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Nature Communications Jun 2024Culture-based microbial natural product discovery strategies fail to realize the extraordinary biosynthetic potential detected across earth's microbiomes. Here we...
Culture-based microbial natural product discovery strategies fail to realize the extraordinary biosynthetic potential detected across earth's microbiomes. Here we introduce Small Molecule In situ Resin Capture (SMIRC), a culture-independent method to obtain natural products directly from the environments in which they are produced. We use SMIRC to capture numerous compounds including two new carbon skeletons that were characterized using NMR and contain structural features that are, to the best of our knowledge, unprecedented among natural products. Applications across diverse marine habitats reveal biome-specific metabolomic signatures and levels of chemical diversity in concordance with sequence-based predictions. Expanded deployments, in situ cultivation, and metagenomics facilitate compound discovery, enhance yields, and link compounds to candidate producing organisms, although microbial community complexity creates challenges for the later. This compound-first approach to natural product discovery provides access to poorly explored chemical space and has implications for drug discovery and the detection of chemically mediated biotic interactions.
Topics: Biological Products; Drug Discovery; Metabolomics; Microbiota; Metagenomics; Magnetic Resonance Spectroscopy; Small Molecule Libraries
PubMed: 38898025
DOI: 10.1038/s41467-024-49367-x -
ELife Jun 2024Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying...
Spinal pain affects individuals of all ages and is the most common musculoskeletal problem globally. Its clinical management remains a challenge as the underlying mechanisms leading to it are still unclear. Here, we report that significantly increased numbers of senescent osteoclasts (SnOCs) are observed in mouse models of spinal hypersensitivity, like lumbar spine instability (LSI) or aging, compared to controls. The larger population of SnOCs is associated with induced sensory nerve innervation, as well as the growth of H-type vessels, in the porous endplate. We show that deletion of senescent cells by administration of the senolytic drug Navitoclax (ABT263) results in significantly less spinal hypersensitivity, spinal degeneration, porosity of the endplate, sensory nerve innervation, and H-type vessel growth in the endplate. We also show that there is significantly increased SnOC-mediated secretion of Netrin-1 and NGF, two well-established sensory nerve growth factors, compared to non-senescent OCs. These findings suggest that pharmacological elimination of SnOCs may be a potent therapy to treat spinal pain.
Topics: Animals; Mice; Osteoclasts; Cellular Senescence; Sensory Receptor Cells; Disease Models, Animal; Male; Nerve Growth Factor; Netrin-1; Mice, Inbred C57BL
PubMed: 38896465
DOI: 10.7554/eLife.92889 -
Clinical, Cosmetic and Investigational... 2024Zoledronic acid is a bisphosphonate that can be administered intravenously and used to treat several bone disorders. It decreases bone resorption, thereby improving bone...
Zoledronic acid is a bisphosphonate that can be administered intravenously and used to treat several bone disorders. It decreases bone resorption, thereby improving bone mineral density (BMD) and reducing fractures. The Food and Drug Administration (FDA) has approved zoledronic acid for the prevention and treatment of osteoporosis in postmenopausal females and males and for other conditions. Zoledronic acid is generally well tolerated, with most side effects being musculoskeletal or gastrointestinal. Cutaneous side effects include maculopapular rash and other mild skin reactions. Rare severe skin rashes, such as toxic epidermal necrolysis, have been reported. Here, we report the case of a 64-year-old female with a medical history of breast cancer status post-radical mastectomy and chemotherapy presenting with delayed hypersensitivity reaction to a hyaluronic acid dermal filler two days after receiving zoledronic acid intravenously given to maintain bone density, symptoms completely resolved with oral prednisolone 20 mg once daily and cetirizine 10 mg. Cases of delayed inflammatory reaction to hyaluronic acid soft tissue filler have previously been reported in patients who have received vaccination or those with viral infections. However, to our knowledge, there have been no reports of delayed inflammatory reactions to facial hyaluronic acid injections after zoledronic acid administration.
PubMed: 38895606
DOI: 10.2147/CCID.S458750 -
BioRxiv : the Preprint Server For... Jun 2024An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here we show that adeno-associated virus (AAV)-delivery of two...
An alternative to lifelong antiretroviral therapy (ART) is needed to achieve durable control of HIV-1. Here we show that adeno-associated virus (AAV)-delivery of two rhesus macaque antibodies to the SIV envelope glycoprotein (Env) with potent neutralization and antibody-dependent cellular cytotoxicity can prevent viral rebound in macaques infected with barcoded SIV239M after discontinuing suppressive ART. Following AAV administration, sustained antibody expression with minimal anti-drug antibody responses was achieved in all but one animal. After ART withdrawal, SIV replication rebounded within two weeks in all of the control animals but remained below the threshold of detection in plasma (<15 copies/mL) for more than a year in four of the eight animals that received AAV vectors encoding Env-specific antibodies. Viral sequences from animals with delayed rebound exhibited restricted barcode diversity and antibody escape. Thus, sustained expression of antibodies with potent antiviral activity can afford durable, ART-free containment of pathogenic SIV infection.
