical pathways involving sulfur. It was found that the inorganic sulfur compounds react with organic matter to produce organic sulfur compounds. Dimethyl sulfide is the most abundant of these products. The HS- concentration correlates with the amount of dimethyl sulfide produced. Because methanethiol has also been qualitatively detected, the reaction mechanism of Karnofski et al. for the formation of dimethyl sulfide in the Kraft process also applies to the hydrothermal liquefaction of black liquor. Increased sulfide concentration in the feed leads to an accelerated depolymerization of lignin. In contrast, the yields of some aromatic monomers decrease slightly, possibly as a result of repolymerization reactions also occurring more quickly.
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Multiple studies indicate that iron chelators enhance their anti-cancer properties by inducing NDRG1, a known tumor and metastasis suppressor. However, the exact role of NDRG1 remains controversial, as newer studies have shown that NDRG1 can also act as an oncogene. Our group recently introduced mitochondrially targeted iron chelators deferoxamine (mitoDFO) and deferasirox (mitoDFX) as effective anti-cancer agents. In this study, we evaluated the ability of these modified chelators to induce NDRG1 and the role of NDRG1 in breast cancer. We demonstrated that both compounds specifically increase NDRG1 without inducing other NDRG family members. We have documented that the effect of mitochondrially targeted chelators is at least partially mediated by GSK3α/ß, leading to phosphorylation of NDRG1 at Thr346 and to a lesser extent on Ser330. Loss of NDRG1 increases cell death induced by mitoDFX. Notably, MDA-MB-231 cells lacking NDRG1 exhibit reduced extracellular acidification rate and grow slower than parental cells, while the opposite is true for ER+ MCF7 cells. Moreover, overexpression of full-length NDRG1 and the N-terminally truncated isoform (59112) significantly reduced sensitivity towards mitoDFX in ER+ cells. Furthermore, cells overexpressing full-length NDRG1 exhibited a significantly accelerated tumor formation, while its N-terminally truncated isoforms showed significantly impaired capacity to form tumors. Thus, overexpression of full-length NDRG1 promotes tumor growth in highly aggressive triple-negative breast cancer.
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Iron, as an essential micronutrient, plays a crucial role in host-pathogen interactions. In order to limit the growth of the pathogen, a common strategy of innate immunity includes withdrawing available iron to interfere with the cellular processes of the microorganism. Against that, unicellular parasites have developed powerful strategies to scavenge iron, despite the effort of the host. Iron-sequestering compounds, such as the approved and potent chelator deferoxamine (DFO), are considered a viable option for therapeutic intervention. Since iron is heavily utilized in the mitochondrion, targeting iron chelators in this organelle could constitute an effective therapeutic strategy. This work presents mitochondrially targeted DFO, mitoDFO, as a candidate against a range of unicellular parasites with promising in vitro efficiency. Intracellular Leishmania infection can be cleared by this compound, and experimentation with Trypanosoma brucei 427 elucidates its possible mode of action. The compound not only affects iron homeostasis but also alters the physiochemical properties of the inner mitochondrial membrane, resulting in a loss of function. Furthermore, investigating the virulence factors of pathogenic yeasts confirms that mitoDFO is a viable candidate for therapeutic intervention against a wide spectrum of microbe-associated diseases.
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Antiinfecciosos , Hierro , Deferoxamina/química , Antiparasitarios/farmacología , Quelantes del Hierro/farmacología , Quelantes del Hierro/uso terapéutico , MitocondriasRESUMEN
Heteroatom analogues of hydrocodone, in which the N-methyl functionality was replaced with oxygen, sulfur, sulfoxide, and sulfone, were prepared by a short sequence from the ethylene glycol ketal of hydrocodone; a carbocyclic analogue of bisnorhydrocodone was also prepared. The compounds were tested for receptor binding and revealed moderate levels of activity for the sulfone analogue of hydrocodone.
