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IScience May 2024Drug resistance threatens the effective control of infections, including parasitic diseases such as leishmaniases. Neutrophils are essential players in antimicrobial...
Drug resistance threatens the effective control of infections, including parasitic diseases such as leishmaniases. Neutrophils are essential players in antimicrobial control, but their role in drug-resistant infections is poorly understood. Here, we evaluated human neutrophil response to clinical parasite strains having distinct natural drug susceptibility. We found that antimony drug resistance significantly altered the expression of neutrophil genes, some of them transcribed by specific neutrophil subsets. Infection with drug-resistant parasites increased the expression of detoxification pathways and reduced the production of cytokines. Among these, the chemokine CCL3 was predominantly impacted, which resulted in an impaired ability of neutrophils to attract myeloid cells. Moreover, decreased myeloid recruitment when CCL3 levels are reduced was confirmed by blocking CCL3 in a mouse model. Collectively, these findings reveal that the interplay between naturally drug-resistant parasites and neutrophils modulates the infected skin immune microenvironment, revealing a key role of neutrophils in drug resistance.
PubMed: 38711445
DOI: 10.1016/j.isci.2024.109773 -
PLoS Neglected Tropical Diseases May 2024The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship...
The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 μg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.
Topics: Animals; Leishmaniasis, Cutaneous; Meglumine Antimoniate; Humans; Mice, Inbred BALB C; Antiprotozoal Agents; Treatment Failure; Female; Drug Resistance; Meglumine; Organometallic Compounds; Mice; Macrophages; Male; Leishmania guyanensis; Adult; Middle Aged; Young Adult; Parasite Load; Adolescent
PubMed: 38709850
DOI: 10.1371/journal.pntd.0012156 -
BMC Plant Biology May 2024This study aimed to investigate the alterations in biochemical and physiological responses of oat plants exposed to antimony (Sb) contamination in soil. Specifically, we...
BACKGROUND
This study aimed to investigate the alterations in biochemical and physiological responses of oat plants exposed to antimony (Sb) contamination in soil. Specifically, we evaluated the effectiveness of an arbuscular mycorrhizal fungus (AMF) and olive mill waste (OMW) in mitigating the effects of Sb contamination. The soil was treated with a commercial strain of AMF (Rhizophagus irregularis) and OMW (4% w/w) under two different levels of Sb (0 and 1500 mg kg soil).
RESULTS
The combined treatment (OMW + AMF) enhanced the photosynthetic rate (+ 40%) and chlorophyll a (+ 91%) and chlorophyll b (+ 50%) content under Sb condition, which in turn induced more biomass production (+ 67-78%) compared to the contaminated control plants. More photosynthesis in OMW + AMF-treated plants gives a route for phenylalanine amino acid synthesis (+ 69%), which is used as a precursor for the biosynthesis of secondary metabolites, including flavonoids (+ 110%), polyphenols (+ 26%), and anthocyanins (+ 63%) compared to control plants. More activation of phenylalanine ammonia-lyase (+ 38%) and chalcone synthase (+ 26%) enzymes in OMW + AMF-treated plants under Sb stress indicated the activation of phenylpropanoid pathways in antioxidant metabolites biosynthesis. There was also improved shifting of antioxidant enzyme activities in the ASC/GSH and catalytic pathways in plants in response to OMW + AMF and Sb contamination, remarkably reducing oxidative damage markers.
CONCLUSIONS
While individual applications of OMW and AMF also demonstrated some degree of plant tolerance induction, the combined presence of AMF with OMW supplementation significantly enhanced plant biomass production and adaptability to oxidative stress induced by soil Sb contamination.
