scholarly journals Peptides to Tackle Leishmaniasis: Current Status and Future Directions

2021 ◽  
Vol 22 (9) ◽  
pp. 4400
Author(s):  
Alberto A. Robles-Loaiza ◽  
Edgar A. Pinos-Tamayo ◽  
Bruno Mendes ◽  
Cátia Teixeira ◽  
Cláudia Alves ◽  
...  
Keyword(s):  
Structural Characteristics ◽  
Treatment Options ◽  
Peptide Sequence ◽  
Current Status ◽  
In Vitro Assays ◽  
Amino Acid Residues ◽  
Future Directions ◽  
Innovative Therapies ◽  
Antileishmanial Drug

Peptide-based drugs are an attractive class of therapeutic agents, recently recognized by the pharmaceutical industry. These molecules are currently being used in the development of innovative therapies for diverse health conditions, including tropical diseases such as leishmaniasis. Despite its socioeconomic influence on public health, leishmaniasis remains long-neglected and categorized as a poverty-related disease, with limited treatment options. Peptides with antileishmanial effects encountered to date are a structurally heterogeneous group, which can be found in different natural sources—amphibians, reptiles, insects, bacteria, marine organisms, mammals, plants, and others—or inspired by natural toxins or proteins. This review details the biochemical and structural characteristics of over one hundred peptides and their potential use as molecular frameworks for the design of antileishmanial drug leads. Additionally, we detail the main chemical modifications or substitutions of amino acid residues carried out in the peptide sequence, and their implications in the development of antileishmanial candidates for clinical trials. Our bibliographic research highlights that the action of leishmanicidal peptides has been evaluated mainly using in vitro assays, with a special emphasis on the promastigote stage. In light of these findings, and considering the advances in the successful application of peptides in leishmaniasis chemotherapy, possible approaches and future directions are discussed here.

scholarly journals Treatment of Toxoplasmosis and Neosporosis in Farm Ruminants: State of Knowledge and Future Trends

2018 ◽  
Vol 18 (15) ◽  
pp. 1304-1323 ◽  
Author(s):  
Roberto Sánchez-Sánchez ◽  
Patricia Vázquez ◽  
Ignacio Ferre ◽  
Luis Miguel Ortega-Mora
Keyword(s):  
Vaccine Development ◽  
Neospora Caninum ◽  
Treatment Options ◽  
Small Ruminants ◽  
Additional Treatment ◽  
Current Status ◽  
Caninum Infection ◽  
Zoonotic Parasites ◽  
Toxoplasma Gondii Infection

Toxoplasmosis and neosporosis are closely related protozoan diseases that lead to important economic impacts in farm ruminants. Toxoplasma gondii infection mainly causes reproductive failure in small ruminants and is a widespread zoonosis, whereas Neospora caninum infection is one of the most important causes of abortion in cattle worldwide. Vaccination has been considered the most economic measure for controlling these diseases. However, despite vaccine development efforts, only a liveattenuated T. gondii vaccine has been licensed for veterinary use, and no promising vaccines against neosporosis have been developed; therefore, vaccine development remains a key goal. Additionally, drug therapy could be a valuable strategy for disease control in farm ruminants, as several drugs that limit T. gondii and N. caninum proliferation and dissemination have been evaluated. This approach may also be relevant to performing an initial drug screening for potential human therapy for zoonotic parasites. Treatments can be applied against infections in adult ruminants to minimize the outcomes of a primo-infection or the reactivation of a chronic infection during gestation or in newborn ruminants to avoid infection chronification. In this review, the current status of drug development against toxoplasmosis and neosporosis in farm ruminants is presented, and in an effort to promote additional treatment options, prospective drugs that have shown efficacy in vitro and in laboratory animal models of toxoplasmosis and neosporosis are examined.

scholarly journals Use of Antimony in the Treatment of Leishmaniasis: Current Status and Future Directions

2011 ◽  
Vol 2011 ◽  
pp. 1-23 ◽  
Author(s):  
Arun Kumar Haldar ◽  
Pradip Sen ◽  
Syamal Roy
Keyword(s):  
Leishmania Donovani ◽  
Indian Subcontinent ◽  
Current Status ◽  
Vanadium Compounds ◽  
Future Directions ◽  
Kala Azar ◽  
Efflux Mechanism ◽  
Transplantation Antigens ◽  
Antigen Presenting

In the recent past the standard treatment of kala-azar involved the use of pentavalent antimonials Sb(V). Because of progressive rise in treatment failure to Sb(V) was limited its use in the treatment program in the Indian subcontinent. Until now the mechanism of action of Sb(V) is not very clear. Recent studies indicated that both parasite and hosts contribute to the antimony efflux mechanism. Interestingly, antimonials show strong immunostimulatory abilities as evident from the upregulation of transplantation antigens and enhanced T cell stimulating ability of normal antigen presenting cells when treated with Sb(V) in vitro. Recently, it has been shown that some of the peroxovanadium compounds have Sb(V)-resistance modifying ability in experimental infection with Sb(V) resistant Leishmania donovani isolates in murine model. Thus, vanadium compounds may be used in combination with Sb(V) in the treatment of Sb(V) resistance cases of kala-azar.

