Article
Microbiology
Norida Velez, Lucia Monteoliva, Zilpa-Adriana Sanchez-Quitian, Ahinara Amador-Garcia, Rocio Garcia-Rodas, Andres Ceballos-Garzon, Concha Gil, Patricia Escandon, Oscar Zaragoza, Claudia-Marcela Parra-Giraldo
Summary: This study found that the combination of iron and copper can enhance the pathogenicity of Cryptococcus neoformans and increase the abundance of proteins related to virulence factors. This suggests that the uptake of metals may affect the pathogenicity of fungi.
Article
Biochemistry & Molecular Biology
Shams Aaghaz, Chander S. Digwal, Naziya Neshat, Indresh K. Maurya, Vinod Kumar, Kulbhushan Tikoo, Rahul Jain, Ahmed Kamal
Summary: Despite attempts to develop newer pharmacophores, the benz-imidazole scaffold remains highly sought after for designing antimicrobial compounds. This study reports the synthesis of a new class of 4-(1,3-thiazol-2-yl)morpholine-benzimidazole hybrids as potent antimicrobial agents, with analog 6g showing significant activity against various microorganisms. It exhibits selectivity towards cryptococcal cells and induces cell death through apoptosis, with cell membrane disruption and pore formation observed.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Krishna K. Sharma, Ravikant Ravi, Indresh Kumar Maurya, Akshay Kapadia, Shabana Khan, Vinod Kumar, Kulbhushan Tikoo, Rahul Jain
Summary: A new structural class of ultrashort peptide-based antifungal, His(2-aryl)-Trp-Arg, was reported in this study. Structural changes on the His-Trp-Arg scaffold showed the impact of charge and lipophilic character on biological activity. Peptide 14f exhibited potent anticryptococcal activity and showed no cytotoxic effects, acting through nuclear fragmentation, membrane permeabilization, and pore formations in microbial cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Immunology
Bruno Sada Salerno, Aline Beatriz Mahler Pereira, Henrique Ismarsi de Souza, Mario Leon Silva-Vergara, Bruce David Levy, Alexandre Paula Rogerio
Summary: AT-RvD1 demonstrates significant anti-inflammatory effects in bronchial epithelial cells infected with C. neoformans, reducing the concentrations of IL-8 and IL-6 and increasing IL-10 production, with its anti-inflammatory effects dependent on ALX/FPR2.
INFLAMMOPHARMACOLOGY
(2021)
Article
Microbiology
Zhun Li, Zhengtu Li, Jun Yang, Chun Lu, Yongming Li, Yinzhu Luo, Feng Cong, Rongmei Shi, Zhen Wang, Huaying Chen, Xinxia Li, Jinglu Yang, Feng Ye
Summary: Allicin has shown strong antimicrobial activity against Cryptococcus by disrupting cell membrane permeability and function.
FRONTIERS IN MICROBIOLOGY
(2022)
Article
Chemistry, Medicinal
Shams Aaghaz, Komal Sharma, Indresh K. Maurya, Shivaprakash M. Rudramurthy, Shreya Singh, Vinod Kumar, Kulbhushan Tikoo, Rahul Jain
Summary: This study synthesizes a series of modified L-histidine-containing peptides that show promising activity against C. neoformans. One of these peptides, 11d, exhibits potent antifungal activity with an IC50 of 3.02 mu g/ml. This peptide is noncytotoxic and nonhemolytic, and synergizes with amphotericin B at subinhibitory concentrations. Mechanistic investigations reveal that 11d disrupts the cell wall and membrane of C. neoformans, leading to cell death through apoptosis. This study demonstrates the antifungal potential of 11d and its rapid onset of action.
ARCHIV DER PHARMAZIE
(2023)
Article
Chemistry, Medicinal
Shams Aaghaz, Komal Sharma, Indresh K. Maurya, Shivaprakash M. Rudramurthy, Shreya Singh, Vinod Kumar, Kulbhushan Tikoo, Rahul Jain
Summary: The limited availability of antifungal drugs has led to the necessity to develop new antifungals with different modes of action. Our investigation on a new series of peptides identified Boc-His-Trp-His[1-(4-tert-butylphenyl)] (10g) as the most promising inhibitor, exhibiting an IC50 value of 4.4 μg/mL against Cryptococcus neoformans. 10g showed high selectivity towards fungal cells and was nonhemolytic and noncytotoxic at its minimum inhibitory concentration. It exerted a fungicidal effect on growing cryptococcal cells and showed synergistic effect with amphotericin B.