Topics: Mycorrhizae; Olea; Soil Pollutants; Antimony; Adaptation, Physiological; Industrial Waste; Photosynthesis; Biodegradation, Environmental; Biomass
PubMed: 38702592
DOI: 10.1186/s12870-024-05044-1 -
Acta Dermato-venereologica Apr 2024Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's... (Comparative Study)
Comparative Study
Israel is endemic for Old-World cutaneous leishmaniasis. The most common species is Leishmania major. However, the available treatment options are limited. This study's objective was to compare the authors' experience with different antimony intralesional treatments of Leishmania major cutaneous leishmaniasis. A retrospective evaluation was undertaken for cases of Leishmania major cutaneous leishmaniasis treated by pentavalent antimony in a university-affiliated medical centre in Israel. The previous treatment of intralesional sodium stibogluconate (Pentostam®) was compared with the current treatment of meglumine antimoniate (Glucantime®). One hundred cases of cutaneous leishmaniasis were treated during the study period, of whom 33 were treated with intralesional sodium stibogluconate and 67 were treated with intralesional meglumine antimoniate. The patients were 78 males and 22 females, mean age 24 (range 10-67) and there was a total of 354 skin lesions. Within 3 months from treatment, 91% (30/33) of the intralesional sodium stibogluconate group and 88% (59/67) of the intralesional meglumine antimoniate group had complete healing of the cutaneous lesions after an average of 3 treatment cycles (non-statistically significant). In conclusion, the 2 different medications have the same efficacy and safety for treating cutaneous leishmaniasis. Pentavalent antimoniate intralesional infiltration treatment is safe, effective, and well tolerated with minimal side effects for Old-World cutaneous leishmaniasis.
Topics: Humans; Meglumine Antimoniate; Leishmaniasis, Cutaneous; Female; Male; Injections, Intralesional; Antimony Sodium Gluconate; Retrospective Studies; Adult; Antiprotozoal Agents; Middle Aged; Leishmania major; Aged; Young Adult; Adolescent; Treatment Outcome; Child; Time Factors; Israel; Meglumine; Organometallic Compounds
PubMed: 38682801
DOI: 10.2340/actadv.v104.35089 -
Molecules (Basel, Switzerland) Apr 2024Two mixed -substituted phosphine-chlorostibines, Acenap(PPr)(SbPhCl) and Acenap(PPr)(SbCl) (Acenap = acenaphthene-5,6-diyl) reacted cleanly with Grignard reagents or...
Two mixed -substituted phosphine-chlorostibines, Acenap(PPr)(SbPhCl) and Acenap(PPr)(SbCl) (Acenap = acenaphthene-5,6-diyl) reacted cleanly with Grignard reagents or BuLi to give the corresponding tertiary phosphine-stibines Acenap(PPr)(SbRR') (R, R' = Me, Pr, Bu, Ph). In addition, the Pt(II) complex of the tertiary phosphine-stibine Acenap(PPr)(SbPh) as well as the Mo(0) complex of Acenap(PPr)(SbMePh) were synthesised and characterised. Two of the phosphine-stibines and the two metal complexes were characterised by single-crystal X-ray diffraction. The -substituted species act as bidentate ligands through both P and Sb atoms, forming rather short Sb-metal bonds. The tertiary phosphine-stibines display through-space (CP) couplings between the phosphorus atom and carbon atoms bonded directly to the Sb atom of up to 40 Hz. The sequestration of the P and Sb lone pairs results in much smaller corresponding (CP) being observed in the metal complexes. QTAIM (Quantum Theory of Atoms in Molecules) and EDA-NOCV (Energy Decomposition Analysis employing Naturalised Orbitals for Chemical Valence) computational techniques were used to provide additional insight into a weak n(P)→σ*(Sb-C) intramolecular bonding interaction (pnictogen bond) in the phosphine-stibines.
PubMed: 38675660
DOI: 10.3390/molecules29081841 -
Pharmaceutics Apr 2024Cutaneous leishmaniasis (CL) is a neglected tropical disease. The treatment is restricted to drugs, such as meglumine antimoniate and amphotericin B, that exhibit toxic...