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Hidrocodona/síntesis química , Hidrocodona/farmacología , Antagonistas de Narcóticos , Animales , Células CHO , Cricetinae , Ciclización , Relación Dosis-Respuesta a Droga , Humanos , Hidrocodona/química , Estructura Molecular , Relación Estructura-ActividadRESUMEN
BACKGROUND: Atypical haemolytic uremic syndrome (aHUS) is often associated with a high risk of disease recurrence and subsequent graft loss after isolated renal transplantation. Evidence-based recommendations for a mutation-based management after renal transplantation in aHUS caused by a combined mutation with complement factor I (CFI) and membrane cofactor protein CD46 (MCP) are limited. CASE-DIAGNOSIS/TREATMENT: We describe a 9-year-old boy with a first manifestation of aHUS at the age of 9 months carrying combined heterozygous mutations in the CFI and MCP genes. At the age of 5 years, he underwent isolated cadaveric renal transplantation. Fresh frozen plasma was administered during and after transplantation, tapered and finally stopped after 3 years. CONCLUSIONS: During the 5-year follow-up after transplantation there have been no signs of aHUS recurrence and graft function has remained good. The combination of heterozygous MCP and CFI mutations with aHUS might have a positive impact on the post-transplant course, possibly predicting a lower risk of aHUS recurrence after an isolated cadaveric renal transplantation.
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Factor I de Complemento/genética , Supervivencia de Injerto , Síndrome Hemolítico-Urémico/cirugía , Trasplante de Riñón , Proteína Cofactora de Membrana/genética , Mutación , Síndrome Hemolítico Urémico Atípico , Transfusión de Componentes Sanguíneos , Niño , Predisposición Genética a la Enfermedad , Síndrome Hemolítico-Urémico/genética , Heterocigoto , Humanos , Inmunosupresores/uso terapéutico , Masculino , Fenotipo , Factores de Tiempo , Resultado del TratamientoRESUMEN
A recent paper published in Nature Medicine reported on the Phase I clinical trial of a mitochondria-targeting anti-cancer agent IACS-01059 in patients with acute myeloid leukemia (AML) and solid tumors [...].
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Mitochondrially targeted anticancer drugs (mitocans) that disrupt the energy-producing systems of cancer are emerging as new potential therapeutics. Mitochondrially targeted tamoxifen (MitoTam), an inhibitor of mitochondrial respiration respiratory complex I, is a first-in-class mitocan that was tested in the phase I/Ib MitoTam-01 trial of patients with metastatic cancer. MitoTam exhibited a manageable safety profile and efficacy; among 37% (14/38) of responders, the efficacy was greatest in patients with metastatic renal cell carcinoma (RCC) with a clinical benefit rate of 83% (5/6) of patients. This can be explained by the preferential accumulation of MitoTam in the kidney tissue in preclinical studies. Here we report the mechanism of action and safety profile of MitoTam in a case series of RCC patients. All six patients were males with a median age of 69 years, who had previously received at least three lines of palliative systemic therapy and suffered progressive disease before starting MitoTam. We recorded stable disease in four, partial response in one, and progressive disease (PD) in one patient. The histological subtype matched clear cell RCC (ccRCC) in the five responders and claro-cellular carcinoma with sarcomatoid features in the non-responder. The number of circulating tumor cells (CTCs) was evaluated longitudinally to monitor disease dynamics. Beside the decreased number of CTCs after MitoTam administration, we observed a significant decrease of the mitochondrial network mass in enriched CTCs. Two patients had long-term clinical responses to MitoTam, of 50 and 36 weeks. Both patients discontinued treatment due to adverse events, not PD. Two patients who completed the trial in November 2019 and May 2020 are still alive without subsequent anticancer therapy. The toxicity of MitoTam increased with the dosage but was manageable. The efficacy of MitoTam in pretreated ccRCC patients is linked to the novel mechanism of action of this first-in-class mitochondrially targeted drug.
