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International Journal of Rheumatic... Apr 2020As glucocorticoids and immunosuppressive drugs are non-specific therapeutic agents that cause many adverse reactions, the development of biologicals aiming to control... (Review)
Review
As glucocorticoids and immunosuppressive drugs are non-specific therapeutic agents that cause many adverse reactions, the development of biologicals aiming to control specific molecular targets is anticipated for the treatment of systemic lupus erythematosus (SLE). The antibody targeting B cell-activating factor belonging to the tumor necrosis factor family (BAFF) belimumab was the first biological approved for SLE. At present, many biologicals, such as anifrolumab (anti-type I interferon receptor antibody) and ustekinumab (antibody against interleukin 12/23 [p40]), are in clinical trials. Thus, successful treatments with biologicals targeting "bridging cytokines" produced by dendritic cells, which form a bridge between the innate and acquired immune/autoimmune systems, is of particular interest. Moreover, a phase IIb clinical trial of baricitinib, a low-molecular-weight compound targeting Janus kinase 1/2, in patients with SLE revealed that baricitinib was significantly more effective for relieving arthritis and skin manifestations than placebo, and the trial met the primary endpoint. In the future, it is expected that drugs with better efficacy and safety profiles will be used to apply therapeutic strategies, such as precision medicine, in which different molecular target drugs are used for patients classified by their conditions, and to set a therapeutic goal of the discontinuation of glucocorticoids.
Topics: Biological Products; Glucocorticoids; Humans; Immunosuppressive Agents; Janus Kinase Inhibitors; Lupus Erythematosus, Systemic; Molecular Targeted Therapy; Treatment Outcome
PubMed: 32134201
DOI: 10.1111/1756-185X.13817 -
The Journal of Investigative Dermatology Jul 2022Since the foundation of the European Society for Dermatological Research, pathogenesis of psoriasis has been studied by many research groups, focusing on various... (Review)
Review
Since the foundation of the European Society for Dermatological Research, pathogenesis of psoriasis has been studied by many research groups, focusing on various compartments of the skin. Understanding of the pathogenesis of psoriasis has evolved into a branching model of innate and acquired immunity. Insights in the genetics of psoriasis proved to be compatible with this model. Inspired by these insights, pathogenesis-based treatments have emerged with unprecedented efficacy and sustainability. In particular, the cytokine network harbors major treatment targets for biologics with TNF-α, the IL-17 family, IL-23 and, in the case of generalized pustular psoriasis, IL-36. Furthermore, the Jak TYK2, PDE-4, and AHR are targets for new small molecules in the treatment of psoriasis. Psoriasis research is a showcase par excellence of translational medicine, resulting in pathogenesis-based treatments.
Topics: Adaptive Immunity; Biological Products; Humans; Psoriasis; Skin; Tumor Necrosis Factor-alpha
PubMed: 35249726
DOI: 10.1016/j.jid.2022.01.014 -
Clinical Gastroenterology and... Jan 2022Biologics are used routinely in pregnant women with inflammatory bowel disease (IBD), but large-scale data reporting adverse pregnancy outcomes among biologic users are... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
Biologics are used routinely in pregnant women with inflammatory bowel disease (IBD), but large-scale data reporting adverse pregnancy outcomes among biologic users are lacking. We sought to estimate the prevalence of adverse pregnancy outcomes in women with IBD on biologic therapies.
METHODS
We searched major databases from inception to June 2020 for studies estimating the prevalence of adverse pregnancy outcomes in IBD when using biologics (anti-tumor necrosis factor [TNF], anti-integrins, and anticytokines). Prevalence and relative risk (RR) were pooled using a random-effects model.
RESULTS
Forty-eight studies were included in the meta-analysis comprising 6963 patients. Biologic therapy in IBD pregnancies was associated with a pooled prevalence of 8% (95% CI, 6%-10%; I = 87.4%) for early pregnancy loss, 9% (95% CI, 7%-11%; I = 89.9%) for preterm birth, 0% (95% CI, 0%-0%; I = 0%) for stillbirth, 8% (95% CI, 5%-10%; I = 87.0%) for low birth weight, and 1% (95% CI, 1%-2%; I = 78.3%) for congenital malformations. These rates are comparable with those published in the general population. In subgroup analyses of a small number of studies, the prevalence of early pregnancy loss and preterm birth were higher in vedolizumab vs anti-TNF users. Meta-regression did not show an association of disease activity or concomitant thiopurine on adverse outcomes. Continued TNF inhibitor use during the third trimester was not associated with risk of preterm birth (RR, 1.41; 95% CI, 0.77-2.60; I = 0%), low birth weight (RR, 1.32; 95% CI, 0.80-2.18; I = 0%), or congenital malformations (RR, 1.28; 95% CI, 0.47-3.49; I = 0%).
CONCLUSIONS
Adverse pregnancy outcomes among pregnant IBD women using biologics are comparable with that of the general population. PROSPERO protocol #CRD42019135721.
