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Lipids in Health and Disease Dec 2023Previous studies demonstrated that mast cells with their degranulated component heparin are the major endogenous factors that stimulate preadipocyte differentiation and...
BACKGROUND
Previous studies demonstrated that mast cells with their degranulated component heparin are the major endogenous factors that stimulate preadipocyte differentiation and promote fascial adipogenesis, and this effect is related to the structure of heparin. Regarding the structural and physiological properties of the negatively charged polymers, hexasulfonated suramin, a centuries-old medicine that is still used for treating African trypanosomiasis and onchocerciasis, is assumed to be a heparin-related analog or heparinoid. This investigation aims to elucidate the influence of suramin on the adipogenesis.
METHODS
To assess the influence exerted by suramin on adipogenic differentiation of primary white adipocytes in rats, this exploration was conducted both in vitro and in vivo. Moreover, it was attempted to explore the role played by the sulfonic acid groups present in suramin in mediating this adipogenic process.
RESULTS
Suramin demonstrated a dose- and time-dependent propensity to stimulate the adipogenic differentiation of rat preadipocytes isolated from the superficial fascia tissue and from adult adipose tissue. This stimulation was concomitant with a notable upregulation in expression levels of pivotal adipogenic factors as the adipocyte differentiation process unfolded. Intraperitoneal injection of suramin into rats slightly increased adipogenesis in the superficial fascia and in the epididymal and inguinal fat depots. PPADS, NF023, and NF449 are suramin analogs respectively containing 2, 6, and 8 sulfonic acid groups, among which the last two moderately promoted lipid droplet formation and adipocyte differentiation. The number and position of sulfonate groups may be related to the adipogenic effect of suramin.
CONCLUSIONS
Suramin emerges as a noteworthy pharmaceutical agent with the unique capability to significantly induce adipocyte differentiation, thereby fostering adipogenesis.
Topics: Rats; Animals; Adipogenesis; Suramin; Antiparasitic Agents; Cell Differentiation; Adipocytes, White; Heparin
PubMed: 38093311
DOI: 10.1186/s12944-023-01980-3 -
Molecules (Basel, Switzerland) Nov 2023(indolyl)methanes (BIMs) are a class of compounds that have been recognized as an important core in the design of drugs with important pharmacological properties, such...
(indolyl)methanes (BIMs) are a class of compounds that have been recognized as an important core in the design of drugs with important pharmacological properties, such as promising anticancer and antiparasitic activities. Here, we explored the biological activity of the BIM core functionalized with different (hetero)aromatic moieties. We synthesized substituted BIM derivatives with triphenylamine, -dimethyl-1-naphthylamine and 8-hydroxylquinolyl groups, studied their photophysical properties and evaluated their in vitro antiproliferative and antiparasitic activities. The triphenylamine BIM derivative displayed an IC of 3.21, 3.30 and 3.93 μM against , and HT-29 cancer cell line, respectively. The selectivity index demonstrated that compound was up to eight-fold more active against the parasites and HT-29 than against the healthy cell line MRC-5. Fluorescence microscopy studies with MRC-5 cells and parasites incubated with derivative indicate that the compound seems to accumulate in the cell's mitochondria and in the parasite's nucleus. In conclusion, the BIM scaffold functionalized with the triphenylamine moiety proved to be the most promising antiparasitic and anticancer agent of this series.
Topics: Humans; Antiparasitic Agents; Methane; Trypanosoma brucei brucei; Antineoplastic Agents; Neoplasms; Structure-Activity Relationship
PubMed: 38067459
DOI: 10.3390/molecules28237728 -
European Journal of Pharmaceutical... Jan 2024African trypanosomiasis is a significant vector-borne disease of humans and animals in the tsetse fly belt of Africa, particularly affecting production animals such as...