Soaps and Detergents: Alternatives to Animal Eye Irritation Tests

1996 ◽  
Vol 15 (1) ◽  
pp. 1-44 ◽  
Author(s):  
Mildred S. Christian ◽  
Robert M. Diener
Keyword(s):  
False Negative ◽  
Screening Tools ◽  
Current Status ◽  
In Vitro Assays ◽  
Computer Search ◽  
Eye Irritation ◽  
Vitro Assay ◽  
Predictive Values ◽  
The Impact

An extensive computer search was conducted, and a comprehensive overview of the current status of alternatives to animal eye irritation tests was obtained. A search of Medline and Toxline databases (1988 to present) was supplemented with references from sources regarding in vitro eye irritation. Particular attention was paid to soap and detergent products and related ingredients. Eighty-five references are included in the review; the in vitro assays are categorized, and their predictive values for assessing acute ocular irritation are evaluated and compared with the Draize rabbit eye irritation assay and with each other. The present review shows that the increased activity of scientists from academia, industry, and regulatory agencies has resulted in substantial progress in developing alternative in vitro procedures and that a number of large, interlaboratory evaluations and international workshops have assisted in the selection process. However, none of these methodologies has obtained acceptance for regulatory classification purposes. Conclusions drawn from this review include that (a) no single in vitro assay is considered capable of replacing the Draize eye irritation test; (b) the chorioallantoic membrane vascular assay (CAMVA) or the hen egg test-chorio-allantoic membrane test (HET-CAM), the chicken or bovine enucleated eye test, the neutral red and plasminogen activation assays for cytotoxicity, and the silicon microphysiometer appear to have the greatest potential as screening tools for eye irritation; and (c) choosing a specific assay or series of assays will depend on the type of agent tested and the impact of false-negative or false-positive results. New assays will continue to be developed and should be included in future evaluations, when sufficient data are available.

Systemic treatment of advanced and recurrent endometrial carcinoma: current status and future directions.

1991 ◽  
Vol 9 (6) ◽  
pp. 1071-1088 ◽  
Author(s):  
T D Moore ◽  
P H Phillips ◽  
S R Nerenstone ◽  
B D Cheson
Keyword(s):  
Treatment Options ◽  
Randomized Study ◽  
Single Agent ◽  
Cytotoxic Agents ◽  
Current Status ◽  
Hematopoietic Growth Factors ◽  
Future Directions ◽  
A Current ◽  
Modest Activity ◽  
Systemic Therapies

Multiple systemic therapies have been used to treat patients with endometrial cancer. Although progestins have been the standard initial treatment for metastatic disease for the past 30 years, they are effective in only 20% of patients, and several large randomized trials have failed to demonstrate any benefit in the adjuvant setting. Alternative agents such as tamoxifen have shown modest activity. Few studies have investigated combinations of hormonally active drugs. Doxorubicin and cisplatin are the most active cytotoxic agents; a current randomized study is comparing the combination of these drugs with single-agent doxorubicin. Maximizing the effectiveness of established drugs, possibly with hematopoietic growth factors, and identifying alternative hormonal and cytotoxic agents with a sound scientific rationale will hopefully increase the effective treatment options for these patients.

A review of the flavor profile of metal salts: understanding the complexity of metallic sensation

2021 ◽  
Author(s):  
Michelle J Y Ecarma ◽  
Alissa A Nolden
Keyword(s):  
Treatment Options ◽  
Metal Salts ◽  
In Vitro Assays ◽  
Knock Out ◽  
Anion Complex ◽  
Knock Out Mice ◽  
Definition Of ◽  
Psychophysical Studies ◽  
Chemosensory Systems