Combination of the Topical Photodynamic Therapy of Chloroaluminum Phthalocyanine Liposomes with Fexinidazole Oral Self-Emulsifying System as a New Strategy for Cutaneous Leishmaniasis Treatment.
Cutaneous leishmaniasis (CL) is a neglected tropical disease. The treatment is restricted to drugs, such as meglumine antimoniate and amphotericin B, that exhibit toxic effects, high cost, long-term treatment, and limited efficacy. The development of new alternative therapies, including the identification of effective drugs for the topical and oral treatment of CL, is of great interest. In this sense, a combination of topical photodynamic therapy (PDT) with chloroaluminum phthalocyanine liposomes (Lip-ClAlPc) and the oral administration of a self-emulsifying drug delivery system containing fexinidazole (SEDDS-FEX) emerges as a new strategy. The aim of the present study was to prepare, characterize, and evaluate the efficacy of combined therapy with Lip-ClAlPc and SEDDS-FEX in the experimental treatment of . Lip-ClAlPc and SEDDS-FEX were prepared, and the antileishmanial efficacy study was conducted with the following groups: 1. Lip-ClAlPc (0.05 mL); 2. SEDDS-FEX (50 mg/kg/day); 3. Lip-ClAlPc (0.05 mL)+SEDDS-FEX (50 mg/kg/day) combination; 4. FEX suspension (50 mg/kg/day); and 5. control (untreated). BALB/c mice received 10 sessions of topical Lip-ClAlPc on alternate days and 20 consecutive days of SEDDS-FEX or FEX oral suspension. Therapeutical efficacy was evaluated via the parasite burden (limiting-dilution assay), lesion size (mm), healing of the lesion, and histological analyses. Lip-ClAlPc and SEDDS-FEX presented physicochemical characteristics that are compatible with the administration routes used in the treatments. Lip-ClAlPc+SEDDS-FEX led to a significant reduction in the parasitic burden in the lesion and spleen when compared to the control group ( < 0.05) and the complete healing of the lesion in 43% of animals. The Lip-ClAlPc+SEDDS-FEX combination may be promising for the treatment of CL caused by
PubMed: 38675171
DOI: 10.3390/pharmaceutics16040509 -
International Journal of Molecular... Apr 2024In the face of flourishing industrialization and global trade, heavy metal and metalloid contamination of the environment is a growing concern throughout the world. The... (Review)
Review
In the face of flourishing industrialization and global trade, heavy metal and metalloid contamination of the environment is a growing concern throughout the world. The widespread presence of highly toxic compounds of arsenic, antimony, and cadmium in nature poses a particular threat to human health. Prolonged exposure to these toxins has been associated with severe human diseases, including cancer, diabetes, and neurodegenerative disorders. These toxins are known to induce analogous cellular stresses, such as DNA damage, disturbance of redox homeostasis, and proteotoxicity. To overcome these threats and improve or devise treatment methods, it is crucial to understand the mechanisms of cellular detoxification in metal and metalloid stress. Membrane proteins are key cellular components involved in the uptake, vacuolar/lysosomal sequestration, and efflux of these compounds; thus, deciphering the multilevel regulation of these proteins is of the utmost importance. In this review, we summarize data on the mechanisms of arsenic, antimony, and cadmium detoxification in the context of membrane proteome. We used yeast as a eukaryotic model to elucidate the complex mechanisms of the production, regulation, and degradation of selected membrane transporters under metal(loid)-induced stress conditions. Additionally, we present data on orthologues membrane proteins involved in metal(loid)-associated diseases in humans.
Topics: Saccharomyces cerevisiae; Metalloids; Humans; Stress, Physiological; Membrane Proteins; Arsenic; Cadmium; Saccharomyces cerevisiae Proteins
PubMed: 38674035
DOI: 10.3390/ijms25084450 -
Pathogens (Basel, Switzerland) Apr 2024Cutaneous leishmaniasis (CL), caused by in recent decades has shown decreasing cure rates after treatment with meglumine antimoniate (MA). Granulocyte...