Topics: Biological Products; Female; Humans; Infant, Newborn; Inflammatory Bowel Diseases; Pregnancy; Pregnancy Outcome; Premature Birth; Tumor Necrosis Factor Inhibitors
PubMed: 32931960
DOI: 10.1016/j.cgh.2020.09.021 -
Drugs Aug 2021Hidradenitis suppurativa (HS) is a chronic, recurrent, auto-inflammatory skin disease originating from the hair follicles. The typical inflammatory nodules, abscesses,... (Review)
Review
Hidradenitis suppurativa (HS) is a chronic, recurrent, auto-inflammatory skin disease originating from the hair follicles. The typical inflammatory nodules, abscesses, and draining sinus tracts (tunnels) are characterized by a massive influx of neutrophils, macrophages, B-cells, plasma cells, T helper (Th)1, Th17 cells and upregulation of pro-inflammatory cytokines such as IL-1, IL-17, IL-12/23, and TNF-α. Over the last decades, several clinical trials evaluated the clinical efficacy of different biologics targeting these pro-inflammatory cytokines, in particular TNF-α and IL-1. However, adalimumab is still the only registered drug for HS. This review discusses biologics and small molecules with high level of evidence for their clinical application, provides guidance on when and how to use these biologics and small molecules in clinical practice, and elaborates on the combination with medical and surgical treatment options beyond the current guidelines. Furthermore this review provides an overview of potential biologics and small molecules currently under investigation for novel targets in HS such as IL-36, C5a, Janus kinase family members, CD-40, LTA4 and CXCR1/2.
Topics: Adalimumab; Anti-Bacterial Agents; Antibodies, Monoclonal, Humanized; Biological Products; CD40 Antigens; Complement Inactivating Agents; Epoxide Hydrolases; Etanercept; Hidradenitis Suppurativa; Humans; Immunologic Factors; Infliximab; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Interleukin-17; Interleukin-23; Janus Kinase Inhibitors; Protein Kinase Inhibitors; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Severity of Illness Index; Surgical Procedures, Operative; Thalidomide; Tumor Necrosis Factor Inhibitors
PubMed: 34283386
DOI: 10.1007/s40265-021-01566-2 -
Natural Product Reports May 2021Covering: up to mid-2020 Terpenoids, also called isoprenoids, are the largest and most structurally diverse family of natural products. Found in all domains of life,... (Review)
Review
Covering: up to mid-2020 Terpenoids, also called isoprenoids, are the largest and most structurally diverse family of natural products. Found in all domains of life, there are over 80 000 known compounds. The majority of characterized terpenoids, which include some of the most well known, pharmaceutically relevant, and commercially valuable natural products, are produced by plants and fungi. Comparatively, terpenoids of bacterial origin are rare. This is counter-intuitive to the fact that recent microbial genomics revealed that almost all bacteria have the biosynthetic potential to create the C5 building blocks necessary for terpenoid biosynthesis. In this review, we catalogue terpenoids produced by bacteria. We collected 1062 natural products, consisting of both primary and secondary metabolites, and classified them into two major families and 55 distinct subfamilies. To highlight the structural and chemical space of bacterial terpenoids, we discuss their structures, biosynthesis, and biological activities. Although the bacterial terpenome is relatively small, it presents a fascinating dichotomy for future research. Similarities between bacterial and non-bacterial terpenoids and their biosynthetic pathways provides alternative model systems for detailed characterization while the abundance of novel skeletons, biosynthetic pathways, and bioactivies presents new opportunities for drug discovery, genome mining, and enzymology.
Topics: Bacteria; Biological Products; Biosynthetic Pathways; Terpenes
PubMed: 33169126
DOI: 10.1039/d0np00066c -
Nature Chemical Biology Jan 2020Genome mining has become a key technology to exploit natural product diversity. Although initially performed on a single-genome basis, the process is now being scaled up...
Genome mining has become a key technology to exploit natural product diversity. Although initially performed on a single-genome basis, the process is now being scaled up to mine entire genera, strain collections and microbiomes. However, no bioinformatic framework is currently available for effectively analyzing datasets of this size and complexity. In the present study, a streamlined computational workflow is provided, consisting of two new software tools: the 'biosynthetic gene similarity clustering and prospecting engine' (BiG-SCAPE), which facilitates fast and interactive sequence similarity network analysis of biosynthetic gene clusters and gene cluster families; and the 'core analysis of syntenic orthologues to prioritize natural product gene clusters' (CORASON), which elucidates phylogenetic relationships within and across these families. BiG-SCAPE is validated by correlating its output to metabolomic data across 363 actinobacterial strains and the discovery potential of CORASON is demonstrated by comprehensively mapping biosynthetic diversity across a range of detoxin/rimosamide-related gene cluster families, culminating in the characterization of seven detoxin analogues.
Topics: Actinobacteria; Algorithms; Biological Products; Biosynthetic Pathways; Cluster Analysis; Computational Biology; Data Mining; Genome, Bacterial; Genomics; Metabolomics; Microbiota; Multigene Family; Phylogeny; Reproducibility of Results; Software
PubMed: 31768033
DOI: 10.1038/s41589-019-0400-9 -
Nature Jan 2015Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced...
Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.
Topics: Animals; Anti-Bacterial Agents; Betaproteobacteria; Biological Products; Cell Wall; Depsipeptides; Disease Models, Animal; Drug Resistance, Microbial; Female; Mice; Microbial Sensitivity Tests; Microbial Viability; Molecular Sequence Data; Multigene Family; Mycobacterium tuberculosis; Peptidoglycan; Staphylococcal Infections; Staphylococcus aureus; Teichoic Acids; Time Factors
PubMed: 25561178
DOI: 10.1038/nature14098 -
International Journal of Molecular... Oct 2018The history of cosmetics goes back to early Egyptian times for hygiene and health benefits while the history of topical applications that provide a medicinal treatment... (Review)
Review
The history of cosmetics goes back to early Egyptian times for hygiene and health benefits while the history of topical applications that provide a medicinal treatment to combat dermal aging is relatively new. For example, the term cosmeceutical was first coined by Albert Kligman in 1984 to describe topical products that afford both cosmetic and therapeutic benefits. However, beauty comes from the inside. Therefore, for some time scientists have considered how nutrition reflects healthy skin and the aging process. The more recent link between nutrition and skin aging began in earnest around the year 2000 with the demonstrated increase in peer-reviewed scientific journal reports on this topic that included biochemical and molecular mechanisms of action. Thus, the application of: (a) topical administration from outside into the skin and (b) inside by oral consumption of nutritionals to the outer skin layers is now common place and many journal reports exhibit significant improvement for both on a variety of dermal parameters. Therefore, this review covers, where applicable, the history, chemical structure, and sources such as biological and biomedical properties in the skin along with animal and clinical data on the oral applications of: (a) collagen, (b) ceramide, (c) β-carotene, (d) astaxanthin, (e) coenzyme Q, (f) colostrum, (g) zinc, and (h) selenium in their mode of action or function in improving dermal health by various quantified endpoints. Lastly, the importance of the human skin microbiome is briefly discussed in reference to the genomics, measurement, and factors influencing its expression and how it may alter the immune system, various dermal disorders, and potentially be involved in chemoprevention.
Topics: Administration, Oral; Biological Products; Humans; Microbiota; Skin; Trace Elements; Vitamins
PubMed: 30301271
DOI: 10.3390/ijms19103059 -
Digestive Diseases and Sciences Sep 2023Targeting interleukin-23 (IL-23) is an important therapeutic strategy for Crohn's disease (CD). (Meta-Analysis)
Meta-Analysis
BACKGROUND
Targeting interleukin-23 (IL-23) is an important therapeutic strategy for Crohn's disease (CD).
AIMS
This systematic review and meta-analysis assessed the efficacy and safety of selective IL-23p19 and IL-12/23p40 inhibitors in patients with moderate-to-severe CD.
METHODS
MEDLINE, Embase, and the Cochrane library (CENTRAL) were searched from inception to May 24, 2023, for randomized, placebo- or active comparator-controlled induction and/or maintenance trials of selective IL-23p19 and IL-12/23p40 inhibitors in pediatric and adult patients with CD. The primary outcome was the proportion of patients in clinical remission. Secondary outcomes were clinical response, endoscopic remission, endoscopic response, and safety. Data were pooled using a random-effects model. Risk of bias and certainty of evidence were assessed using the Cochrane risk of bias tool and the GRADE criteria, respectively.
RESULTS
Eighteen trials (n = 5561) were included. Most studies were rated as low risk of bias. Targeting IL-23 was significantly superior to placebo for inducing clinical (risk ratio [RR] = 1.87, 95% confidence interval [CI] 1.58-2.21) and endoscopic (RR = 3.20, 95%CI 2.17-4.70) remission and maintaining clinical remission (RR = 1.39, 95%CI 1.10-1.77) (GRADE high certainty evidence for all outcomes). Subgroup analysis showed that targeting IL-23 was superior to placebo for inducing clinical remission in biologic-naïve (RR = 2.20, 95%CI 1.46-3.32, I = 0%, p = 0.39) and biologic-experienced patients (RR = 1.82, 95%CI 1.27-2.60, I = 56.5%, p = 0.01). Targeting IL-23 was associated with a decreased risk of serious adverse events in induction (RR = 0.55, 95%CI 0.44-0.73) and maintenance (RR = 0.72, 95%CI 0.53-0.98) trials compared to placebo (high certainty evidence).
CONCLUSION
Targeting IL-23 is effective and safe for inducing and maintaining clinical and endoscopic remission in patients with moderate-to-severe CD.
Topics: Adult; Humans; Child; Crohn Disease; Interleukin-12; Interleukin-23 Subunit p19; Interleukin Inhibitors; Remission Induction; Interleukin-23; Biological Products
PubMed: 37378711
DOI: 10.1007/s10620-023-08014-z -
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