Abstract The oral sensation of metallic is a complex experience. Much of our current understanding of metallic sensation is from the investigation of metal salts, which elicit diverse sensations, including taste, smell, and chemesthetic sensations, and therefore meet the definition of a flavor rather than a taste. Due to the involvement of multiple chemosensory systems, it can be challenging to define and characterize metallic sensation. Here, we provide a comprehensive review of the psychophysical studies quantifying and characterizing metallic sensation, focusing on metal salts. We examine the factors that impact perception, including anion complex, concentration, nasal occlusion, and pH. In addition, we summarize the receptors thought to be involved in the perception of metallic sensation (i.e., TRPV1, T1R3, TRPA1, and T2R7) either as a result of in vitro assays or from studies in knock-out mice. By enhancing our scientific understanding of metallic sensation and its transduction pathways, it has the potential to improve food, pharmaceuticals, help identify suppression or masking strategies, and improve the ability to characterize individual differences in metallic sensation. It also has the potential to translate to clinical populations by addressing the disparities in knowledge and treatment options for individuals suffering from metallic taste disorder (i.e., phantom taste or “metal mouth”). Future psychophysical studies investigating the sensory perception of metal salts should include a range of compounds and diverse food matrices, coupled with modern sensory methods, which will help to provide a more comprehensive understanding of metallic sensation.

scholarly journals The penicillin binding protein 1A of Helicobacter pylori, its amoxicillin binding site and access routes

Gut Pathogens ◽  
2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Bahareh Attaran ◽  
Najmeh Salehi ◽  
Bahareh Ghadiri ◽  
Maryam Esmaeili ◽  
Shadi Kalateh ◽  
...  
Keyword(s):  
Amino Acid ◽  
Binding Site ◽  
3D Structure ◽  
Resistance Mechanisms ◽  
Drug Binding ◽  
In Vitro Assays ◽  
Amino Acid Residues ◽  
Clinical Strains ◽  
H Pylori

Abstract Background Amoxicillin-resistant H. pylori strains are increasing worldwide. To explore the potential resistance mechanisms involved, the 3D structure modeling and access tunnel prediction for penicillin-binding proteins (PBP1A) was performed, based on the Streptococcus pneumoniae, PBP 3D structure. Molecular covalent docking was used to determine the interactions between amoxicillin (AMX) and PBP1A. Results The AMX-Ser368 covalent complex interacts with the binding site residues (Gly367, Ala369, ILE370, Lys371, Tyr416, Ser433, Thr541, Thr556, Gly557, Thr558, and Asn560) of PBP1A, non-covalently. Six tunnel-like structures, accessing the PBP1A binding site, were characterized, using the CAVER algorithm. Tunnel-1 was the ultimate access route, leading to the drug catalytic binding residue (Ser368). This tunnel comprises of eighteen amino acid residues, 8 of which are shared with the drug binding site. Subsequently, to screen the presence of PBP1A mutations, in the binding site and tunnel residues, in our clinical strains, in vitro assays were performed. H. pylori strains, isolated under gastroscopy, underwent AMX susceptibility testing by E-test. Of the 100 clinical strains tested, 4 were AMX-resistant. The transpeptidase domain of the pbp1a gene of these resistant, plus 10 randomly selected AMX-susceptible strains, were amplified and sequenced. Of the amino acids lining the tunnel-1 and binding site residues, three (Ser414Arg, Val469Met and Thr556Ser) substitutions, were detected in 2 of the 4 resistant and none of the sequenced susceptible strains, respectively. Conclusions We hypothesize that mutations in amino acid residues lining the binding site and/or tunnel-1, resulting in conformational/spatial changes, may block drug binding to PBP1A and cause AMX resistance.

scholarly journals Mithramycin delivery systems to develop effective therapies in sarcomas

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Óscar Estupiñán ◽  
Enrique Niza ◽  
Iván Bravo ◽  
Verónica Rey ◽  
Juan Tornín ◽  
...  
Keyword(s):  
Polymeric Nanoparticles ◽  
Antitumour Activity ◽  
Treatment Options ◽  
Therapeutic Index ◽  
Myxoid Liposarcoma ◽  
In Vitro Assays ◽  
Therapeutic Effects ◽  
Ethanol Injection ◽  
Pleomorphic Sarcoma