PubMed: 38895320
DOI: 10.1101/2024.05.30.593694 -
EJHaem Jun 2024Anaphylactic reactions at the time of chimeric antigen receptor T (CAR-T) cell infusion are adverse events that have not been reported in pivotal clinical trials or in...
Anaphylactic reactions at the time of chimeric antigen receptor T (CAR-T) cell infusion are adverse events that have not been reported in pivotal clinical trials or in real-world series. We report the case of patient with severe anaphylaxis with cardiac arrest after tisagenlecleucel injection for Diffuse Large B cell Lymphoma, who recovered after resuscitation and intensive care treatment; we also conducted a Food and Drug Administration Adverse Event Reporting System database analysis and found several cases of severe anaphlyaxis after CAR-T cell injection. Although not reported in pivotal CAR-T cell studies, anaphylaxis can occur after CAR-T cell injection, highlighting the need to include anaphylaxis as a possible side effect in future studies.
PubMed: 38895058
DOI: 10.1002/jha2.874 -
Nutrients May 2024(1) Background: Irritable bowel syndrome (IBS) is a common disease in the gastrointestinal (GI) tract. Koidz (AMK) is known as one of the traditional medicines that...
(1) Background: Irritable bowel syndrome (IBS) is a common disease in the gastrointestinal (GI) tract. Koidz (AMK) is known as one of the traditional medicines that shows a good efficacy in the GI tract. (2) Methods: We investigated the effect of AMK in a network pharmacology and zymosan-induced IBS animal model. In addition, we performed electrophysiological experiments to confirm the regulatory mechanisms related to IBS. (3) Results: Various characteristics of AMK were investigated using TCMSP data and various analysis systems. AMK restored the macroscopic changes and weight to normal. Colonic mucosa and inflammatory factors were reduced. These effects were similar to those of amitriptyline and sulfasalazine. In addition, transient receptor potential (TRP) V1, voltage-gated Na (NaV) 1.5, and NaV1.7 channels were inhibited. (4) Conclusion: These results suggest that AMK may be a promising therapeutic candidate for IBS management through the regulation of ion channels.
Topics: Animals; Irritable Bowel Syndrome; TRPV Cation Channels; Disease Models, Animal; Zymosan; Mice; Atractylodes; Male; Plant Extracts; NAV1.7 Voltage-Gated Sodium Channel; Colon; Intestinal Mucosa
PubMed: 38892616
DOI: 10.3390/nu16111683 -
International Journal of Molecular... May 2024N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. The respiratory syncytial virus (RSV) is one of the most important... (Review)
Review
N-acetylcysteine (NAC) is a mucolytic agent with antioxidant and anti-inflammatory properties. The respiratory syncytial virus (RSV) is one of the most important etiological factors of lower respiratory tract infections, and exposure to air pollution appears to be additionally associated with higher RSV incidence and disease severity. We aimed to systematically review the existing literature to determine which molecular mechanisms mediate the effects of NAC in an RSV infection and air pollution, and to identify the knowledge gaps in this field. A search for original studies was carried out in three databases and a calibrated extraction grid was used to extract data on the NAC treatment (dose, timing), the air pollutant type, and the most significant mechanisms. We identified only 28 studies conducted in human cellular models ( = 18), animal models ( = 7), and mixed models ( = 3). NAC treatment improves the barrier function of the epithelium damaged by RSV and air pollution, and reduces the epithelial permeability, protecting against viral entry. NAC may also block RSV-activated phosphorylation of the epidermal growth factor receptor (EGFR), which promotes endocytosis and facilitates cell entry. EGFR also enhances the release of a mucin gene, MUC5AC, which increases mucus viscosity and causes goblet cell metaplasia; the effects are abrogated by NAC. NAC blocks virus release from the infected cells, attenuates the cigarette smoke-induced shift from necrosis to apoptosis, and reverses the block in IFN-γ-induced antiviral gene expression caused by the inhibited Stat1 phosphorylation. Increased synthesis of pro-inflammatory cytokines and chemokines is induced by both RSV and air pollutants and is mediated by the nuclear factor kappa-B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways that are activated in response to oxidative stress. MCP-1 (monocyte chemoattractant protein-1) and RANTES (regulated upon activation, expressed and secreted by normal T cells) partially mediate airway hyperresponsiveness (AHR), and therapeutic (but not preventive) NAC administration reduces the inflammatory response and has been shown to reduce ozone-induced AHR. Oxidative stress-induced DNA damage and cellular senescence, observed during RSV infection and exposure to air pollution, can be partially reversed by NAC administration, while data on the emphysema formation are disputed. The review identified potential common molecular mechanisms of interest that are affected by NAC and may alleviate both the RSV infection and the effects of air pollution. Data are limited and gaps in knowledge include the optimal timing or dosage of NAC administration, therefore future studies should clarify these uncertainties and verify its practical use.