DRUG DEVELOPMENT RESEARCH
(2023)
Article
Pharmacology & Pharmacy
Natalia Kronbauer Oliveira, Luiza Abrahao Frank, Eamim Daidre Squizani, Julia Catarina Vieira Reuwsaat, Barbara Machado Marques, Heryk Motta, Ane Wichine Acosta Garcia, Uriel Perin Kinskovski, Vanessa Abreu Barcellos, Augusto Schrank, Adriana Raffin Pohlmann, Charley Christian Staats, Silvia Staniscuaski Guterres, Marilene Henning Vainstein, Livia Kmetzsch
Summary: Amiodarone, as an alternative therapy for cryptococcosis, displayed high sensitivity against C. neoformans and synergistic effects with fluconazole. Its use influenced virulence factors and interrupted signaling pathways, showing promising results in the treatment of cryptococcal infections.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Longbing Yang, Zhuqing Tian, Wenjing Zhao, Jin Zhang, Chunren Tian, Luoxiong Zhou, Zhenlong Jiao, Jian Peng, Guo Guo
Summary: This study identified a novel antimicrobial peptide called DvAMP, which has antifungal activity and potential therapeutic effects against cryptococcosis in immunocompromised patients. DvAMP inhibits the growth and biofilm of Cryptococcus neoformans through multiple mechanisms, making it a potential candidate for antifungal drug development.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Physical
Shams Aaghaz, Komal Sharma, Indresh Kumar Maurya, Shivaprakash M. Rudramurthy, Shreya Singh, Vinod Kumar, Kulbhushan Tikoo, Rahul Jain
Summary: We synthesized short sequences of peptides with modified amphiphilic histidine and cationic arginine residues to develop new classes of peptides. The incorporation of 2-cycloalkyl and 1-aryl groups on the histidine's imidazole ring regulated the peptides' amphiphilicity and potency. Peptides 15h and 19k showed potent anticryptococcal activity and exhibited synergistic effects with amphotericin B, leading to permeabilization and nuclear fragmentation of pathogenic fungi.
JOURNAL OF MOLECULAR STRUCTURE
(2023)
Article
Nanoscience & Nanotechnology
Sarigama Rajesh, Sheeana Gangadoo, Han Nguyen, Jiali Zhai, Chaitali Dekiwadia, Calum J. Drummond, James Chapman, Vi Khanh Truong, Nhiem Tran
Summary: This study presents a novel approach using pH-sensitive lipid nanoparticles to deliver fluconazole and effectively inhibit the growth of resistant Cryptococcus neoformans. The nanoparticles change their structure and charge in response to the acidic environment, facilitating their interaction with the fungal cell wall. This targeted antifungal therapy represents a significant advancement in combating fungal antimicrobial resistance.
ACS APPLIED MATERIALS & INTERFACES
(2022)
Article
Nanoscience & Nanotechnology
Sarigama Rajesh, Sheeana Gangadoo, Han Nguyen, Jiali Zhai, Chaitali Dekiwadia, Calum J. Drummond, James Chapman, Vi Khanh Truong, Nhiem Tran
Summary: This study presents a novel approach to improve the delivery of antifungal agent and combat the resistance of Cryptococcus neoformans. By encapsulating the agent in pH-sensitive lipid nanoparticles, the growth of resistant C. neoformans is inhibited. The nanoparticles exhibit different structures and charges at neutral and acidic pH, facilitating interaction with the fungal cell wall and leading to a significant decrease in the minimum inhibitory concentration of the agent. Microscopic observations support these findings, showing distortion and efflux of cytoplasmic molecules in fungal cells exposed to the nanoparticles. This represents a significant advancement in targeted antifungal therapy for combating resistance.
ACS APPLIED MATERIALS & INTERFACES
(2022)
Article
Microbiology
Matthew R. Breuer, Ananya Dasgupta, Joseph G. Vasselli, Xiaorong Lin, Brian D. Shaw, Matthew S. Sachs
Summary: The prevalence and increasing incidence of fungal infections globally is a significant worldwide health problem. Cryptococcosis, primarily caused by the pathogenic yeast Cryptococcus neoformans, is responsible for approximatelyestimated deaths annually. The scarcity of treatments and the increasing resistance to current therapeutics highlight the need for the development of antifungal agents which have novel mechanisms of action and are suitable for clinical use. Repurposing existing FDA-approved compounds as antimycotic therapeutics is a promising strategy for the rapid development of such new treatments. Sertraline (SRT), a commonly prescribed antidepressant, is a broad-spectrum antifungal agent with particular efficacy against C. neoformans. However, the effect of SRT on fungal physiology is not understood. Here, we report that SRT induces the formation of supersized lipid droplets (SLDs) in C. neoformans, and in Candida albicans, Saccharomyces cerevisiae, and Aspergillus fumigatus. SLDs were not induced in C. neoformans by treatment with the antifungal fluconazole (FLC), consistent with SRT and FLC acting differently to perturb C. neoformans physiology. The formation of SLDs in response to SRT indicates that this compound alters the lipid metabolism of C. neoformans. Moreover, the SRT-induced enlargement of LDs in other fungal species may indicate a common fungal response to SRT.