African trypanosomiasis is a significant vector-borne disease of humans and animals in the tsetse fly belt of Africa, particularly affecting production animals such as cattle, and thus, hindering food security. Trypanosoma congolense (T. congolense), the causative agent of nagana, is livestock's most virulent trypanosome species. There is currently no vaccine against trypanosomiasis; its treatment relies solely on chemotherapy. However, pathogenic resistance has been established against trypanocidal agents in clinical use. This underscores the need to develop new therapeutics to curb trypanosomiasis. Many nitroheterocyclic drugs or compounds, including nitrofurantoin, possess antiparasitic activities in addition to their clinical use as antibiotics. The current study evaluated the in vitro trypanocidal potency and in vivo treatment efficacy of previously synthesized antileishmanial active oligomeric ethylene glycol derivatives of nitrofurantoin. The trypanocidal potency of analogues 2a-o varied among the trypanosome species; however, T. congolense strain IL3000 was more susceptible to these drug candidates than the other human and animal trypanosomes. The arylated analogues 2k (IC 0.04 µM; SI >6365) and 2l (IC 0.06 µM; SI 4133) featuring 4-chlorophenoxy and 4-nitrophenoxy moieties, respectively, were revealed as the most promising antitrypanosomal agents of all analogues against T. congolense strain IL3000 trypomastigotes with nanomolar activities. In a preliminary in vivo study involving T. congolense strain IL3000 infected BALB/c mice, the oral administration of 100 mg/kg/day of 2k caused prolonged survival up to 18 days post-infection relative to the infected but untreated control mice which survived 9 days post-infection. However, no cure was achieved due to its poor solubility in the in vivo testing medium, assumably leading to low oral bioavailability. These results confirm the importance of the physicochemical properties lipophilicity and water solubility in attaining not only in vitro trypanocidal potency but also in vivo treatment efficacy. Future work will focus on the chemical optimization of 2k through the investigation of analogues containing solubilizing groups at certain positions on the core structure to improve solubility in the in vivo testing medium which, in the current investigation, is the biggest stumbling block in successfully treating either animal or human Trypanosoma infections.
Topics: Humans; Animals; Cattle; Mice; Nitrofurantoin; Trypanosomiasis, African; Trypanosomiasis; Treatment Outcome; Ethylene Glycols
PubMed: 38065268
DOI: 10.1016/j.ejps.2023.106668 -
Antimicrobial Agents and Chemotherapy Jan 2024The intestinal parasites and are major causes of morbidity and mortality associated with diarrheal diseases. Metronidazole is the most common drug used to treat...
The intestinal parasites and are major causes of morbidity and mortality associated with diarrheal diseases. Metronidazole is the most common drug used to treat giardiasis and amebiasis. Despite its efficacy, treatment failures in giardiasis occur in up to 5%-40% of cases. Potential resistance of to metronidazole is an increasing concern. Therefore, it is critical to search for more effective drugs to treat giardiasis and amebiasis. We identified antigiardial and antiamebic activities of the rediscovered nitroimidazole compound, fexinidazole, and its sulfone and sulfoxide metabolites. Fexinidazole is equally active against and trophozoites, and both metabolites were 3- to 18-fold more active than the parent drug. Fexinidazole and its metabolites were also active against a metronidazole-resistant strain of . and cell extracts exhibited decreased residual nitroreductase activity when metabolites were used as substrates, indicating nitroreductase may be central to the mechanism of action of fexinidazole. In a cell invasion model, fexinidazole and its metabolites significantly reduced the invasiveness of trophozoites through basement membrane matrix. A q.d. oral dose of fexinidazole and its metabolites at 10 mg/kg for 3 days reduced infection significantly in mice compared to control. The newly discovered antigiardial and antiamebic activities of fexinidazole, combined with its FDA-approval and inclusion in the WHO Model List of Essential Medicines for the treatment of human African trypanosomiasis, offer decreased risk and a shortened development timeline toward clinical use of fexinidazole for treatment of giardiasis or amebiasis.
Topics: Mice; Animals; Humans; Giardiasis; Metronidazole; Nitroimidazoles; Amebiasis; Giardia lamblia; Entamoeba histolytica; Nitroreductases
PubMed: 38063401
DOI: 10.1128/aac.00731-23 -
Parasitology Research Dec 2023Suramin was the first drug developed using the approach of medicinal chemistry by the German Bayer company in the 1910s for the treatment of human African sleeping... (Review)
Review
Suramin was the first drug developed using the approach of medicinal chemistry by the German Bayer company in the 1910s for the treatment of human African sleeping sickness caused by the two subspecies Trypanosoma brucei gambiense and Trypanosoma brucei rhodesienese. However, the drug was politically instrumentalized by the German government in the 1920s in an attempt to regain possession of its former African colonies lost after the First World War. For this reason, the formula of suramin was kept secret for more than 10 years. Eventually, the French pharmacist Ernest Fourneau uncovered the chemical structure of suramin by reverse engineering and published the formula of the drug in 1924. During the Nazi period, suramin became the subject of colonial revisionism, and the development of the drug was portrayed in books and films to promote national socialist propaganda. Ever since its discovery, suramin has also been tested for bioactivity against numerous other infections and diseases. However, sleeping sickness caused by Trypanosoma brucei rhodesiense is the only human disease for which treatment with suramin is currently approved.