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Background: Mitochondria present an emerging target for cancer treatment. We have investigated the effect of mitochondrially targeted tamoxifen (MitoTam), a first-in-class anti-cancer agent, in patients with solid metastatic tumours. Methods: MitoTam was tested in an open-label, single-centre (Department of Oncology, General Faculty Hospital, Charles University, Czech Republic), phase I/Ib trial in metastatic patients with various malignancies and terminated oncological therapies. In total, 75 patients were enrolled between May 23, 2018 and July 22, 2020. Phase I evaluated escalating doses of MitoTam in two therapeutic regimens using the 3 + 3 design to establish drug safety and maximum tolerated dose (MTD). In phase Ib, three dosing regimens were applied over 8 and 6 weeks to evaluate long-term toxicity of MitoTam as the primary objective and its anti-cancer effect as a secondary objective. This trial was registered with the European Medicines Agency under EudraCT 2017-004441-25. Findings: In total, 37 patients were enrolled into phase I and 38 into phase Ib. In phase I, the initial application of MitoTam via peripheral vein indicated high risk of thrombophlebitis, which was avoided by central vein administration. The highest dose with acceptable side effects was 5.0 mg/kg. The prevailing adverse effects (AEs) in phase I were neutropenia (30%), anaemia (30%) and fever/hyperthermia (30%), and in phase Ib fever/hyperthermia (58%) together with anaemia (26%) and neutropenia (16%). Serious AEs were mostly related to thromboembolic (TE) complications that affected 5% and 13% of patients in phase I and Ib, respectively. The only statistically significant AE related to MitoTam treatment was anaemia in phase Ib (p = 0.004). Of the tested regimens weekly dosing with 3.0 mg/kg for 6 weeks afforded the best safety profile with almost all being grade 1 (G1) AEs. Altogether, five fatalities occurred during the study, two of them meeting criteria for Suspected Unexpected Serious Adverse Events Reporting (SUSAR) (G4 thrombocytopenia and G5 stroke). MitoTam showed benefit evaluated as clinical benefit rate (CBR) in 37% patients with the largest effect in renal cell carcinoma (RCC) where four out of six patients reached disease stabilisation (SD), one reached partial response (PR) so that in total, five out of six (83%) patients showed CBR. Interpretation: In this study, the MTD was established as 5.0 mg/kg and the recommended dose of MitoTam as 3.0 mg/kg given once per week via central vein with recommended preventive anti-coagulation therapy. The prevailing toxicity included haematological AEs, hyperthermia/fever and TE complications. One fatal stroke and non-fatal G4 thrombocytopenia were recorded. MitoTam showed high efficacy against RCC. Funding: Smart Brain Ltd. Translation: For the Czech translation of the abstract see Supplementary Materials section.
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Type 2 diabetes mellitus represents a major health problem with increasing prevalence worldwide. Limited efficacy of current therapies has prompted a search for novel therapeutic options. Here we show that treatment of pre-diabetic mice with mitochondrially targeted tamoxifen, a potential anti-cancer agent with senolytic activity, improves glucose tolerance and reduces body weight with most pronounced reduction of visceral adipose tissue due to reduced food intake, suppressed adipogenesis and elimination of senescent cells. Glucose-lowering effect of mitochondrially targeted tamoxifen is linked to improvement of type 2 diabetes mellitus-related hormones profile and is accompanied by reduced lipid accumulation in liver. Lower senescent cell burden in various tissues, as well as its inhibitory effect on pre-adipocyte differentiation, results in lower level of circulating inflammatory mediators that typically enhance metabolic dysfunction. Targeting senescence with mitochodrially targeted tamoxifen thus represents an approach to the treatment of type 2 diabetes mellitus and its related comorbidities, promising a complex impact on senescence-related pathologies in aging population of patients with type 2 diabetes mellitus with potential translation into the clinic.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Anciano , Animales , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucosa/metabolismo , Humanos , Ratones , Obesidad/complicaciones , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Tamoxifeno/farmacología , Tamoxifeno/uso terapéuticoRESUMEN
Buprenorphine was synthesized from oripavine by a sequence involving the conversion of oripavine into its cyclopropylmethyl quaternary salt, N-demethylation with thiolate to N-cyclopropylmethyl nororipavine, and conversion of this material to the title compound by previously available methods. The new synthesis avoids toxic reagents used previously, is shorter, and proceeds in comparable yields. Experimental and spectral data are provided for all new compounds.