Review
Biochemistry & Molecular Biology
Pavana Suresh, Erwin London
Summary: Efficient cyclodextrin-induced lipid exchange methods have been developed to replace lipids in artificial or living cell membranes, enabling detailed studies on the influence of lipid composition and asymmetry on membrane domains and proteins. This review summarizes the progress on cyclodextrin exchange in cells and discusses considerations and issues impacting lipid exchange experiments and interpretation.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2022)
Article
Biochemistry & Molecular Biology
Balint Csoboz, Imre Gombos, Zoltan Kota, Barbara Dukic, Eva Klement, Vanda Varga-Zsiros, Zoltan Lipinszki, Tibor Pali, Laszlo Vigh, Zsolt Torok
Summary: In this study, the interaction between HSPB1 and phospholipids was characterized, revealing that HSPB1 associates with membrane-forming lipids and has a strong affinity towards highly fluid membranes. HSPB1 modulates the physical properties of interacting membranes by altering lipid mobility and greatly affects the phase behavior of the plasma membrane under membrane fluidizing stress conditions. These findings suggest a new function for HSPB1 as a membrane chaperone.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Ana Marcela Giudici, Clara Diaz-Garcia, Maria Lourdes Renart, Ana Coutinho, Manuel Prieto, Jose M. Gonzalez-Ros, Jose Antonio Poveda
Summary: Alkylammonium salts, particularly tetraoctylammonium, have been used to investigate the structure and function of potassium channels. In this study, it was found that TOA(+) binds to the channel cavity with high affinity and causes a shift in the equilibrium of the channel's selectivity filter conformation towards an inactivated-like form. Additionally, the TOA(+)-bound state differs significantly from the collapsed channel state described by X-ray crystallography as the inactivated form of KcsA.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Ana C. Carreira, Sarka Pokorna, Ana E. Ventura, Mathew W. Walker, Anthony H. Futerman, Emyr Lloyd-Evans, Rodrigo F. M. de Almeida, Liana C. Silva
Summary: Niemann-Pick disease type C (NPC) is a complex and rare pathology primarily linked to mutations in the NPC1 gene. The abnormal accumulation of sphingosine may play a key role in the development of NPC, impacting membrane fluidity. Research shows that the addition of sphingosine can alter membrane fluidity, providing new insights into the pathophysiology of NPC.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2021)
Article
Biochemistry & Molecular Biology
Tania C. B. Santos, Essa M. Saied, Christoph Arenz, Aleksander Fedorov, Manuel Prieto, Liana C. Silva
Summary: 1-deoxy(methyl)-sphingolipids induce unique changes in the biophysical properties of membranes, suggesting that these alterations might trigger the patho-biological actions of these lipids.
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
(2021)
Article
Biotechnology & Applied Microbiology
Steffen Schmidt, Sandra F. Gallego, Iris Daphne Zelnik, Sergey Kovalchuk, Nanna Albaek, Richard R. Sprenger, Charlotte Overup, Yael Pewzner-Jung, Anthony H. Futerman, Marie W. Lindholm, Ole N. Jensen, Christer S. Ejsing
Summary: Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This study developed a potent N-acetylgalactosamine-conjugated antisense oligonucleotide that specifically targets ceramide synthase 2 in hepatocytes. Results demonstrate that this compound effectively reduces ceramide synthase 2 mRNA level, leading to lower protein expression and activity as well as ceramide levels in the liver. Interestingly, the hepatocyte-specific antisense oligonucleotide also modulates blood plasma ceramides, suggesting that these biomarkers are regulated by ceramide biosynthesis in hepatocytes.
Editorial Material
Biochemistry & Molecular Biology
Manuel Prieto
Summary: This note summarizes Robert W. Cowgill's study in 1963 on the effects of substituents in indole and phenol compounds as models for tryptophan and tyrosine. It aims to contextualize the research within the field of protein fluorescence and highlight its relevance and impact.
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
(2022)
Review
Biochemistry & Molecular Biology
Tania C. B. Santos, Tamir Dingjan, Anthony H. Futerman
Summary: This article discusses the complexity of lipid synthesis in modern cell membranes, specifically focusing on sphingolipids (SLs). The authors introduce the concept of the 'anteome', which describes the network of metabolic pathways that must have evolved to allow for the synthesis of SLs. They also suggest that current models of life origins and evolution lack sufficient experimental evidence to explain the appearance of this complex metabolic pathway and its anteome.