Topics: Humans; Acetylcysteine; Respiratory Syncytial Virus Infections; Animals; Air Pollution; ErbB Receptors
PubMed: 38892239
DOI: 10.3390/ijms25116051 -
International Journal of Molecular... May 2024Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33.... (Review)
Review
Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. TSLP performs its role by binding to a high-affinity heteromeric complex composed of the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα. In recent years, the important role of proinflammatory cytokines in the etiopathogenesis of various chronic diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic obstructive pulmonary diseases (COPDs), and chronic spontaneous urticaria has been studied. Although alarmins have been found to be mainly implicated in the mechanisms of type 2 inflammation, studies on monoclonal antibodies against TSLP demonstrate partial efficacy even in patients whose inflammation is not definable as T2 and the so-called low T2. Tezepelumab is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. Several clinical trials are evaluating the safety and efficacy of Tezepelumab in various inflammatory disorders. In this review, we will highlight major recent advances in understanding the functional role of TSLP, its involvement in Th2-related diseases, and its suitability as a target for biological therapies.
Topics: Humans; Cytokines; Thymic Stromal Lymphopoietin; Antibodies, Monoclonal, Humanized; Animals; Receptors, Cytokine; Molecular Targeted Therapy; Respiratory Tract Diseases; Asthma
PubMed: 38892164
DOI: 10.3390/ijms25115972 -
International Journal of Molecular... May 2024Inflammatory skin diseases highlight inflammation as a central driver of skin pathologies, involving a multiplicity of mediators and cell types, including immune and... (Review)
Review
Inflammatory skin diseases highlight inflammation as a central driver of skin pathologies, involving a multiplicity of mediators and cell types, including immune and non-immune cells. Adenosine, a ubiquitous endogenous immune modulator, generated from adenosine triphosphate (ATP), acts via four G protein-coupled receptors (A, A, A, and A). Given the widespread expression of those receptors and their regulatory effects on multiple immune signaling pathways, targeting adenosine receptors emerges as a compelling strategy for anti-inflammatory intervention. Animal models of psoriasis, contact hypersensitivity (CHS), and other dermatitis have elucidated the involvement of adenosine receptors in the pathogenesis of these conditions. Targeting adenosine receptors is effective in attenuating inflammation and remodeling the epidermal structure, potentially showing synergistic effects with fewer adverse effects when combined with conventional therapies. What is noteworthy are the promising outcomes observed with A agonists in animal models and ongoing clinical trials investigating A agonists, underscoring a potential therapeutic approach for the management of inflammatory skin disorders.
Topics: Humans; Animals; Adenosine; Receptors, Purinergic P1; Skin Diseases; Dermatitis; Inflammation; Psoriasis; Signal Transduction; Anti-Inflammatory Agents
PubMed: 38891997
DOI: 10.3390/ijms25115810 -
International Journal of Molecular... May 2024Although inflammation is primarily a protective response guarding the human body, it can result in a variety of chronic diseases such as allergies, auto-immune,...
Although inflammation is primarily a protective response guarding the human body, it can result in a variety of chronic diseases such as allergies, auto-immune, cardiovascular diseases, and cancer. In NF-κB-mediated inflammation, many small molecules and food compounds characterized as nutraceuticals have shown positive effects associated with immunomodulatory properties. We investigated the effects of selected bioactive small molecules, commonly found in food components, vanillyl alcohol (VA) and lauric acid (LA), on different cell lines exposed to pro-inflammatory stimuli, lipopolysaccharide (LPS), and the food allergen actinidin (Act d 1). Pro-inflammatory cytokines were downregulated in response to both VA and LA, and this downregulation was caused by a decrease in the activation of the NF-κB pathway and the translocation of p65, the pathway's major component. Small nutraceutical molecules, VA and LA, showed not only inhibition of the pro-inflammatory cytokines, but also inhibition of the NF-κB activation, and reduced translocation of the p65 component. The present study may contribute to the therapeutic use of these molecules for various inflammatory diseases, which have in common an increased expression of pro-inflammatory cytokines and NF-κB-mediated inflammation.
Topics: Lipopolysaccharides; Cytokines; Humans; NF-kappa B; Signal Transduction; Inflammation; Down-Regulation; Lauric Acids; Allergens; Animals; Food Hypersensitivity; Mice
PubMed: 38891984
DOI: 10.3390/ijms25115798