Topics: Animals; Humans; Suramin; Trypanosomiasis, African; Trypanosoma brucei rhodesiense; Trypanosoma brucei brucei
PubMed: 38057659
DOI: 10.1007/s00436-023-08027-7 -
Parasitology Research Dec 2023Fish trypanosomiasis is a common blood parasitic disease transmitted by aquatic invertebrates, such as leeches. This study aims to shed light on the cytotoxicity of...
Fish trypanosomiasis is a common blood parasitic disease transmitted by aquatic invertebrates, such as leeches. This study aims to shed light on the cytotoxicity of Trypanosoma sp. on erythrocytes and its impacts on the innate immune response (serum lysozyme activity, nitric oxide production, phagocytic activity, serum total protein, and globulin) in wild African catfish, Clarias gariepinus. One hundred catfish were examined using blood smears stained with Giemsa and confirmed with PCR. The prevalence of infection was found to be 10% by microscope detection and 15% by PCR. The morphological identification of Trypanosoma as Trypanosoma mukasai was determined. Additionally, this study included previously undescribed features of Trypanosoma, such as the width of the anterior and posterior body, the length of the posterior pale region, and the number of folds. Various alterations in erythrocytes were observed, totaling 54.57%. Nuclear abnormalities, including fragmented nuclei, eccentric nuclei, and micronuclei, were also reported. Infected fish showed a reduction in serum total protein and globulin levels, while nitric oxide production, lysozyme activity, and phagocytic activity exhibited a significant increase compared to non-infected fish. We believe that our findings will contribute valuable data to the morphological and molecular identification of Trypanosoma sp. in African catfish, as well as their cytotoxic impact.
Topics: Animals; Catfishes; Muramidase; Nitric Oxide; Trypanosoma; Globulins
PubMed: 38057596
DOI: 10.1007/s00436-023-08026-8 -
PLoS Neglected Tropical Diseases Dec 2023T. b. rhodesiense is the causative agent of Rhodesian human African trypanosomiasis (r-HAT) in Malawi. Clinical presentation of r-HAT in Malawi varies between foci and...
T. b. rhodesiense is the causative agent of Rhodesian human African trypanosomiasis (r-HAT) in Malawi. Clinical presentation of r-HAT in Malawi varies between foci and differs from East African HAT clinical phenotypes. The purpose of this study was to gain more insights into the transcriptomic profiles of patients with early stage 1 and late stage 2 HAT disease in Malawi. Whole blood from individuals infected with T. b. rhodesiense was used for RNA-Seq. Control samples were from healthy trypanosome negative individuals matched on sex, age range, and disease foci. Illumina sequence FASTQ reads were aligned to the GRCh38 release 84 human genome sequence using HiSat2 and differential analysis was done in R Studio using the DESeq2 package. XGR, ExpressAnalyst and InnateDB algorithms were used for functional annotation and gene enrichment analysis of significant differentially expressed genes. RNA-seq was done on 23 r-HAT case samples and 28 healthy controls with 7 controls excluded for downstream analysis as outliers. A total of 4519 genes were significant differentially expressed (p adjusted <0.05) in individuals with early stage 1 r-HAT disease (n = 12) and 1824 genes in individuals with late stage 2 r-HAT disease (n = 11) compared to controls. Enrichment of innate immune response genes through neutrophil activation was identified in individuals with both early and late stages of the disease. Additionally, lipid metabolism genes were enriched in late stage 2 disease. We further identified uniquely upregulated genes (log2 Fold Change 1.4-2.0) in stage 1 (ZNF354C) and stage 2 (TCN1 and MAGI3) blood. Our data add to the current understanding of the human transcriptome profiles during T. b. rhodesiense infection. We further identified biological pathways and transcripts enriched than were enriched during stage 1 and stage 2 r-HAT. Lastly, we have identified transcripts which should be explored in future research whether they have potential of being used in combination with other markers for staging or r-HAT.
Topics: Animals; Humans; Transcriptome; Trypanosoma brucei rhodesiense; Malawi; Trypanosomiasis, African; Phenotype; Repressor Proteins
PubMed: 38055777
DOI: 10.1371/journal.pntd.0011803 -
Chimia Sep 2023Thanks to its expertise in clinical research, epidemiology, infectious diseases, microbiology, parasitology, public health, translational research and tropical medicine,...
