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Journal of Natural Products May 2022Here, we describe two -acetyl-cysteinylated streptophenazines ( and ) produced by the soil-derived sp. ID63040 and identified through a metabolomic approach. These... (Review)
Review
Here, we describe two -acetyl-cysteinylated streptophenazines ( and ) produced by the soil-derived sp. ID63040 and identified through a metabolomic approach. These metabolites attracted our interest due to their low occurrence frequency in a large library of fermentation broth extracts and their consistent presence in biological replicates of the producer strain. The compounds were found to possess broad-spectrum antibacterial activity while exhibiting low cytotoxicity. The biosynthetic gene cluster from sp. ID63040 was found to be highly similar to the streptophenazine reference cluster in the MIBiG database, which originates from the marine sp. CNB-091. Compounds and were the main streptophenazine products from sp. ID63040 at all cultivation times but were not detected in sp. CNB-091. The lack of obvious candidates for cysteinylation in the sp. ID63040 biosynthetic gene cluster suggests that the -acetyl-cysteine moiety derives from cellular functions, most likely from mycothiol. Overall, our data represent an interesting example of how to leverage metabolomics for the discovery of new natural products and point out the often-neglected contribution of house-keeping cellular functions to natural product diversification.
Topics: Anti-Bacterial Agents; Biological Products; Metabolomics; Multigene Family; Streptomyces
PubMed: 35422124
DOI: 10.1021/acs.jnatprod.1c01123 -
Journal of Industrial Microbiology &... Jun 2021Cyanobacteria produce a plethora of compounds with unique chemical structures and diverse biological activities. Importantly, the increasing availability of... (Review)
Review
Cyanobacteria produce a plethora of compounds with unique chemical structures and diverse biological activities. Importantly, the increasing availability of cyanobacterial genome sequences and the rapid development of bioinformatics tools have unraveled the tremendous potential of cyanobacteria in producing new natural products. However, the discovery of these compounds based on cyanobacterial genomes has progressed slowly as the majority of their corresponding biosynthetic gene clusters (BGCs) are silent. In addition, cyanobacterial strains are often slow-growing, difficult for genetic engineering, or cannot be cultivated yet, limiting the use of host genetic engineering approaches for discovery. On the other hand, genetically tractable hosts such as Escherichia coli, Actinobacteria, and yeast have been developed for the heterologous expression of cyanobacterial BGCs. More recently, there have been increased interests in developing model cyanobacterial strains as heterologous production platforms. Herein, we present recent advances in the heterologous production of cyanobacterial compounds in both cyanobacterial and noncyanobacterial hosts. Emerging strategies for BGC assembly, host engineering, and optimization of BGC expression are included for fostering the broader applications of synthetic biology tools in the discovery of new cyanobacterial natural products.
Topics: Animals; Biological Products; Cyanobacteria; Genetic Engineering; Humans; Multigene Family
PubMed: 33928376
DOI: 10.1093/jimb/kuab003 -
Advances in Therapy Mar 2023In routine clinical care, important treatment outcomes among patients with moderate-to-severe plaque psoriasis (PsO) have been shown to vary according to patient...
Comparative Effectiveness of Biologics Across Subgroups of Patients with Moderate-to-Severe Plaque Psoriasis: Results at Week 12 from the PSoHO Study in a Real-World Setting.
INTRODUCTION
In routine clinical care, important treatment outcomes among patients with moderate-to-severe plaque psoriasis (PsO) have been shown to vary according to patient demographics and disease characteristics. This study aimed to provide direct comparative effectiveness data at week 12 between anti-interleukin (IL)-17A biologics relative to other approved biologics for the treatment of PsO across seven clinically relevant patient subgroups in the real-world setting.
METHODS
From the international, non-interventional Psoriasis Study of Health Outcomes (PSoHO), 1981 patients with moderate-to-severe PsO were grouped a priori according to seven clinically relevant demographic and disease variables with binary categories, which were sex (male or female), age (< 65 or ≥ 65 years), body mass index (≤ 30 or > 30 kg/m), race (White or Asian), PsO disease duration (< 15 or ≥ 15 years), psoriatic arthritis (PsA) comorbidity (present or absent), and prior biologic use (never or ≥ 1). Across these subgroups, effectiveness was compared between the anti-IL-17A cohort (ixekizumab, secukinumab) versus all other approved biologics and ixekizumab versus five individual biologics. The proportion of patients in each subgroup who achieved 90% improvement in Psoriasis Area and Severity Index (PASI90) and/or static Physician Global Assessment (sPGA) 0/1, PASI100, or PASI90 at week 12 were assessed. Comparative analyses were conducted using frequentist model averaging (FMA). Missing data were imputed using non-responder imputation.