Abstract Background Sarcomas comprise a group of aggressive malignancies with very little treatment options beyond standard chemotherapy. Reposition of approved drugs represents an attractive approach to identify effective therapeutic compounds. One example is mithramycin (MTM), a natural antibiotic which has demonstrated a strong antitumour activity in several tumour types, including sarcomas. However, its widespread use in the clinic was limited by its poor toxicity profile. Results In order to improve the therapeutic index of MTM, we have loaded MTM into newly developed nanocarrier formulations. First, polylactide (PLA) polymeric nanoparticles (NPs) were generated by nanoprecipitation. Also, liposomes (LIP) were prepared by ethanol injection and evaporation solvent method. Finally, MTM-loaded hydrogels (HG) were obtained by passive loading using a urea derivative non-peptidic hydrogelator. MTM-loaded NPs and LIP display optimal hydrodynamic radii between 80 and 105 nm with a very low polydispersity index (PdI) and encapsulation efficiencies (EE) of 92 and 30%, respectively. All formulations show a high stability and different release rates ranging from a fast release in HG (100% after 30 min) to more sustained release from NPs (100% after 24 h) and LIP (40% after 48 h). In vitro assays confirmed that all assayed MTM formulations retain the cytotoxic, anti-invasive and anti-stemness potential of free MTM in models of myxoid liposarcoma, undifferentiated pleomorphic sarcoma and chondrosarcoma. In addition, whole genome transcriptomic analysis evidenced the ability of MTM, both free and encapsulated, to act as a multi-repressor of several tumour-promoting pathways at once. Importantly, the treatment of mice bearing sarcoma xenografts showed that encapsulated MTM exhibited enhanced therapeutic effects and was better tolerated than free MTM. Conclusions Overall, these novel formulations may represent an efficient and safer MTM-delivering alternative for sarcoma treatment. Graphical abstract

scholarly journals Assessing Preclinical Research Models for Immunotherapy for Gynecologic Malignancies

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1694
Author(s):  
Jhalak Dholakia ◽  
Carly Scalise ◽  
Rebecca C. Arend
Keyword(s):  
Translational Research ◽  
Cytotoxic T Lymphocyte ◽  
Treatment Options ◽  
Gynecologic Oncology ◽  
Three Dimensional ◽  
In Vitro Assays ◽  
Gynecologic Malignancies ◽  
Preclinical Models ◽  
Preclinical Research

Gynecologic malignancies are increasing in incidence, with a plateau in clinical outcomes necessitating novel treatment options. Immunotherapy and modulation of the tumor microenvironment are rapidly developing fields of interest in gynecologic oncology translational research; examples include the PD-1 (programmed cell death 1) and CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) axes and the Wnt pathway. However, clinical successes with these agents have been modest and lag behind immunotherapy successes in other malignancies. A thorough contextualization of preclinical models utilized in gynecologic oncology immunotherapy research is necessary in order to effectively and efficiently develop translational medicine. These include murine models, in vitro assays, and three-dimensional human-tissue-based systems. Here, we provide a comprehensive review of preclinical models for immunotherapy in gynecologic malignancies, including benefits and limitations of each, in order to inform study design and translational research models. Improved model design and implementation will optimize preclinical research efficiency and increase the translational value to positive findings, facilitating novel treatments that improve patient outcomes.

scholarly journals Saccharomyces cerevisiae Rhodanese RDL2 Uses the Arg Residue of the Active-Site Loop for Thiosulfate Decomposition

Antioxidants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 1525
Author(s):  
Qingda Wang ◽  
Huanjie Li ◽  
Yongzhen Xia ◽  
Luying Xun ◽  
Huaiwei Liu
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Amino Acid ◽  
Active Site ◽  
In Vitro Assays ◽  
Amino Acid Residues ◽  
Sulfane Sulfur ◽  
Sulfur Transfer ◽  
Sulfur Containing ◽  
Positively Charged

Persulfide, polysulfide and thiosulfate are examples of sulfane sulfur containing chemicals that play multiple functions in biological systems. Rhodaneses are widely present in all three kingdoms of life, which catalyze sulfur transfer among these sulfane sulfur-containing chemicals. The mechanism of how rhodaneses function is not well understood. Saccharomyces cerevisiae rhodanese 2 (RDL2) is involved in mitochondrial biogenesis and cell cycle control. Herein, we report a 2.47 Å resolution structure of RDL2 co-crystallized with thiosulfate (PDB entry: 6K6R). The presence of an extra sulfur atom Sδ, forming a persulfide bond with the Sγ atom of Cys106, was observed. Distinct from the persulfide groups in GlpE (PDB entry:1GMX) and rhobov (PDB entry:1BOI), the persulfide group of RDL2 is located in a peanut-like pocket of the neutral electrostatic field and is far away from positively charged amino acid residues of its active-site loop, suggesting no interaction between them. This finding suggests that the positively charged amino acid residues are not involved in the stabilization of the persulfide group. Activity assays indicate that the Arg111 of the active-site loop is critical for the sulfane sulfur transfer. In vitro assays indicate that Arg propels the thiosulfate decomposition. Thus, we propose that Arg can offer a hydrogen bond-rich, acidic-like microenvironment in RDL2 in which thiosulfate decomposes to release sulfane sulfur. Thr of the active-site loop of rhodaneses has the same functions as Arg. Our proposal may explain the catalyzing mechanism of rhodaneses.

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