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Buprenorfina/síntesis química , Nitrógeno/química , Tebaína/análogos & derivados , Bromuro de Cianógeno/química , Tecnología Química Verde , Metilación , Sales (Química)/química , Tebaína/químicaRESUMEN
Four generations of chemoenzymatic approaches to oseltamivir are presented. The first two generations relied on the use of cyclohexadiene-cis-diol derived enzymatically from bromobenzene. The third and fourth generation used the corresponding diol obtained from ethyl benzoate by fermentation with E. coli JM109(pDTG601a). Oseltamivir was obtained from ethyl benzoate by intersecting intermediate 39 (third-generation synthesis) and intermediate 45 (fourth-generation synthesis). Both of these advanced approaches benefited from symmetry considerations and translocation of the acrylate double bond with concomitant elimination of the C-1 hydroxyl. The syntheses are evaluated for overall efficiency by the use of efficiency metrics and compared with other syntheses of oseltamivir (both academic and industrial).
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Antivirales/síntesis química , Bromobencenos/química , Ciclohexenos/síntesis química , Oseltamivir/síntesis química , Benzoatos/química , Escherichia coli/enzimología , Fermentación , Humanos , Espectroscopía de Resonancia Magnética , Neuraminidasa/antagonistas & inhibidores , EstereoisomerismoRESUMEN
Deferoxamine (DFO) represents a widely used iron chelator for the treatment of iron overload. Here we describe the use of mitochondrially targeted deferoxamine (mitoDFO) as a novel approach to preferentially target cancer cells. The agent showed marked cytostatic, cytotoxic, and migrastatic properties in vitro, and it significantly suppressed tumor growth and metastasis in vivo. The underlying molecular mechanisms included (i) impairment of iron-sulfur [Fe-S] cluster/heme biogenesis, leading to destabilization and loss of activity of [Fe-S] cluster/heme containing enzymes, (ii) inhibition of mitochondrial respiration leading to mitochondrial reactive oxygen species production, resulting in dysfunctional mitochondria with markedly reduced supercomplexes, and (iii) fragmentation of the mitochondrial network and induction of mitophagy. Mitochondrial targeting of deferoxamine represents a way to deprive cancer cells of biologically active iron, which is incompatible with their proliferation and invasion, without disrupting systemic iron metabolism. Our findings highlight the importance of mitochondrial iron metabolism for cancer cells and demonstrate repurposing deferoxamine into an effective anticancer drug via mitochondrial targeting. SIGNIFICANCE: These findings show that targeting the iron chelator deferoxamine to mitochondria impairs mitochondrial respiration and biogenesis of [Fe-S] clusters/heme in cancer cells, which suppresses proliferation and migration and induces cell death. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2289/F1.large.jpg.
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Carcinogénesis/efectos de los fármacos , Deferoxamina/administración & dosificación , Quelantes del Hierro/administración & dosificación , Hierro/metabolismo , Mitocondrias/metabolismo , Mitofagia/efectos de los fármacos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Carga Tumoral/efectos de los fármacos , Animales , Muerte Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Hemo/metabolismo , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Mitocondrias/efectos de los fármacos , Neoplasias/patología , Células PC-3 , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Pancreatic cancer is one of the deadliest forms of cancer, which is attributed to lack of effective treatment options and drug resistance. Mitochondrial inhibitors have emerged as a promising class of anticancer drugs, and several inhibitors of the electron transport chain (ETC) are being clinically evaluated. We hypothesized that resistance to ETC inhibitors from the biguanide class could be induced by inactivation of SMAD4, an important tumor suppressor involved in transforming growth factor ß (TGFß) signaling, and associated with altered mitochondrial activity. Here we show that, paradoxically, both TGFß-treatment and the loss of SMAD4, a downstream member of TGFß signaling cascade, induce resistance to biguanides, decrease mitochondrial respiration, and fragment the mitochondrial network. Mechanistically, the resistance of SMAD4-deficient cells is mediated by increased mitophagic flux driven by MAPK/ERK signaling, whereas TGFß-induced resistance is autophagy-independent and linked to epithelial-to-mesenchymal transition (EMT). Interestingly, mitochondria-targeted tamoxifen, a complex I inhibitor under clinical trial, overcomes resistance mediated by SMAD4-deficiency or TGFß signaling. Our data point to differential mechanisms underlying the resistance to treatment in PDAC arising from TGFß signaling and SMAD4 loss, respectively. The findings will help the development of mitochondria-targeted therapy for pancreatic cancer patients with SMAD4 as a plausible predictive marker.