Thanks to its expertise in clinical research, epidemiology, infectious diseases, microbiology, parasitology, public health, translational research and tropical medicine, coupled with deeply rooted partnerships with institutions in low- and middle-income countries (LMICs), the Swiss Tropical and Public Health Institute (Swiss TPH) has been a key contributor in many drug research and development consortia involving academia, pharma and product development partnerships. Our know-how of the maintenance of parasites and their life-cycles in the laboratory, plus our strong ties to research centres and disease control programme managers in LMICs with access to field sites and laboratories, have enabled systems for drug efficacy testing in vitro and in vivo, clinical research, and modelling to support the experimental approaches. Thus, Swiss TPH has made fundamental contributions towards the development of new drugs - and the better use of old drugs - for neglected tropical diseases and infectious diseases of poverty, such as Buruli ulcer, Chagas disease, food-borne trematodiasis (e.g. clonorchiasis, fascioliasis and opisthorchiasis), human African trypanosomiasis, leishmaniasis, malaria, schistosomiasis, soil-transmitted helminthiasis and tuberculosis. In this article, we show case the success stories of molecules to which Swiss TPH has made a substantial contribution regarding their use as anti-infective compounds with the ultimate aim to improve people's health and well-being.
Topics: Humans; Public Health; Tropical Medicine; Switzerland; Buruli Ulcer; Communicable Diseases
PubMed: 38047835
DOI: 10.2533/chimia.2023.593 -
Chimia Sep 2023In pursuing novel therapeutic solutions, drug discovery and development rely on efficiently utilising existing knowledge and resources. Repurposing know-how, a strategy... (Review)
Review
In pursuing novel therapeutic solutions, drug discovery and development rely on efficiently utilising existing knowledge and resources. Repurposing know-how, a strategy that capitalises on previously acquired information and expertise, has emerged as a powerful approach to accelerate drug discovery and development processes, often at a fraction of the costs of de novo developments. For 80 years, collaborating within a network of partnerships, the Swiss Tropical and Public Health Institute (Swiss TPH) has been working along a value chain from innovation to validation and application to combat poverty-related diseases. This article presents an overview of selected know-how repurposing initiatives conducted at Swiss TPH with a particular emphasis on the exploration of drug development pathways in the context of neglected tropical diseases and other infectious diseases of poverty, such as schistosomiasis, malaria and human African trypanosomiasis.
Topics: Humans; Drug Development; Drug Discovery; Drug Repositioning; Public Health; Switzerland
PubMed: 38047834
DOI: 10.2533/chimia.2023.582 -
ACS Omega Nov 2023African trypanosomiasis is a vector-borne disease of animals and humans in the tsetse fly belt of Africa. ("nagana") is the most pathogenic trypanosome in livestock and...
African trypanosomiasis is a vector-borne disease of animals and humans in the tsetse fly belt of Africa. ("nagana") is the most pathogenic trypanosome in livestock and causes high morbidity and mortality rates among cattle. In the absence of effective preventative vaccines, the management of trypanosomiasis relies on chemoprophylaxis and/or -therapy. However, the trypanocides in clinical use exhibit poor oral bioavailability and toxicity, and therapeutic failures occur because of resistant strains. Because nitrofurantoin displayed, in addition to its clinical use, promising antiparasitic activity, the current study was conducted to evaluate the trypanocidal activity and preliminary treatment efficacy of previously synthesized nitrofuranylazines. The trypanocidal activity of these nitrofuran derivatives varied among the evaluated trypanosome species; however, strain IL3000 was more susceptible than other animal and human trypanosomes. The nitrofurylazines (IC 0.04 μM; SI > 7761) and (IC 0.03 μM; SI > 9542) as well as the nitrothienylazine (IC 0.04 μM; SI 232), with nanomolar IC values, were revealed as early antitrypanosomal leads. Although these derivatives showed strong trypanocidal activity , no treatment efficacy was observed in IL3000 infected mice after both oral and intraperitoneal administration in a preliminary study. This was attributed to the poor solubility of the test compounds in the testing media. Indeed, a challenge in drug discovery is finding a balance between the physicochemical properties of a drug candidate, particularly lipophilicity and water solubility, and maintaining adequate potency to provide an effective dose. Hence, future chemical modifications may be required to generate lead-like to lead-like nitrofuranylazines that possess optimal physicochemical and pharmacokinetic properties while retaining and, ultimately, trypanocidal efficacy.
PubMed: 38024678
DOI: 10.1021/acsomega.3c06508