UNLABELLED
Cutaneous leishmaniasis (CL), caused by in recent decades has shown decreasing cure rates after treatment with meglumine antimoniate (MA). Granulocyte colony-stimulating factor (G-CSF) is a cytokine associated with epithelialization and healing processes.
METHODS
This study compares the effectiveness of G-CSF associated with MA in the treatment of CL. A total of 32 patients aged between 18 and 50 years with CL confirmed for were included in this study. G-CSF or placebo (0.9% saline) was applied by intralesional infiltration at four equidistant points on the edges of the largest ulcer on days 0 and 15 of treatment associated with intravenous MA.
RESULTS
Males predominated in the G-CSF group (59%), while females predominated in the control group (53%). Injuries to the lower limbs predominated in both study groups. The cure rate in the G-CSF group was 65% and in the control group it was 47%, 90 days after initiation of therapy.
CONCLUSIONS
Our data indicate that the association of G-CSF with MA is not superior to MA monotherapy. Although not significant, the potential benefit of this combination deserves further investigation. The use of higher doses or other routes of application of G-CSF in a greater number of patients should contribute to a definitive response.
PubMed: 38668256
DOI: 10.3390/pathogens13040301 -
Ecotoxicology and Environmental Safety Jun 2024The crucial role of the fluorescent components of dissolved organic matter (DOM) in controlling antimony (Sb) mobilization in groundwater has been confirmed. However,...
The crucial role of the fluorescent components of dissolved organic matter (DOM) in controlling antimony (Sb) mobilization in groundwater has been confirmed. However, the molecular signatures contributing to Sb enrichment in DOM remain unknown. This study aims to investigate the origins and molecular compositions of DOM in different high-Sb aquifers (Sb-mining and no-Sb-mining aquifer), as well as compare different molecular signatures of DOM and mechanisms for Sb migration. The findings showed that Sb concentrations in Sb-mining aquifer exhibited a positive correlation with lignin- and tannin-like molecules characterized by high O/C and low H/C ratios, indicating an increased abundance of aromatic components with higher Humification Index and SUV-absorbance at 254 nm, compared to no-Sb-mining aquifer. Correspondingly, the complexation and competitive adsorption were considered as the predominate formation mechanisms on Sb enrichment in Sb-mining aquifer. In addition, high abundances of bioreactivity DOM may facilitated the migration of Sb via electron transfer and competitive adsorption in native no-Sb-mining aquifer. The outcomes of this investigation offer novel insights into the mechanism on Sb enrichment influenced by DOM at the molecule level.
Topics: Antimony; Water Pollutants, Chemical; Groundwater; Environmental Monitoring; Mining; Adsorption; Humic Substances
PubMed: 38657454
DOI: 10.1016/j.ecoenv.2024.116377 -
The Science of the Total Environment Jun 2024The metalloids arsenic (As) and antimony (Sb) belong to the pnictogen group of the periodic table; they share many characteristics, including their toxic and... (Review)
Review
The metalloids arsenic (As) and antimony (Sb) belong to the pnictogen group of the periodic table; they share many characteristics, including their toxic and carcinogenic properties; and rank as high-priority pollutants in the United States and the European Union. Adsorption is one of the most effective techniques for removing both elements and desorption, for further reuse, is a part of the process to make adsorption more sustainable and feasible. This review presents the current state of knowledge on arsenic and antimony desorption from exhausted adsorbents previously used in water treatment, that has been reported in the literature. The application of different types of eluents to desorb As and Sb and their desorption performance are described. The regeneration of saturated adsorbents and adsorbate recovery techniques are outlined, including the fate of spent media and possible alternatives for waste disposal of exhausted materials. Future research directions are discussed, as well as current issues including the lack of environmental impact analysis of emerging adsorbents.
PubMed: 38653411
DOI: 10.1016/j.scitotenv.2024.172602