RESULTS
Patients in each of the seven subgroups achieved similar response rates to those of the overall treatment cohort, apart from patients with PsA treated with other biologics who had 7-10% lower response rates. Consequently, patients with comorbid PsA had significantly higher odds of achieving skin clearance at week 12 with anti-IL-17A biologics compared to other biologics. Patients in all subgroups had significantly higher odds of achieving PASI90 and/or sPGA (0,1), PASI100, and PASI90 in the anti-IL-17A cohort relative to the other biologics cohort, except for the Asian subgroup. No sex- or age-specific differences in treatment effectiveness after 12 weeks were identified, neither between the treatment cohorts nor between the individual treatment comparisons.
CONCLUSIONS
Despite relative consistency of comparative treatment effectiveness across subgroups, the presence of comorbid PsA may affect a patient's clinical response to some treatments.
Topics: Humans; Male; Female; Aged; Infant; Arthritis, Psoriatic; Psoriasis; Treatment Outcome; Biological Products; Severity of Illness Index
PubMed: 36515803
DOI: 10.1007/s12325-022-02379-9 -
Molecules (Basel, Switzerland) Nov 2019Spirocyclic motifs are emerging privileged structures for drug discovery. They are also omnipresent in the natural products domain. However, until today, no attempt to... (Review)
Review
Spirocyclic motifs are emerging privileged structures for drug discovery. They are also omnipresent in the natural products domain. However, until today, no attempt to analyze the structural diversity of various spirocyclic motifs occurring in natural products and their relative populations with unique compounds reported in the literature has been undertaken. This review aims to fill that void and analyze the diversity of structurally unique natural products containing spirocyclic moieties of various sizes.
Topics: Biological Products; Models, Chemical; Spiro Compounds; Structure-Activity Relationship
PubMed: 31744211
DOI: 10.3390/molecules24224165 -
Molecules (Basel, Switzerland) Aug 2022Cancer is still one of the most widespread diseases globally, it is considered a vital health challenge worldwide and one of the main barriers to long life expectancy.... (Review)
Review
Cancer is still one of the most widespread diseases globally, it is considered a vital health challenge worldwide and one of the main barriers to long life expectancy. Due to the potential toxicity and lack of selectivity of conventional chemotherapeutic agents, discovering alternative treatments is a top priority. Plant-derived natural products have high potential in cancer treatment due to their multiple mechanisms of action, diversity in structure, availability in nature, and relatively low toxicity. In this review, the anticancer mechanisms of the most common phytochemicals were analyzed. Furthermore, a detailed discussion of the anticancer effect of combinations consisting of natural product or natural products with chemotherapeutic drugs was provided. This review should provide a strong platform for researchers and clinicians to improve basic and clinical research in the development of alternative anticancer medicines.
Topics: Antineoplastic Agents; Biological Products; Humans; Neoplasms; Phytochemicals
PubMed: 36080219
DOI: 10.3390/molecules27175452 -
Chembiochem : a European Journal of... Dec 2022Epipolythiodioxopiperazines (ETPs) are fungal secondary metabolites that share a 2,5-diketopiperazine scaffold built from two amino acids and bridged by a sulfide... (Review)
Review
Epipolythiodioxopiperazines (ETPs) are fungal secondary metabolites that share a 2,5-diketopiperazine scaffold built from two amino acids and bridged by a sulfide moiety. Modifications of the core and the amino acid side chains, for example by methylations, acetylations, hydroxylations, prenylations, halogenations, cyclizations, and truncations create the structural diversity of ETPs and contribute to their biological activity. However, the key feature responsible for the bioactivities of ETPs is their sulfide moiety. Over the last years, combinations of genome mining, reverse genetics, metabolomics, biochemistry, and structural biology deciphered principles of ETP production. Sulfurization via glutathione and uncovering of the thiols followed by either oxidation or methylation crystallized as fundamental steps that impact expression of the biosynthesis cluster, toxicity and secretion of the metabolite as well as self-tolerance of the producer. This article showcases structure and activity of prototype ETPs such as gliotoxin and discusses the current knowledge on the biosynthesis routes of these exceptional natural products.
Topics: Biological Products; Gliotoxin; Multigene Family; Sulfides; Piperazines
PubMed: 35997236
DOI: 10.1002/cbic.202200341 -
Journal of Leukocyte Biology Nov 2022Since their discovery in the 1970s, purinergic receptors have been shown to play key roles in a wide variety of biologic systems and cell types. In the immune system,... (Review)
Review
Since their discovery in the 1970s, purinergic receptors have been shown to play key roles in a wide variety of biologic systems and cell types. In the immune system, purinergic receptors participate in innate immunity and in the modulation of the adaptive immune response. In particular, P2 receptors, which respond to extracellular nucleotides, are widely expressed on leukocytes, causing the release of cytokines and chemokines and the formation of inflammatory mediators, and inducing phagocytosis, degranulation, and cell death. The activity of these receptors is regulated by ectonucleotidases-expressed in these same cell types-which regulate the availability of nucleotides in the extracellular environment. In this article, we review the characteristics of the main purinergic receptor subtypes present in the immune system, focusing on the P2 family. In addition, we describe the physiologic roles of the P2 receptors already identified in leukocytes and how they can positively or negatively modulate the development of infectious diseases, inflammation, and pain.