Article
Multidisciplinary Sciences
Jiyoon Kim, Yael Pewzner-Jung, Tammar Joseph, Shifra Ben-Dor, Anthony H. Futerman
Summary: In this study, we generated a CerS6 mouse model using CRISPR-Cas9 technology and found that replacing the DDRSDIE motif in CerS6 may affect an unknown mechanism of regulation of ceramide synthesis in vivo, resulting in significantly reduced ceramide levels. By crossing CerS6(ADAAAIA) mice with CerS5 null mice, we demonstrated that other ceramide species with different acyl chain lengths may compensate for the depletion of C16-ceramide levels.
Article
Biochemistry & Molecular Biology
Luis Borges-Araujo, Marina E. Monteiro, Dalila Mil-Homens, Nuno Bernardes, Maria J. Sarmento, Ana Coutinho, Manuel Prieto, Fabio Fernandes
Summary: Despite its low abundance, PI(4,5)P-2 plays a key role in membrane-associated signaling events in eukaryotic cells. The presence of physiological divalent cations can affect the clustering of PI(4,5)P-2 and its interactions with proteins, which can have a significant impact on the organization and downstream interactions of PI(4,5)P-2-binding proteins in the plasma membrane. This study characterizes the effects of Ca2+ on the organization and protein-protein interactions of PI(4,5)P-2-binding proteins, providing insights into the complex regulation of PI(4,5)P-2 in cell signaling.
Article
Neurosciences
Shani Blumenreich, Tamar Nehushtan, Or B. Barav, Jennifer T. Saville, Tamir Dingjan, John Hardy, Maria Fuller, Anthony H. Futerman
Summary: In the past decade, several genetic risk factors, including GBA variants, have been identified for Parkinson's Disease (PD). This study analyzes lipid levels in different brain regions of PD patients with GBA mutations and suggests that changes in ganglioside levels may contribute to the association between PD and GBA mutations.
NPJ PARKINSONS DISEASE
(2022)
Article
Biochemistry & Molecular Biology
Tiago P. Dias, Sandra N. Pinto, Sandra Carvalho, Tiago G. Fernandes, Fabio Fernandes, Maria Margarida Diogo, Maria C. Peleteiro, Manuel Prieto, Joaquim M. S. Cabral
Summary: This study demonstrates the development of a culture system that supports the self-organization of hiPSC-derived cardiac microtissues. It combines manual aggregation, Matrigel encapsulation, and dynamic culture to enhance cardiac differentiation and the formation of organized structures. Furthermore, VEGF supplementation enhances the emergence of microvessel-like structures.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Cell & Tissue Engineering
Tiago P. Dias, Tania Baltazar, Sandra N. Pinto, Tiago G. Fernandes, Fabio Fernandes, Maria Margarida Diogo, Manuel Prieto, Joaquim M. S. Cabral
Summary: A xeno-free differentiation platform for human induced pluripotent stem cells (hiPSCs) was established, allowing efficient differentiation into cardiomyocytes (CMs). The replating step and integration with purification/enrichment metabolic approaches improved CM yield and purity, while maintaining CM sheet integrity and functionality.
STEM CELLS INTERNATIONAL
(2022)
Article
Multidisciplinary Sciences
Iris D. D. Zelnik, Beatriz Mestre, Jonathan J. J. Weinstein, Tamir Dingjan, Stav Izrailov, Shifra Ben-Dor, Sarel J. J. Fleishman, Anthony H. H. Futerman
Summary: Researchers validate a one-step algorithm called mPROSS for stabilizing membrane proteins directly from an AlphaFold2 model structure. By applying this algorithm to ceramide synthase, they obtained a more stable form of human CerS2 enzyme through 37 designed mutations. With the help of molecular dynamics simulations, a potential pathway for substrate delivery to ceramide synthases is proposed.
NATURE COMMUNICATIONS
(2023)
Article
Biochemistry & Molecular Biology
Shani Blumenreich, Doreen Padan Ben-Yashar, Tali Shalit, Meital Kupervaser, Ivan Milenkovic, Tammar Joseph, Anthony H. Futerman
Summary: Gaucher's disease is caused by a defective enzyme called acid beta-glucosidase. This study used a mouse model of neurological Gaucher's disease to identify differentially expressed proteins in the brain. The researchers discovered that a protein called transglutaminase 1 was highly expressed in the brains of the diseased mice. These findings provide further insights into the pathological mechanisms of neurological Gaucher's disease.
JOURNAL OF NEUROCHEMISTRY
(2023)
Meeting Abstract
Biochemistry & Molecular Biology
T. Sousa, G. Damas, N. Bernardes, A. Coutinho, M. Prieto, A. M. Melo