Topics: Receptors, Purinergic; Nucleotides; Inflammation Mediators; Leukocytes; Cytokines; Biological Products; Adenosine Triphosphate
PubMed: 35837975
DOI: 10.1002/JLB.2RU0421-226RR -
Translational Psychiatry Apr 2023Peripartum depression (PPD) is a prevalent and debilitating disorder that adversely affects the development of mothers and infants. Recently, there has been a plea for... (Review)
Review
Peripartum depression (PPD) is a prevalent and debilitating disorder that adversely affects the development of mothers and infants. Recently, there has been a plea for increased mental health screening during the peripartum period; however, currently, there is no accurate screening tool to identify women at risk of PPD. In addition, some women do not respond to current treatment schemes and develop treatment-resistant depression. The current perspective aims to propose a unified understanding of the biological underpinnings of PPD (UmPPD) that considers the heterogeneity in the onset, symptoms cluster, and severity of PPD. Such a model could promote basic and applied research on PPD and suggest new treatment avenues. The central hub of the model is the kynurenine pathway (KP) and the KP-serotonin ratio. The forces and specific processes at play that cause an imbalance within the KP and between KP and serotonin are inflammation, stress, reproductive hormones (especially estradiol and progesterone), and oxytocin. UmPPD predicts that the most severe PPD would comprise prolonged inflammation, ongoing or multiple stressors, excessive estrogen, progesterone resistance, and avoidance of breastfeeding, skin-to-skin contact, and social proximity. These factors would be associated with a higher likelihood of developing PPD, early onset, and more significant symptom severity. In addition, subtypes of PPD would consist of different compositions and expressions of these components, with one central common factor. UmPPD could aid in directing future research and possibly detecting critical processes that could help discover, develop, and utilize novel treatments for PPD.
Topics: Infant; Female; Humans; Depression, Postpartum; Depression; Serotonin; Peripartum Period; Mothers; Kynurenine; Inflammation; Depressive Disorder, Treatment-Resistant; Biology
PubMed: 37117197
DOI: 10.1038/s41398-023-02439-w -
Journal of Natural Products May 2021Spliceostatins and thailanstatins are intriguing natural products due to their structural features as well as their biological significance. This family of natural... (Review)
Review
Spliceostatins and thailanstatins are intriguing natural products due to their structural features as well as their biological significance. This family of natural products has been the subject of immense synthetic interest because they exhibit very potent cytotoxicity in representative human cancer cell lines. The cytotoxic properties of these natural products are related to their ability to inhibit spliceosomes. FR901564 and spliceostatins have been shown to inhibit spliceosomes by binding to their SF3B component. Structurally, these natural products contain two highly functionalized tetrahydropyran rings with multiple stereogenic centers joined by a diene moiety and an acyclic side chain linked with an amide bond. Total syntheses of this family of natural products led to the development of useful synthetic strategies, which enabled the synthesis of potent derivatives. The spliceosome modulating properties of spliceostatins and synthetic derivatives opened the door for understanding the underlying spliceosome mechanism as well as the development of new therapies based upon small-molecule splicing modulators. This review outlines the total synthesis of spliceostatins, synthetic studies of structural derivatives, and their bioactivity.
Topics: Antineoplastic Agents; Biological Products; Humans; Molecular Structure; Pyrans; RNA Splicing; Spliceosomes
PubMed: 33974423
DOI: 10.1021/acs.jnatprod.1c00100 -
Drug Discovery Today May 2020Prodigiosin (PG), a red tripyrrole pigment, belongs to a member of the prodiginine family and is normally secreted by various sources including Serratia marcescens and... (Review)
Review
Prodigiosin (PG), a red tripyrrole pigment, belongs to a member of the prodiginine family and is normally secreted by various sources including Serratia marcescens and other Gram-negative bacteria. The studies of PG have received innovative devotion as a result of reported antimicrobial, larvicidal and anti-nematoid immunomodulation and antitumor properties, owing to its antibiotic and cytotoxic activities. This review provides a comprehensive summary of research undertaken toward the isolation and structural elucidation of the prodiginine family of natural products. Additionally, the current evidence-based understanding of the biological activities and medicinal potential of PG is employed to determine the efficacy, with some reports of information related to pharmacokinetics, pharmacodynamics and toxicology.
Topics: Animals; Biological Products; Humans; Prodigiosin; Serratia marcescens
PubMed: 32251776
DOI: 10.1016/j.drudis.2020.03.017